GSK Clinical Study Register

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1 In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register. The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all named persons associated with the study Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered

2 CONFIDENTIAL Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Study Report Title: Phase: A Randomised, Double-Blind, Placebo-Controlled, Two-Week Crossover, Knemometric Assessment of the Effect of Fluticasone Furoate Nasal Spray 100mcg Once Daily on Short- Term Growth in Children Aged 6 to 11 Years with Seasonal and/or Perennial Allergic Rhinitis III Compound Number: GW685698X (Fluticasone Furoate) Effective Date: 09-MAR-2006 Description: was a two-week, randomised, crossover, placebo-controlled study of 58 children aged 6 to 11 years with seasonal and/or perennial allergic rhinitis (SAR/PAR) conducted at a single study centre in Denmark. The study evaluated the effect on short-term lower-leg growth of two weeks treatment with fluticasone furoate nasal spray 100mcg QD versus Placebo nasal spray once daily (QD), using a knemometer. Eligible subjects were premenarchal females 6 to <11 years of age or male subjects 6 to <12 years of age, in Tanner Stage 1 and with documented clinical history of SAR and/or PAR during at least one year prior to study entry. Additionally, subjects had to have normal growth at the time of Screening, as reflected by a height between the 5 th and 95 th percentile of normal for age and gender, as determined by stadiometry and Danish longitudinal standard charts. After completing a two-week Screening period where subjects received single-blind, Placebo nasal spray treatment QD, eligible subjects were randomised to a double-blind treatment sequence of either fluticasone furoate nasal spray 100mcg QD followed by Placebo nasal spray QD, or Placebo nasal spray QD followed by fluticasone furoate nasal spray 100mcg QD. Each double-blind treatment in the sequence was administered for two weeks. The two double-blind treatment periods were separated by a two-week, washout period during which single-blind, Placebo nasal spray QD was administered. There were no efficacy measures evaluated in this study. The primary safety endpoint was the mean growth rate (mm/wk) in lower-leg length, as determined by knemometry, over a two-week treatment period with fluticasone furoate nasal spray 100mcg QD versus a two-week treatment period with Placebo nasal spray QD. Secondary safety measures included adverse events, nasal examinations and vital signs. The primary objective of the study was to demonstrate that fluticasone furoate 100mcg QD was non-inferior compared with Placebo on lower-leg growth rate, based on a non-inferiority margin of -0.20mm/wk in lower-leg growth rate. Results of this study showed that fluticasone furoate nasal spray 100mcg once-daily was non-inferior to Placebo on short-term lower-leg growth rate of pre-pubertal children with allergic rhinitis (treatment difference = mm/wk; 95% CI: [-0.13, 0.10]) and was well tolerated. Subject: Fluticasone Furoate Nasal Spray, Seasonal Allergic Rhinitis, Perennial Allergic Rhinitis Author(s): Indication Studied: Seasonal Allergic Rhinitis, Perennial Allergic Rhinitis Initiation Date: 11 April 2005 Completion Date: 16 November 2005 Date of Report: March

3 CONFIDENTIAL Sponsor Signatory: (and Medical Officer) M.D. VP, Respiratory Medicine Development Centre, Europe GlaxoSmithKline This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents. Copyright 2006 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 2

4 CONFIDENTIAL Synopsis Identifier: Study Number: Title: A Randomised, Double-blind, Placebo-Controlled, Two-Week Crossover, Knemometric Assessment of the Effect of Fluticasone Furoate Nasal Spray 100mcg Once Daily on Short-Term Growth in Children Aged 6 to 11 Years with Seasonal and/or Perennial Allergic Rhinitis Investigator: M.D., DMSci, BA Study centre: One centre in Denmark. Publication(s): None at the time of this report. Study Period: 11 April November 2005 Phase of Development: III Objectives: The primary objective of this study was to evaluate for any potential effect on lower-leg growth rate from treatment with fluticasone furoate (FF) nasal spray 100mcg once daily (QD) versus Placebo nasal spray QD in children aged 6 to 11 years with seasonal allergic rhinitis (SAR) and/or perennial allergic rhinitis (PAR). Methodology: This was a double-blind, randomised, placebo-controlled, crossover trial conducted at one centre in Denmark. Following a two-week, single-blind, Placebo run-in period, subjects were randomly allocated in a 1:1 ratio to a double-blind treatment sequence of either fluticasone furoate nasal spray 100mcg QD followed by Placebo nasal spray QD, or Placebo nasal spray QD followed by fluticasone furoate nasal spray 100mcg QD. Each double-blind treatment in the sequence was administered for two weeks. The two double-blind treatment periods were separated by a two-week, washout period, during which single-blind, Placebo nasal spray was administered. A follow-up phone call was made three to seven days after completing the last treatment to assess for adverse events. The study consisted of five visits and four treatment periods: Run-in (Screening), Treatment Period 1, Washout and Treatment Period 2. Each treatment period lasted approximately two weeks. 3

5 CONFIDENTIAL Number of subjects: Number (%) of Subjects Planned, N 56 Randomised (N) 58 (100) Completed, n (%) 57 (98) Total Number Subjects Withdrawn, n (%) 1 (2) Withdrawn due to Protocol Violation, n (%) 1 (2) Diagnosis and main criteria for inclusion: Eligible subjects were male subjects 6 to <12 years of age or premenarchal female subjects 6 to <11 years of age at the time of randomisation, in Tanner Stage 1 and with documented clinical history of SAR and/or PAR during at least one year prior to study entry. Additionally, subjects had to have normal growth at the time of Screening, as reflected by a height between the 5th and 95th percentile of normal for age and gender, as determined by stadiometry and Danish longitudinal standard charts. Treatment and administration: All randomised subjects received single-blind, Placebo nasal spray treatment at Visit 1. The subject/parent/guardian was instructed to administer two sprays per nostril each morning beginning the morning of the following day, through to and including the morning of Visit 2. Administration of the dose was performed by alternately spraying one spray to each nostril followed by a second spray to each nostril. The first dose of double-blind study treatment was administered on the morning of the first day following Visit 2 through and including the morning of Visit 3. Following this, subjects underwent a washout period during which subjects administered single-blind Placebo nasal spray on the morning after Visit 3 through to and including the morning of Visit 4. After the wash-out period, subjects received the alternate study treatment of their treatment sequence at Visit 4 to begin using the morning following Visit 4 through to and including the morning of Visit 5. The batch numbers for fluticasone furoate 100mcg nasal spray and Placebo nasal spray were and respectively Criteria for evaluation: There were no efficacy endpoints in this study. The primary safety endpoint was based on knemometry assessments carried out at every visit (approximately two-week intervals). A knemometer was used to measure the distance between the top of the knee and the bottom of the heel of a seated subject. The length of the lower-leg was electronically calculated based on the maximum distance detected between a footplate and a knee-level measuring board. Four measurements were taken of the right leg at each visit and the final three measurements were recorded in the case report form (CRF). The three recorded measurements were averaged. The 4

6 CONFIDENTIAL difference between the average at the start of the period and the end of the period was divided by the period length (weeks) to obtain the lower-leg growth rate in millimetres per week for each period. Primary Safety Endpoint Mean growth rate (mm/wk) in lower-leg length, as determined by knemometry, over a two-week treatment period with fluticasone furoate nasal spray 100mcg QD versus a two-week treatment period with Placebo nasal spray QD. Secondary Safety Endpoints The frequency and type of clinical adverse events (AEs) experienced during treatment Nasal examinations Vital signs (systolic and diastolic blood pressure, heart rate [pulse]) Statistical methods: The primary objective of this study was to demonstrate that fluticasone furoate nasal spray 100mcg QD was non-inferior compared with Placebo on lower-leg growth rate, measured by knemometry. The primary analysis method was the non-inferiority comparison of the treatment groups (fluticasone furoate vs. Placebo) using analysis of covariance (ANCOVA), adjusting for baseline lower-leg growth rate measured by knemometry, age, and gender. Treatment and period were included as fixed effects in the model and subject was included as a random effect. The primary analysis was conducted on the Growth Population that excluded from the intent to treat (ITT) population subjects who did not have sufficient or reliable lower-leg growth data in order to provide an estimate for both two-week treatment periods (fluticasone furoate and Placebo) or subjects who received any protocol-prohibited medications that may have affected short term growth (e.g. systemic or inhaled corticosteroid medications that could have confounding effects on the interpretation of the growth rate). An ITT analysis of the primary safety endpoint was also performed. Data obtained from the literature for other knemometry studies gave estimates of mean lower-leg growth rate for Placebo-treated subjects of 0.40mm/wk to 0.50mm/wk, and an estimate of the standard deviation of 0.30mm/wk. Fluticasone furoate 100mcg QD was considered to be non-inferior to Placebo with respect to lower-leg growth rate if the lower limit of the two-sided 95% confidence interval for the treatment difference (fluticasone furoate minus Placebo) was greater than or equal to -0.20mm/wk (approximately 40-50% of the expected Placebo growth rate). Assuming normally distributed data and a true treatment difference (fluticasone furoate minus Placebo) of 0.0mm/wk, 50 completed subjects (25 subjects per sequence) provided at least 90% power. In anticipation of a drop-out rate of 10% after randomisation, at least 56 subjects were required to be randomised to achieve completion of at least 50 subjects. 5

7 CONFIDENTIAL Summary of Results: Exposure to Treatment All subjects were exposed to 11 days of fluticasone furoate 100mcg QD. The proportions of subjects exposed to treatment with fluticasone furoate 100mcg QD were generally unaffected by the order of the treatment sequence. Primary Safety Endpoint: Mean growth rate (mm/wk) in lower-leg length Fluticasone furoate nasal spray 100mcg QD was shown to be non-inferior to Placebo nasal spray based on the lower bound of the 95% CI being above the pre-specified noninferiority margin of -0.20mm/wk in lower-leg growth rate. In the Growth Population, following two weeks of treatment, mean lower-leg growth rate was 0.40mm/wk for the fluticasone furoate nasal spray 100mcg QD group and 0.42mm/wk for the Placebo group, with a treatment difference of mm/wk (95% CI: [-0.13, 0.10]). Results in the ITT population were supportive of those in the Growth Population. Lowerleg growth rates in the ITT Population were 0.40mm/wk for fluticasone furoate 100mcg QD and 0.41mm/wk for Placebo, with a treatment difference of mm/wk (95% CI: [-0.12, 0.10]). 6

8 CONFIDENTIAL Summary of Results and Statistical Analysis of Lower-Leg Growth Rate (mm/wk) (Growth Population) Placebo (N= 53) FF 100mcg QD (N= 53) Raw Change in Rate 1 Raw Change in Rate 1 Baseline (Run-in) N Mean (SE) 0.38 (0.066) (0.042) - Median Min Max Treatment Period 1 N Mean (SE) 0.45 (0.046) 0.07 (0.085) 0.44 (0.059) 0.04 (0.085) Median Min Max Washout N Mean (SE) 0.40 (0.059) 0.02 (0.088) 0.45 (0.065) 0.05 (0.073) Median Min Max Treatment Period 2 N Mean (SE) 0.40 (0.050) 0.00 (0.065) 0.39 (0.078) 0.01 (0.113) Median Min Max Comparison against Placebo N LS Mean (SE) 0.42 (0.04) 0.40 (0.04) LS Mean Difference p-value against Placebo 2 95% C.I , Change calculated relative to baseline rate. 2. ANCOVA adjusted for baseline lower-leg growth rate, age and gender. Treatment and period included as fixed effects and subject included as a random effect. Note: for ease of reporting, washout and baseline data are both displayed under the treatment for Period 1, although baseline (run-in) growth rate was used as a covariate in calculating mean growth rates in both Period 1 and Period 2. SE = Standard error; LS = Least square; CI = Confidence Interval ; LS mean Difference = LS mean Change in active LS mean Change in Placebo Secondary Safety Endpoints: Fluticasone furoate nasal spray 100mcg QD was well tolerated and comparable to Placebo nasal spray with respect to the AE profile and as evaluated by nasal examination 7

9 CONFIDENTIAL during the study. Similar numbers of subjects experienced AEs whilst receiving fluticasone furoate 100mcg QD and Placebo. The most common AE was nasopharyngitis, with a greater incidence for Placebo. The only AEs more common with fluticasone furoate 100mcg QD than with Placebo were epistaxis and cough. Epistaxis was also the only reported drug-related AE. All three events of epistaxis were mild in intensity and resolved by treatment end. There were no serious adverse events, deaths or adverse events leading to withdrawal during the study. No subjects developed nasal septal or turbinate ulcers during the study and the majority of subjects experienced no changes in nasal examinations. All AEs and Drug-Related AEs Reported in >=2 Subjects in any Treatment Group during the Treatment Period (ITT Population) Number (%) of Subjects Adverse Event Placebo (N= 57) FF 100mcg QD (N= 58) Subjects with any Adverse Event 10 (18) 10 (17) Nasopharyngitis (cold syndrome) 4 (7) 1 (2) Epistaxis 0 3 (5) Headache 3 (5) 1 (2) Cough 1 (2) 2 (3) Vomiting 3 (5) 0 Diarrhoea 2 (4) 0 Drug-related Adverse Events Epistaxis 0 3 (5) Conclusion: The data from this study suggest that there is a very low potential for a clinically relevant effect from treatment with fluticasone furoate nasal spray 100mcg once daily on shortterm lower-leg growth rate in pre-pubertal children with allergic rhinitis. Date of Report: March

10 CONFIDENTIAL TABLE OF CONTENTS Page SYNOPSIS ABBREVIATIONS ETHICS Independent Ethics Committee (IEC) or Institutional Review Board (IRB) Ethical Conduct of the Study Subject Information and Consent INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE INTRODUCTION STUDY OBJECTIVE(S) INVESTIGATIONAL PLAN Overall Study Design Protocol Amendment(s) Selection of Study Population Inclusion/Exclusion Criteria Predetermined Criteria for Subject Withdrawal Investigational Product Description of Investigational Product Dosages and Administration Dose Rationale Blinding Treatment Assignment Assessment of Compliance Treatment of Investigational Product Overdose Nasal Spray Malfunctions Prior and Concomitant Medications and Non-Drug Therapies Permitted Medications Allergy rescue medication Prohibited Medications Non-drug Therapies Study Assessments and Procedures Demographic and Baseline Assessments Efficacy Assessments

11 CONFIDENTIAL Safety Assessments Data Quality Assurance Data Analysis Methods Timings of Planned Analyses Sample Size Considerations Analysis Populations Treatment Comparisons General Considerations for Data Analyses Data Handling Conventions Study Population Safety Analyses STUDY POPULATION RESULTS Protocol Deviations Populations Analysed Demographics and Other Baseline Characteristics Demographics and Allergy History Other Current Medical Conditions Other Factors Affecting Response to Therapy Concomitant Medications Concomitant Medications Taken During the Run-in Period Concomitant Medications Taken During the Treatment Period and Washout Treatment Compliance Nasal Spray Compliance Based on Diary Card Record Nasal Spray Compliance Based on Bottle Weights SAFETY RESULTS Extent of Exposure Primary Safety Results Secondary Safety Results Adverse Events Serious Adverse Events Adverse Events Leading to Premature Discontinuation of Investigational Product and/or Study Nasal Examination Vital Signs Safety Conclusion(s) DISCUSSION AND CONCLUSIONS

12 CONFIDENTIAL 8.1. Discussion Conclusion REFERENCES STUDY POPULATION DATA SOURCE TABLES SAFETY DATA SOURCE FIGURES AND TABLES ATTACHMENTS Reporting and Analysis Plan Attachment 2 AADF Submission Confirmation

13 CONFIDENTIAL LIST OF FIGURES Page Figure 1 Study Schematic for Study Figure 2 Lower-Leg Growth Rate (mm/wk) (Growth Population ) Figure 3 Lower-Leg Growth Rate (mm/wk, Run-in and Washout Periods) (Growth Population ) Figure 4 Lower-Leg Growth Rates (mm/wk, Treatment Period 1 vs Treatment Period 2) (Growth Population ) Figure 5 Lower-Leg Growth Rates for Each Subject (mm/wk) (Growth Population ) Figure 6 Lower-Leg Growth Rate (mm/wk) (ITT Population ) Figure 7 Lower-Leg Growth Rate (mm/wk) (ITT Population ) Figure 8 Plot of Lower-Leg Growth Rates (mm/wk, Treatment Period 1 vs Treatment Period 2) (ITT Population )

14 CONFIDENTIAL LIST OF TABLES Page Table 1 Time and Events Schedule Table 2 Treatment Lot Numbers Table 3 Laboratory Tests Table 4 Summary of Subject Accountability: End of Study Record (ITT Population ) Table 5 Summary of Protocol Deviations (ITT Population ) Table 6 Demographics and Baseline Characteristics (ITT Population ) Table 7 Summary of Treatment Compliance Based on Diary Card Record (Growth Population ) Table 8 Summary of Treatment Compliance Based on Nasal Device Weight (Growth Population ) Table 9 Summary of Extent of Exposure to Study Medication (Growth Population ) Table 10 Summary of Lower-Leg Growth Rate (mm/wk) (Growth Population - ) Table 11 Summary of Lower-Leg Growth Rate (mm/wk) (ITT Population ) Table 12 Adverse Events Reported in Two or More Subjects in any Treatment Group during the Treatment Period (ITT Population ) Table 13 Summary of Nasal Examination Shifts from Baseline to Visit 3 (Start of Washout) (ITT Population ) Table 14 Summary of Nasal Examination Shifts from Baseline to Visit 4 (Start of Period 2) (ITT Population ) Table 15 Summary of Nasal Examination Shifts from Baseline to Visit 5 (Final Visit) (ITT Population )

15 CONFIDENTIAL Abbreviations ADHD AE ALT ANCOVA AST CI CRF/eCRF CRP CSR dbp EW FDA FF GCP GCSP GSK HR ICH IEC IgE IRB ITT LLQ IVRS LS MedDRA mm PAR PDF PGx PIN QC QD RAMOS RAP rtnss SAE SAR sbp SD SE URL W/W Attention Deficit Hyperactivity Disorder Adverse Event Alanine Aminotransferase Analysis of Covariance Aspartate Aminotransferase Confidence Interval Case Report Form/electronic Case Report Form C-Reactive Protein Clinical Study Report Diastolic Blood Pressure Early Withdrawal Food and Drug Administration Fluticasone Furoate Good Clinical Practice Global Clinical Safety and Pharmacovigilance GlaxoSmithKline Heart Rate International Conference on Harmonisation Independent Ethics Committee Immunoglobulin E Institutional Review Board Intent to Treat Lower Limit of Quantification Interactive Voice Response System Least Square Medical Dictionary of Regulatory Activities Millimetre Perennial Allergic Rhinitis Portable Document Format Pharmacogenetics Personal Identification Number Quality Control Once daily Registration and Medication Ordering System Reporting and Analysis Plan Reflective Total Nasal Symptom Score Serious Adverse Event Seasonal Allergic Rhinitis Systolic Blood Pressure Standard Deviation Standard Error Uniform Resource Locator Weight for Weight 14

16 CONFIDENTIAL Trademark Information Trademarks of the GlaxoSmithKline group of companies None Trademarks not owned by the GlaxoSmithKline group of companies InForm SAS 15

17 CONFIDENTIAL 1. ETHICS 1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) The study protocol, any amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a regional centre ethics committee Ethical Conduct of the Study This study was conducted in accordance with "good clinical practice" (GCP) and all applicable regulatory requirements, and, the guiding principles of the Declaration of Helsinki Subject Information and Consent Written informed consent was obtained for each subject prior to the performance of any study-specific procedures at Visit 1 (Screening Visit). As the subjects were 6 years to less than 12 years of age at the time of randomisation, an appropriately signed and dated consent was obtained from each subject s parent or guardian. Electronic case report forms were provided for each subject s data to be recorded. Paper diaries were provided to subjects to capture compliance and rescue medication usage information. 2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE The study was conducted at a single centre in Denmark. The principal investigator was Dr. The study was administered by the sponsor, GlaxoSmithKline (GSK). An independent data monitoring committee was not enlisted to evaluate study data. Central laboratory facilities were provided by Quest Laboratories. 16

18 CONFIDENTIAL 3. INTRODUCTION Intranasal corticosteroids are considered a highly effective treatment for the symptoms of allergic rhinitis, both in children and in adults. For this reason, they are recommended as a first-line treatment in expert guidelines, specifically when congestion is a major component of the patient s presentation [Task Force on Allergic Disorders, 2004]. In support of this treatment guideline, a meta-analysis of 16 randomised, controlled trials found intranasal corticosteroids significantly more effective at relieving nasal congestion, discharge, itch, and postnasal drip than oral antihistamines, the most prescribed treatment for allergic rhinitis [Weiner, 1998]. From a general perspective, intranasally-administered corticosteroids have generally demonstrated a low incidence of systemic adverse effects; however one concern in children has been their effects on growth. For example, intranasal and inhaled forms of the corticosteroid budesonide have demonstrated transient effects on growth rate and bone growth in children, although their effect on final height was insignificant [Agertoft, 2000; Agertoft, 1999; Childhood Asthma Management Program Research Group, 2000; Wolthers, 1993a; Wolthers, 1993b; Wolthers, 1990]. Studies with other intranasal corticosteroid moieties such as fluticasone propionate and mometasone furoate have found no significant effect on growth [Scadding, 2001; Skoner, 2003; Allen, 2002; MacKenzie, 1994]. Since the effect on growth has varied with the particular corticosteroid studied and by route, the possibility of an effect must be explored as new compounds become available. One of the methodologies used to evaluate the potential effect of intranasal corticosteroids on longitudinal growth in children is knemometry, which measures the distance between the top of the knee and the bottom of the heel of a seated subject using a knemometer. The length of the lower-leg is electronically calculated based on the maximum distance detected between a footplate and a knee-level measuring board. With repeated measurements, the instrument is able to detect very small changes in lower-leg length with an accuracy of 0.09 to 0.16mm over periods as short as one week [Wales, 1987; Wit, 1987; Hermanussen, 1988]. It is currently the preferred method for growth studies of short duration [Wolthers, 1990; Wolthers, 1992b; Wolthers, 1993b; Wolthers, 1995; Agertoft, 1997; Agertoft, 1999]. Confounding influences on the leg growth resulting from possible inter-group differences in spontaneous growth rates are reduced in a crossover study design [Wolthers, 1997]. Children with seasonal and/or or perennial allergic rhinitis (SAR and/or PAR), 6 to 11 years of age, comprised the population for this study. This range was selected because children of at least 6 years of age are more likely to comply with the requirements of the measuring procedure and because most boys <12 and girls <11 years of age are prepubertal. For the purposes of growth studies, it is not recommended to recruit children near the time of puberty because of the rapid increase in growth rate that may occur over a relatively brief period [Tanner, 1985]. Fluticasone furoate, the investigational drug for this study, is a novel corticosteroid with potent glucocorticoid activity. In a seven-day, intranasal study of 24 healthy adult males 17

19 CONFIDENTIAL [GlaxoSmithKline Document Number GM2002/00324/00, Study FFR10001] using oncedaily doses of 50, 100, 200, 400, and 800mcg, all doses demonstrated low systemic bioavailability with no significant effects on serum cortisol at any of the administered doses and no significant safety findings. In a two-week dose ranging study of 641 subjects with seasonal allergic rhinitis [GlaxoSmithKline Document Number RM2004/00150/00, Study FFR20001], approximately 5% of blood samples had measurable plasma concentrations of fluticasone furoate, generally no more than three times the lower limit of quantification (LLQ = 10pg/mL), with no significant effects on urine cortisol levels. Of the doses investigated in this study (fluticasone furoate 50, 100, 200, and 400mcg), 100mcg once daily was determined to be the optimal adult and adolescent dose. Thus, as the maximal dose that is likely to be prescribed, fluticasone furoate 100mcg once-daily was evaluated in a paediatric population aged 6 to 11 years with SAR and/or PAR in order to assess any potential effect on short-term lower-leg growth. 4. STUDY OBJECTIVE(S) The primary objective of this study was to evaluate for any potential effect on lower-leg growth rate from treatment with fluticasone furoate nasal spray 100mcg QD versus Placebo nasal spray in children ages 6 to 11 years with seasonal allergic rhinitis (SAR) and/or perennial allergic rhinitis (PAR). 18

20 CONFIDENTIAL 5. INVESTIGATIONAL PLAN 5.1. Overall Study Design This randomised, double blind, placebo-controlled, crossover study evaluated the effect on lower-leg growth rate of once daily treatment with fluticasone furoate nasal spray 100mcg QD versus Placebo nasal spray in children aged 6 to 11 years with SAR and/or PAR. The study consisted of five visits and four treatment periods: Screening, Treatment Period 1, Washout and Treatment Period 2, as shown in Figure 1. Each treatment period lasted approximately two weeks. The study was conducted at one site in Denmark. All subjects were outpatients. The Screening Period began at Visit 1 and ranged between 14±3 days prior to randomisation. The purpose of this two-week period was to obtain a treatment-free, growth rate assessment that would be used for comparison of growth following active treatment. Visit 1 (Day 0) was the beginning of the single-blind, two-week Placebo Run-in Period. At Visit 2, and following the Placebo Run-in Period, subjects were randomly allocated in a 1:1 ratio to a double-blind treatment sequence to receive either fluticasone furoate nasal spray 100mcg QD followed by Placebo nasal spray QD, or Placebo nasal spray QD followed by fluticasone furoate nasal spray 100mcg QD. Each double-blind treatment in the sequence was administered for two weeks and the two treatment periods were separated by a two-week single-blind Placebo Washout Period. Visit 3 (Day 15) marked the end of first double-blind Treatment Period. Subjects began the single-blind, Placebo Washout Period the morning after Visit 3. Visit 4 (Day 29) marked the end of the single-blind, Placebo Washout period. Subjects began the first day of the alternate double-blind treatment the morning after Visit 4. Visit 5 (Day 43) marked the end of the alternate double-blind Treatment Period and the last day of the study. A Follow-Up phone call was made three to seven days after taking the last dose to assess for adverse events. Rescue medication (loratadine) was permitted throughout the study. The daily dose was not to exceed the maximum labelled dose for a given subject s age. No other anti-allergy/anti-rhinitis medications, including oral and intranasal products, were allowed during the study. 19

21 CONFIDENTIAL Figure 1 Study Schematic for Study Randomisation FF 100mcg QD Placebo Placebo Placebo FF 100mcg QD Week -2 Screening Visit 1 Day 0 Baseline Visit 2 Week 2 Visit 3 Week 4 Visit 4 Week 6 Visit days after end of treatment Single Blind Placebo Screening Period Double Blind Treatment Period 1 Single Blind Placebo Washout Double Blind Treatment Period 2 Follow-Up Period 20

22 CONFIDENTIAL The time and events schedule is presented in Table 1. Table 1 Time and Events Schedule Visits F/U b Study Day or 46 EW a Activity ±3 ±3 ±3 ±3 ± Informed consent X Subject number assignment X Demography X Medical history X Rhinitis history X Evaluate Inclusion/Exclusion criteria X Height/Weight X Vital Signs X X X X X Physical examination X X Tanner staging X X Nasal examination X X X X X Nasal spray technique demonstration X Concomitant medication assessment X X X X Knemometric assessment X X X X X Blood sample for laboratory tests X Randomisation number assignment X Weigh and dispense single-blind, X X placebo nasal spray Dispense rescue medication X Issue diary card X X X X Collect and weigh single-blind, X X placebo nasal spray Weigh and dispense double-blind, X X treatment nasal spray Collect and weigh double-blind, X X treatment nasal spray Adverse event assessment X X X X X Diary card assessment X X X X Follow-up phone call a. EW = Early Withdrawal b. F/U=Follow-Up X 5.2. Protocol Amendment(s) Two protocol amendments were implemented in this study. Amendment No. 01 (18 February 2005) provided additional detail on the volume and retention period for the 21

23 CONFIDENTIAL blood sample drawn at Visit 1 and for the blood sample drawn for a serum pregnancy test, if required, at the Early Withdrawal Visit. C-Reactive Protein (CRP) was deleted from the list of chemistry and haematology analytes. Amendment No.2 (14 June 2005) changed the exclusionary period for intranasal and inhaled corticosteroids from four to two weeks prior to Visit 1; the amendment also allowed for the use of loratadine syrup as well as loratadine tablets provided by GSK and removed physical examination as a safety endpoint (new abnormalities found during physical examination were recorded as clinical adverse events, an existing safety endpoint) Selection of Study Population Inclusion/Exclusion Criteria Inclusion Criteria Subjects were eligible for inclusion in this study only if all of the following criteria were met: 1. Pre-menarcheal female subjects who were 6 years to less than 11 years of age at the time of randomization; 2. Male subjects who were 6 years to less than 12 years of age at the time of randomization; 3. Tanner Stage 1; 4. Documented clinical history of SAR and/or PAR of at least one year prior to study entry with (in the opinion of the investigator): a. a level of allergic rhinitis symptoms that warranted treatment with an intranasal corticosteroid and/or b. expected symptoms during a majority of the study period; Diagnosis had to be confirmed by a positive skin test (by skin prick method) to an appropriate seasonal or perennial allergen within 12 months prior to Visit 1 or at Visit 1. A positive skin test was defined as a wheal 3mm larger than the diluent control for prick testing. In vitro tests for specific IgE (such as RAST, PRIST) were also permitted as confirmation for a diagnosis of SAR or PAR if performed within the 12 months prior to Visit 1 or at Visit 1. For these tests, 5mL of blood were collected to determine allergenicity. Following analysis, the blood sample was held for two weeks and then destroyed. The sample was drawn in conjunction with the blood required for the clinical laboratory tests such that only one venipuncture was required at this visit. 5. Normal current growth as reflected by baseline height within the 5 th and 95 th percentiles of normal for age and gender as determined by stadiometry and Danish longitudinal standard charts; 22

24 CONFIDENTIAL 6. Subjects had to be willing and able to comply with study procedures; 7. Written informed consent had to be provided by the parent or guardian Randomisation Criteria At Visit 2, the subject must have met the following criteria: 1. Subject had completed at least 80% of responses to the diary compliance questions during the two-week, single-blind, Placebo Run-in Period Exclusion Criteria Subjects were not eligible for inclusion in this study if any of the following criteria were met: 1. History of abnormal growth or gross malnutrition; 2. Findings of a clinically significant laboratory abnormality; 3. History of any condition that may have substantially affected growth; 4. Subjects with historical or current evidence of clinically significant, uncontrolled disease of any body system (in addition to allergic rhinitis), such as uncontrolled, epilepsy, active tuberculosis, attention deficit hyperactive disorder, psychological disorders or eczema, were not eligible. Significant was defined as any disease that, in the opinion of the investigator, could put the safety of the subject at risk through study participation or which could confound the interpretation of the study results if the disease/condition exacerbated during the study; 5. Any asthma other than mild, intermittent asthma controlled by short-acting, β- agonists [GINA, 2003]; 6. Recent major surgery and/or trauma to the legs; 7. Current or history of glaucoma and/or cataracts or ocular herpes simplex; 8. History of adrenal insufficiency; 9. Current or prior treatment with any medication that may have had a potential for an ongoing effect on linear growth; 10. Use of corticosteroids, defined as: Inhaled and intranasal corticosteroids within two weeks prior to Visit 1; Corticosteroids by all other routes (e.g., oral, intramuscular, intravenous, dermatological, ocular, otic) within four weeks prior to Visit 1; 11. Any nasal condition or deformity that could have impaired nasal breathing or deposition of medication (i.e., nasal polyps, marked septal deviation); 12. Physical impairment that could have affected the subject s ability to participate in the study; 13. Documented evidence of acute or significant chronic sinusitis; 23

25 CONFIDENTIAL 14. Upper or lower respiratory or sinus infection during the seven days before screening; 15. Clinical evidence of a nasal or oropharyngeal Candida infection; 16. Rhinitis medicamentosa; 17. Severe dehydration; 18. Use of any medications that significantly inhibited the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazole; 19. Subjects with known hypersensitivity to any excipients in the study medications; 20. Previous clinical trial experience with fluticasone furoate nasal spray; 21. Exposure to clinical trial/experimental medication within 30 days of Visit 1; 22. Affiliation with investigational site such that the subject was an immediate family member of any site personnel; 23. Chickenpox or measles infections; A subject was not eligible if he/she currently had chickenpox or measles, or had been exposed to chickenpox or measles during the last three weeks and was nonimmune. If a subject developed chickenpox or measles during the study, he/she was withdrawn from the study. If a non-immune subject was exposed to chickenpox or measles during the study, his/her continuation in the study was at the discretion of the investigator, taking into consideration the likelihood of developing active disease Predetermined Criteria for Subject Withdrawal Subject withdrawal from the investigational product Premature discontinuation of the study drug was defined as discontinuation of the doubleblind study treatment for more than two consecutive days before the end of that study period. Subjects who discontinued administration of study drug prematurely were withdrawn from the study Subject withdrawal from the study Subject withdrawal from the study was required and Early Withdrawal procedures must have been performed, when: a subject was significantly non-compliant with the requirements of the protocol; a subject had not completed the two 2-week treatment periods; a subject became pregnant; a subject had an adverse event that would have made continued participation in the study an unacceptable risk, in the investigator s judgment; a subject demonstrated a decline in pulmonary function, as determined by the investigator, that warranted administration of inhaled or oral corticosteroids; 24

26 CONFIDENTIAL a subject experienced major trauma to the legs, required major surgery, or, in the opinion of the investigator, became severely dehydrated; a subject had a change in Tanner stage; the treatment blind was broken for a subject (by other than GSK GCSP personnel), or GSK discontinued the study. A subject could have voluntarily discontinued participation in this study at any time. The investigator may have also, at his or her discretion, discontinued the subject from participating in this study at any time. If a subject was prematurely discontinued from participation in the study for any reason, the investigator was to make every effort to perform the following evaluations at an Early Withdrawal visit: Knemometry; Review all information recorded on the diary cards; Conduct adverse event assessment; Physical examination; Nasal examination; Concomitant medication assessment; Study drug collection (single-blind, double-blind, and rescue). These data were to be recorded in the subject record and ecrf, as appropriate, as they comprised an essential evaluation that should have been done prior to discharging any subject from the study. Any clinically significant adverse event (AE), nasal examination, or clinically significant unfavourable change observed during the Early Withdrawal Visit necessitated that the subject be followed or treated until satisfactory resolution occurred. In the event that a subject was prematurely discontinued from the study at any time due to an AE or serious AE (SAE), the procedures stated in the protocol were followed Investigational Product Description of Investigational Product GlaxoSmithKline manufactured all study medication. Study medication was to be stored at a temperature of up to 30 C and protected from light. Fluticasone furoate nasal spray was manufactured as a preserved, aqueous suspension containing 0.05% w/w of micronised fluticasone furoate. The preservative system consisted of benzalkonium chloride and disodium edetate. Each nasal spray bottle contained a volume of suspension sufficient to deliver a minimum of 120 actuations. 25

27 CONFIDENTIAL Each spray of the suspension contained approximately 25mcg of fluticasone furoate. The matching Placebo nasal spray was comprised of the vehicle alone. Batch information is provided in Table 2. Table 2 Treatment Lot Numbers Treatment Manufacturing Batch # Vehicle Placebo Fluticasone furoate 0.05% w/w To ensure proper functioning, spray devices were primed prior to dispensing at Visits 1, 2, 3 and 4. This ensured that a full dose was delivered when the spray was used in the nose. Demonstration devices were also made available to allow site staff to demonstrate proper administration Dosages and Administration All randomised subjects received a single-blind, Placebo nasal spray treatment at Visit 1. The subject/parent/guardian was instructed to administer two sprays per nostril each morning beginning the morning of the following day. At the entry to the double-blind Treatment Period (Visit 2), eligible subjects were assigned to a study treatment sequence in accordance with the randomisation schedule, i.e., Fluticasone furoate nasal spray or Placebo nasal spray for two weeks, and were then crossed over to the alternate study treatment for two weeks, following a two-week, Placebo Washout Period. The first dose of double-blind study treatment was administered beginning the morning of the first day following Visit 2 through and including the morning of Visit 3. Singleblind Placebo nasal spray was dispensed at Visit 3 and subjects began administering their dose from this spray device the morning after Visit 3 through and including the morning of Visit 4. Following this Washout Period, subjects received the alternate study treatment of their treatment sequence at Visit 4 to begin using the morning following Visit 4 through and including the morning of Visit 5. If the subject was capable of administering the dose from the nasal spray device with supervision, both subject and parent(s)/guardian(s) were educated in the use of the nasal spray using a placebo demonstration device. If the subject required the parent/guardian to administer the daily dose, only the parent(s)/guardian(s) were educated in the use of the nasal spray device. The daily dose was administered each morning. Administration of the spray was conducted according to the subject instruction leaflet that was given to them for reference during the study. Administration of the dose throughout the study period was performed by alternately spraying one spray to each nostril followed by a second spray to each nostril. 26

28 CONFIDENTIAL Dose Rationale The Phase IIb dose-ranging study [GlaxoSmithKline Document Number RM2004/00150/00, Study FFR20001] examined once daily doses of fluticasone furoate 50mcg, 100mcg, 200mcg and 400mcg. Based on results from this study, fluticasone furoate nasal spray 100mcg once daily was selected as the adult dose to move forward in Phase III clinical trials for the treatment of SAR. All doses of fluticasone furoate studied in the dose-ranging study [GlaxoSmithKline Document Number RM2004/00150/00, Study FFR20001] were statistically superior to Placebo for the primary and key secondary endpoints. On evaluating the lowest optimal dose to select to take forward into Phase III, fluticasone furoate 100mcg exhibited numerically greater improvement in symptom scores for most endpoints compared with 50mcg. The 100mcg dose also achieved an onset of 8 hours compared with 24 hours for 50mcg. The 100mcg dose exhibited a statistically significant difference over Placebo of 21% in the primary endpoint (daily reflective total nasal symptom score, rtnss) and was rated by more subjects than any other dose (28%) as providing significant improvement in an overall evaluation of treatment at study end. A continued effect at 24 hours was also seen, providing further support for once daily dosing. For the paediatric programme, doses of fluticasone furoate nasal spray 50mcg and 100mcg QD are being examined in the Phase III programme to determine the optimal labeled dose in children aged 2 to 11 years. This study examined the higher of these two doses (100mcg QD) Blinding At Visit 1 and Visit 3, a single-blinded, Placebo nasal spray was dispensed to each subject. At Visit 2 and Visit 4, a treatment pack containing a double-blinded nasal spray treatment was assigned to randomised subjects. A copy of the randomisation code was stored electronically in GSK s randomisation system so that all investigators, subjects and GSK personnel remained blinded. Each treatment pack dispensed contained a single-or double-blinded nasal spray treatment labeled with a single-language label containing the protocol number, pack number, dosing instructions, contents, storage conditions, and sponsor name and address. The contents of the label met all applicable regulatory requirements. Only in the case of an emergency, when knowledge of the investigational product was essential for the clinical management or welfare of the subject, could the investigator unblind a subject s treatment assignment. If the blind was broken for any reason, the investigator was instructed to notify GSK immediately of the unblinding incident without revealing the subject s study treatment assignment. In addition, the investigator was instructed to record the date and reason for revealing the blinded treatment assignment for that subject in the appropriate CRF. If a SAE was reported to GSK, Global Clinical Safety and Pharmacovigilance (GCSP) staff could also unblind the treatment assignment for the individual subject. If an 27

29 CONFIDENTIAL expedited regulatory report to one or more regulatory agencies was required, the report would identify the subject s treatment assignment. When applicable, a copy of the regulatory report was to be sent to investigators in accordance with relevant regulations, GSK policy, or both Treatment Assignment Eligible subjects were randomly assigned to study treatment, in accordance with a GSK computer-generated randomisation schedule (block size=4). The treatment assignment was made via an Interactive Voice Response System (IVRS) called Registration and Medication Ordering System (RAMOS) and accessed via personal identification numbers (PIN) assigned to authorised site personnel. A unique randomisation number and medication pack was assigned to the subject via RAMOS. A container number on the medication pack determined the numbering of the medication packs. The container number of the medication pack was linked to that subject s unique randomisation number. Once assigned, container numbers and randomisation numbers could not be reassigned to any other subject. The randomisation number was documented in the subject s clinic notes and in the CRF Assessment of Compliance Compliance was assessed by the subject s (and/or subject s parent/guardian) confirmation on the treatment diary card that they had administered their daily dose. Subjects (and/or subject s parent/guardian) were instructed to circle Y (yes) or N (no) each morning in response to the question Did you spray two sprays of your medication into each nostril today? Compliance was also assessed by site staff weighing study nasal spray devices prior to dispensing and again when returned by the subjects at each visit. The subjects or their parent(s)/guardian(s) were not made aware that the devices have been weighed. Weights of the nasal spray devices were documented in the CRF. An appropriate balance for weighing the nasal spray devices was provided to the study sites by the sponsor along with detailed information regarding the proper use and maintenance of the balance Treatment of Investigational Product Overdose GSK did not recommend specific treatment to treat a product overdose. In the event of an overdose of study medication, the investigator was to use clinical judgment in treating the overdose and to contact the study medical monitor. It was recommended that the investigator brochure for fluticasone furoate should be referenced for any safety concerns Nasal Spray Malfunctions Any nasal spray that failed to actuate properly was identified and returned to GSK for testing. Details of the failure were documented in the investigator comments. If a 28

30 CONFIDENTIAL subject or their parent(s)/guardian(s) experienced a malfunction, they were to return the spray to the clinic as soon as possible to avoid missing any doses. The site would then call RAMOS, obtain a new container number for the subject, and dispense a new medication pack from the site s investigational product supply as instructed by RAMOS Prior and Concomitant Medications and Non-Drug Therapies Permitted Medications All concomitant medications taken during the study were to be recorded in the CRF, as well as any medications, such as asthma or allergy medication, taken in the previous six months that had the potential to affect growth. The minimum requirement was that drug name and the dates of administration were included. Subjects could continue use of their current medication(s) if it did not affect allergy or rhinitis symptoms, if the dose remained constant and if their use would not be expected to affect the subject s growth. The rescue medication loratadine was permitted during the study Allergy rescue medication Loratadine tablets and/or loratadine syrup, a non-prescription antihistamine, was provided by GSK to all subjects to use as allergy rescue medication during the study on an as needed basis, and dispensed to the subject by the site. The subject s parent/guardian or the subject, when deemed appropriate, recorded their daily use of allergy rescue medication. The daily dose was not to exceed the maximum labeled dose for a given subject s age. No other anti-allergy/anti-rhinitis medications, including oral and intranasal products, were allowed during this study Prohibited Medications No other anti-allergy or anti-rhinitis medications, including oral, intranasal, ocular or throat treatments, were permitted during the study except for the rescue medication loratadine. Immunotherapy subjects could be enrolled in the study as long as the immunotherapy was not initiated within 30 days of Visit 1. Inhaled or intranasal corticosteroids were not permitted within two weeks of study start to ensure at least four weeks washout before randomisation to study medication. Corticosteroids administered by other routes (e.g., oral, intramuscular, intravenous, dermatological, ocular, otic) were not permitted within four weeks of study start. Concurrent use of any prescription or non-prescription medication containing a corticosteroid was not allowed during the study. Subjects with mild, intermittent asthma could be treated with short-acting, inhaled β 2 -agonists on an as needed basis only. Concomitant use of any treatment that could potentially influence linear growth was not allowed, including, but not limited to, the following medications: methylphenidate, 29

31 CONFIDENTIAL thyroid hormone, growth hormone, androgens, calcitonin, estrogens, progestins, biphosphonates, anticonvulsants, or phosphate-binding antacids. Use of any medications that significantly inhibited the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazole, were prohibited Non-drug Therapies No non-drug therapies were permitted in the study Study Assessments and Procedures Demographic and Baseline Assessments The following demographic and baseline information was obtained: age, sex, race, ethnicity, height, weight, concomitant medication use, the subject s allergic rhinitis history and results of a skin prick/in vitro test for pertinent allergen(s) if undocumented. All subjects also had a physical examination, vital signs assessment, Tanner staging assessment, nasal examination, knemometric measurements, blood haematology and chemistry analyses. During the two-week, single-blind, Placebo Run-in Period prior to randomisation, a treatment-free, growth rate assessment provided the baseline for comparison of growth following active treatment. All demographic and baseline assessments were completed according to the Time and Events Schedule in Table Efficacy Assessments No efficacy assessments were performed during this study Safety Assessments Primary safety endpoint(s) The primary safety endpoint was the mean growth rate (mm/wk) in lower-leg length, as determined by knemometry, over a two-week treatment period with fluticasone furoate nasal spray 100mcg QD versus a two-week treatment with Placebo nasal spray QD Secondary safety endpoint(s) Secondary safety endpoints were: The frequency and type of clinical adverse events experienced during treatment Nasal examinations Vital signs (systolic and diastolic blood pressure, heart rate [pulse]) 30

32 CONFIDENTIAL A nasal examination and vital signs were performed at Visits 1 to 5. The investigator performed the nasal examination. The investigator, nurse practitioner, or physician s assistant listed in the FDA Form 1572 performed the vital signs measurements Knemometry assessments The primary safety endpoint was based on knemometry assessments carried out at every visit (at approximately two-week intervals). Measurements were performed by a trained observer (the investigator or site personnel), according to detailed guidelines available at the centre. The same person was to perform all measurements on a subject if possible, during the hours of 13:00 to 19:00, with each subsequent visit occurring within +/- 2 hours of the Visit 1 time. The knemometer was calibrated prior to each visit. The subject must not have participated in heavy exercises within three hours prior to the assessment. For the knemometry measurements, the subject was dressed in underwear and had to rest in a chair five minutes prior to the measurements. The observer measured the distance between the top of the knee and the bottom of the heel of the lower-leg of the seated subject using digital parameters and without reference to previous measurements. The length of the lower-leg was electronically calculated based on the maximum distance detected between a footplate and a knee-level measuring board. Four measurements were taken of the right leg at each visit and the final three measurements were recorded in the CRF [Hermanussen, 1988]. The three recorded measurements were averaged. The difference between the average at the start of the period and the end of the period was divided by the period length (weeks) to obtain the lower-leg growth rate in millimetres per week for each period Other safety assessments Safety was also assessed by clinical laboratory tests at Visit 1 and a physical examination at Visits 1 and 5. The investigator, nurse practitioner, or physician s assistant listed in the FDA Form 1572 performed the physical examination Diary Cards Subjects were provided with a diary card on which to document that they took their dose each morning. Additionally, subjects recorded any medical problem (other than allergic rhinitis) that they experienced and any concomitant medications and/or rescue medications taken in the designated area on the diary card Adverse events All AEs occurring during study participation were collected from Visit 1 through to the Follow-Up phone call. 31

33 CONFIDENTIAL An AE was defined as Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. Examples of an AE included: Significant or unexpected worsening or exacerbation of the condition/indication under study; Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition; New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study; Signs, symptoms, or the clinical sequelae of a suspected interaction; Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concurrent medication (overdose per se was not to be reported as an AE/SAE). Examples of an AE did not include a/an: Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that led to the procedure was the AE; Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital); Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that did not worsen; The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject s condition. The definition of AEs included pre- or post-treatment events that occurred as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject s previous therapeutic regimen). At every visit, after the subject had had an opportunity to spontaneously mention any problems, the Investigator was to enquire about AEs by asking the following standard questions: Have you had any (other) medical problems or worsening of any medical problems since your last visit/assessment? Have you taken any new medicines, other than those given to you in this study, since your last visit/assessment? 32

34 CONFIDENTIAL Diary cards were reviewed at each visit and if the subject did not mention an event that was recorded, he/she was questioned for further information in order to determine if there was some occurrence of an AE. In the event that an AE occurred, the investigator made an assessment of intensity and causality for each AE and SAE reported during the study. The assessment of intensity was based on the investigator s clinical judgment and was assigned to one of the following categories: Mild: An event that was easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities; Moderate: An event that was sufficiently discomforting to interfere with normal everyday activities; Severe: An event that prevented normal everyday activities. Causality was also based on the investigator s clinical judgment. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the investigational product were to be considered and investigated in making this decision. There may have been situations when an SAE occurred and the investigator had minimal information to include in the initial report to GSK. However, it was very important that the investigator always made an assessment of causality for every event prior to transmission of the SAE CRF to GSK. The investigator may have changed his/her opinion of causality in light of follow-up information, amending the SAE CRF accordingly. The causality assessment was one of the criteria used when determining regulatory reporting requirements. After the initial AE/SAE report, the investigator was to follow each subject and provide further information to GSK on the subject s condition. All AEs and SAEs documented at a previous visit/contact and designated as ongoing, were reviewed at subsequent visits/contacts and followed until resolution, until the condition stabilised, until the event was otherwise explained, or until the subject was lost to follow-up. Once resolved, the appropriate AE/SAE CRF page(s) was updated. The investigator also followed up with any supplemental investigations needed to elucidate the nature and/or causality of the AE or SAE Serious adverse events All SAEs related to study participation were collected from Visit 1 through to the followup phone call. An SAE was defined as any untoward medical occurrence that, at any dose: a. Resulted in death; b. Was life-threatening. 33

35 CONFIDENTIAL NOTE: The term 'life-threatening' in the definition of 'serious' referred to an event in which the subject was at risk of death at the time of the event. It did not refer to an event, which hypothetically might have caused death, if it were more severe. c. Required hospitalisation or prolongation of existing hospitalisation. NOTE: In general, hospitalisation signified that the subject had been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician s office or out patient setting. Complications that occurred during hospitalisation were AEs. If a complication prolonged hospitalisation or fulfilled any other serious criteria, the event was serious. When in doubt as to whether hospitalisation occurred or was necessary, the AE was considered serious. Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline was not considered an AE. d. Resulted in disability/incapacity, or NOTE: The term disability meant a substantial disruption of a person s ability to conduct normal life functions. This definition was not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may have interfered or prevented everyday life functions but did not constitute a substantial disruption. e. Was a congenital anomaly/birth defect. f. Medical or scientific judgment was to be exercised in deciding whether reporting was appropriate in other situations, such as important medical events that may not have been immediately life-threatening or resulted in death or hospitalisation but may have jeopardised the subject or may have required medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These were also to be considered serious. Examples of such events were invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that did not result in hospitalisation, or development of drug dependency or drug abuse. Once an investigator became aware that an SAE had occurred in a study subject, she/he was to report the information to GSK, preferably by fax, within 24 hours. In rare circumstances and in the absence of facsimile equipment, notification by telephone was acceptable, with a copy of the "SAE" CRF sent by overnight mail. The SAE CRF was completed as thoroughly as possible with all available details of the event, signed by the investigator (or designee), and forwarded to GSK. If the investigator did not have all information regarding an SAE, he/she was not to wait to receive additional information before notifying GSK of the event and completing the form. The form was updated when additional information was received. The investigator also provided an assessment of causality at the time of the initial report. 34

36 CONFIDENTIAL Pregnancies Only premenarchal females were eligible to participate in this study (Tanner Stage 1). Any female who began to menstruate during the study had to be discontinued and have a serum pregnancy test at the Early Withdrawal visit. The investigator or his/her designee collected pregnancy information on any female subject who became pregnant while participating in this study. Information concerning the pregnancy was to be recorded on the appropriate form and submitted to GSK within two weeks of learning of a subject's pregnancy. The subject was to be followed to determine the outcome of the pregnancy and the status of the mother and child was to be forwarded to GSK. Generally, follow-up was no longer than six to eight weeks following the estimated delivery date. Any premature termination of the pregnancy was also to be reported. A spontaneous abortion was always considered to be an SAE and was to be reported. Any SAE occurring as a result of a post-study pregnancy and that was considered reasonably related to the investigational product by the investigator, was also to be reported to GSK Clinical laboratory evaluations Routine laboratory tests (haematology and clinical chemistry) were performed at Visit 1. Subjects were not required to fast prior to collection of the laboratory specimens. Quest Diagnostics, a central laboratory, analysed the blood samples and provided a manual to each site containing detailed instructions for collecting all specimens. A printout of the results from the central laboratory was sent to the site for review by the investigator and was signed and dated by the investigator confirming review. The investigator was to assess the results of all clinical laboratory tests to determine each subject s eligibility to participate in the study. Any subject with all analytes within their respective reference range was eligible to continue. For any subject who had an analyte outside the reference range, the investigator had three options: 1. Exclude the subject from the study due to the deviant result and/or the uncertain clinical significance of the deviant result; 2. Repeat, at the earliest opportunity, the test for the analyte on a new specimen to assess the possibility of laboratory error; 3. Document the subject s eligibility for the study on the basis of one of the following explanations for the deviant result: Abnormality due to concurrent illness, disease process, or condition that would not have rendered the subject in question at higher risk than a subject without a similar deviation in laboratory tests (e.g., eosinophilia in atopic subjects). Normal deviation for age (e.g., elevated alkaline phosphatase). Clinically insignificant deviation from normal values (i.e., in the judgment of the physician/investigator, the deviation did not indicate the presence of a disease 35

37 CONFIDENTIAL state or compromised, predisposing state which rendered the subject in question at higher risk than a subject without a similar deviation in laboratory tests). Abnormal laboratory values resulting in an adverse event or serious adverse event (e.g., hospitalisation) were reported to GSK as an AE or SAE. Abnormal laboratory findings (e.g., clinical chemistry, hematology) judged by the investigator as clinically significant were recorded as AEs or SAEs if they met the definition of an AE. Clinically significant abnormal laboratory findings or other abnormal assessments that were detected during the study or were present at baseline and significantly worsened following the start of the study, were reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that were associated with the disease being studied, unless judged by the investigator as more severe than expected for the subject s condition, or that were present or detected at the start of the study and did not worsen, were not reported as AEs or SAEs. The investigator exercised his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment was clinically significant. After the laboratory report was reviewed, it was signed and dated by the investigator confirming review. The analytes shown in Table 3 were evaluated at Visit 1. A pregnancy test was required at an Early Withdrawal visit for any female who began to menstruate during the study. Table 3 Laboratory Tests Chemistry Haematology Electrolytes Total Bilirubin Haemoglobin Sodium Alkaline Phosphatase Haematocrit Potassium Alanine Amino-transferase (ALT or RBC SGPT) Aspartate Amino-transferase (AST WBC or SGOT) Glucose Neutrophils Creatinine Lymphocytes Urea nitrogen Monocytes Calcium Eosinophils Total Protein Basophils Albumin Platelets A pregnancy test was required at an Early Withdrawal visit for any female who began to menstruate during the study Physical Examination A physical examination including a Tanner staging assessment was conducted at Visit 1 (Screening) and Visit 5/Early Withdrawal by the investigator, nurse practitioner, or physician s assistant listed on the FDA Form Physical examination results were documented in the source documents only. At Visit 5 any unfavourable changes from the 36

38 CONFIDENTIAL Visit 1 assessment, were recorded as an AE, including the start and stop dates of the event. At each study visit, subjects were also clinically assessed by the investigator with regard to the status of concurrent asthma (if present). A subject was withdrawn if he or she demonstrated any deterioration in asthma that warranted introduction of inhaled or oral corticosteroid therapy Nasal Examination A detailed nasal examination of the turbinates, mucosa, septum, and secretions was performed by the investigator at all visits (Visits 1 through 5 or Early Withdrawal) and the findings recorded on the nasal examination CRF page. This examination included an evaluation of nasal patency and the size of any polyps and ulcers that may have been present. Any unfavourable changes not reflective of the symptoms of allergic rhinitis seen at the Visit 1 assessment were recorded as an AE, with the start and stop dates of the event. The same practitioner was to perform the nasal examinations for a given subject at all visits for consistency. If symptoms of a nasal fungal infection were present, a fungal culture was performed. A diagnosis of nasal candidiasis was reported as an AE Vital Signs Vital signs (heart rate [pulse], systolic and diastolic blood pressure) were measured at all visits with the subject in the seated position. The subject was seated at least five minutes before these measurements were done. A single set of values for heart rate [pulse] and blood pressure (systolic and diastolic) were determined and recorded in the CRF. The subject s height was also recorded in the CRF at Visit Data Quality Assurance This study used Phase Forward s InForm system. InForm is a web-based clinical trials data management system that provides investigational sites with a standardised and validated, remote, electronic data capture system for the collection of clinical trial data. Activities performed using InForm include data entry, modification, review and validation. Each activity performed carries a unique user identification code and a datetime stamp. InForm training for this single-center study was provided to site staff at the Investigator meeting by PharmaLink. Study-specific Electronic Case Report Form (ecrf) training for the monitors was provided at a face-to-face meeting, held at Greenford, by GSK Data Management. Additionally, an InForm interactive training database was available to site staff and study monitors for independent follow-up training. The application was fully validated using test data, prior to distributing the Uniform Resource Locator (URL) for site use. 37

39 CONFIDENTIAL Encrypted clinical trial data was transmitted from the site via the internet to a firewallprotected network server, and then via an application server into the clinical database (e.g., InForm puts data into a shared drive). An electronic audit trail of all changes made to the ecrf was kept within the InForm system. This audit trail identified the user making the change by user id, date and time of change. Pre-defined data validation checks were run within the ecrf as the data were entered and submitted by authorised site staff. The resulting data queries were then resolved. Additional queries were generated within the ecrf by authorized GSK staff as a result of data review (e.g., source document review, external data reconciliation). In addition to InForm ecrf data, electronic laboratory data were delivered to GSK by external vendors. These data were reconciled with the ecrf data and resulting discrepancies were queried within the ecrf. Quality Control (QC) was carried out by extracting SAS datasets, and comparing printed copies against the ecrf for 8% of the cases. Adverse events and concomitant medications were coded by the autoencoder using company standard dictionaries (GSK Drug) and industry standard dictionaries (MedDRA). The principal investigator electronically signed and dated each InForm casebook attesting to his/her responsibility for the quality of all data included therein, and that the data represented a complete and accurate record of each subject's participation in the study. At the end of the study once all data queries were resolved, a CD-ROM containing an ecrf portable document format (PDF; these contain the patient's ecrf data, the data queries, and a copy of the audit trail) was sent to site along with a letter explaining how to view the data on the PDF. Upon delivery of the CD-ROM, the study site notified GSK of receipt. After data management procedures were completed the database was released on 06 December Following release the database was frozen on 07 December The original validated data (ecrfs, etc.) were archived according to company standard procedures. During the conduct and reporting of this study, one independent audit was performed by or on behalf of GlaxoSmithKline Clinical Compliance. This was a Routine Investigator Audit conducted in Denmark (02 June 2005). The audit was carried out in accordance with appropriate regulatory requirements and guidelines in order to assess compliance with the study protocol, ICH GCP and appropriate standard operating procedures and policies. 38

40 CONFIDENTIAL 5.8. Data Analysis Methods Timings of Planned Analyses All planned analyses were performed after sign-off of the Reporting and Analysis Plan (RAP), in Attachment 1. After the database was authorised and study population membership agreed, the study treatments were unblinded and data displays were released. No interim analysis was planned or conducted Sample Size Considerations The study randomisation was planned for equal allocation of subjects between two treatment sequences. Data from previous GSK studies and the literature for other knemometry studies provided estimates of mean lower-leg growth rate for Placebo-treated subjects of 0.40 mm/wk to 0.50 mm/wk, and an estimate of the standard deviation of 0.30 mm/wk. Fluticasone furoate 100mcg QD would be considered to be non-inferior to Placebo with respect to lower-leg growth rate if the lower limit of the 2-sided 95% confidence interval for the treatment difference (fluticasone furoate minus Placebo) was greater than or equal to mm/wk (roughly 40-50% of the Placebo growth rate). Assuming normally distributed data and a true treatment difference (fluticasone furoate minus Placebo) of 0.0 mm/wk, 50 completed subjects (25 subjects per group) provided at least 90% power. In anticipation of a drop-out rate of 10%, approximately 56 subjects were required to be randomised to achieve completion of at least 50 subjects Analysis Populations Four populations were defined for this study. The Intent-to-Treat ITT population was defined as all subjects who were randomised and received at least one dose of study drug. Since randomisation did not occur until Visit 2, subjects who took the Placebo spray during the run-in but were not subsequently randomised or took study medication were not included in the ITT population. Unless otherwise specified, analyses based on the ITT population included all available data for these subjects. This population was the basis for all summaries, analyses, listings and figures of demographic and safety data. The primary population was the Growth population. The Growth population was defined to exclude from the ITT population subjects who did not have sufficient or reliable lowerleg growth data in order to provide an estimate for both two-week treatment periods (fluticasone furoate and Placebo) or subjects who received any protocol-prohibited medications that may have affected short term growth (e.g. systemic or inhaled corticosteroid medications that could have confounding effects on the interpretation of the growth rate). The analysis of the primary safety endpoint data, i.e., the lower-leg growth rate, was performed on the growth population (of primary interest), and also in the ITT population (as supportive). The Growth population was used for summaries of 39

41 CONFIDENTIAL demographic and baseline characteristics and summaries, figures and analysis of the primary safety endpoint. The growth population was defined as the ITT population excluding subjects who had any one of the following: 1. Did not fulfill the inclusion, exclusion and randomisation criteria that were growth specific; 2. Did not have growth assessment(s) by knemometry at all protocol planned assessment time points (e.g. growth rate could not be estimated for at least one treatment period); 3. Withdrawal from the study due to adverse events related to major trauma to the legs, major surgery, or severe dehydration; 4. Received protocol-prohibited medications (other than the study medication) prior to randomisation and during the study; 5. A change in Tanner stage during the study; 6. Received incorrect study treatment at any point during the study. The All Subjects Screened Population was defined as all subjects who were screened for inclusion in the study. Subject disposition was summarised for this population. The Screen Failure Population was defined as all subjects screened for inclusion in the study who were discontinued from the study prior to randomisation, or subjects who were misrandomised and received no administration of study drug. The reasons for withdrawal prior to randomisation and SAEs during the screening period were listed for this population Treatment Comparisons The primary comparison was the non-inferiority comparison made on the mean lower-leg growth rate as measured by knemometry over the two week treatment periods, between fluticasone furoate 100mcg QD and Placebo. The primary safety endpoint was the mean growth rate (mm/wk) in lower-leg length, as determined by knemometry, over a twoweek treatment period with fluticasone furoate nasal spray versus a two-week treatment period with Placebo nasal spray General Considerations for Data Analyses In general, discrete variables were summarised using frequency distributions, and continuous variables were summarised using the number of observations, mean, standard deviation or standard error, median, minimum, and maximum. See Attachment 1, Section 8. 40

42 CONFIDENTIAL Multicentre studies This study was conducted in one site in Denmark so there was no need to group centres or adjust for centre in summaries and analyses Other strata and covariates The analysis of mean lower-leg growth rate was adjusted for covariates of baseline lower-leg growth rate measured by knemometry (calculated based on knemometric measurements at Visit 1 and Visit 2), age and gender, all of which were thought to have an influence on lower-leg growth rate. Treatment and period were included in the model as fixed effects. Subject was included in the model as a random effect. Due to the study design the Washout Period growth rate was likely to be affected by carry-over from the first treatment period. As such, the baseline lower-leg growth rate was used as the covariate for both treatment periods (see Attachment 1, Section 8.2) Examination of subgroups Subgroup summaries or analyses were not planned for this study Multiple comparison/multiplicity As there was a single primary endpoint and no statistical testing was to be performed on the secondary endpoints, no adjustments for multiple comparisons or multiplicity were required Data Handling Conventions For handling of missing data, premature withdrawals, calculation of derived variables, assessment windows and adverse event onset date, see Attachment 1, Section Study Population For summaries of subject disposition, protocol deviations, demographic and baseline characteristics, laboratory tests (haematology, clinical chemistry and electrolytes), concomitant medications and treatment compliance, see Attachment 1, Section Safety Analyses For analyses of all safety data (i.e., primary, secondary and other safety measures), refer to Attachment 1, Section 11. The safety endpoints were: the mean growth rate (mm/wk) in lower-leg length, as determined by knemometry, over a two-week treatment period with fluticasone furoate nasal spray versus a two-week treatment with Placebo nasal spray; the frequency and type of AEs; results of the nasal examinations; vital signs (systolic and diastolic blood pressure, heart rate [pulse]). 41

43 CONFIDENTIAL 6. STUDY POPULATION RESULTS A total of 61 subjects were screened for this study at a single investigative site. Of these, three subjects were screening failures (Table 6.1). Any subject who was assigned a subject number but was not randomised was considered a screening failure. Table 6.2 provides the Listing of Reasons for Screening Failure. Fifty-eight (58) subjects were randomised into the study, received at least one dose of study medication and comprise the ITT population (Table 6.1). Of the 58 subjects randomised, 29 were randomised to the fluticasone furoate nasal spray 100mcg QD/Placebo nasal spray QD sequence and 29 were randomised to the Placebo nasal spray QD/ fluticasone furoate nasal spray 100mcg sequence (Table 6.12). Fifty-seven (98%) subjects completed the study (Table 4). A Listing of End of Study Record is provided in Table 6.4 and the numbers of subjects completing each treatment visit is shown in Table 6.5. Table 4 Summary of Subject Accountability: End of Study Record (ITT Population ) Number (% of Subjects) TOTAL (N= 58) Completion Status Completed 57 (98) Prematurely Withdrawn 1 (2) Primary Reason for Withdrawal Protocol Violation 1 (2) Source Data: Table Protocol Deviations The definition of a protocol deviation included failure to meet growth-specific inclusion, exclusion or randomisation criteria; missing knemometry growth assessments at any visit or assessments outside protocol-defined visit window; occurrence of adverse events related to major trauma to the legs, major surgery or severe dehydration; use of prohibited medications prior to randomisation or during the study; a change in Tanner Stage during the study, and incorrect study treatment at any point during the study. There were no inclusion/exclusion or randomisation criteria deviations (Table 6.6 and Table 6.7). 42

44 CONFIDENTIAL Five subjects (8.6%) violated criteria for inclusion into the Growth Population (Table 5). Listings of Reasons for Exclusion from the ITT Population and from the Growth Population are provided in Table 6.10 and Table 6.11, respectively. Table 5 Summary of Protocol Deviations (ITT Population ) Number (% of Subjects) TOTAL (N= 58 ) Any Entrance Criteria Deviation 0 Inclusion Criteria 0 Exclusion Criteria 0 Randomisation Criteria 0 Any Deviation 5 (8.6) Knemometry Assessments 2 (3.4) Adverse Events 0 Prohibited Meds during Screening 0 Prohibited Meds during Treatment 4 (6.9) Change in Tanner Stage 0 Incorrect Study Treatment 0 Source: Table 6.6 and Table 6.11 Table 6.8 summarises the spacing of visits with respect to the visit window specified in the protocol. subject during the study (Table 6.9). The treatment blind was not broken for any 43

45 CONFIDENTIAL 6.2. Populations Analysed Analysis populations (ITT Population and Growth Population) were defined in Section The ITT population was used for all analyses of safety data. The analysis of the primary endpoint (mean lower-leg growth rate) was performed for both the Growth Population (of primary interest) and the ITT Population (supportive). The ITT population consisted of 58 subjects and the Growth Population consisted of 53 subjects. A Listing of Population Membership and Treatment Sequence Allocation is provided in Table Demographics and Other Baseline Characteristics Demographics and Allergy History In the ITT population, mean age of subjects was 9.1 years, with a range of 6 to 11 years (Table 6). There were more males than females (67% vs. 33%) and the majority of subjects (97%) were White. Demographic characteristics in the Growth Population were similar to those in the ITT population as the majority of subjects in the ITT population were included in the Growth Population (Table 6). A subject Listing of Demographic Characteristics (ITT Population) is provided in Table Fifty-five percent (55%) of subjects in the ITT population had a history of allergic rhinitis for 3years (Table 6). Thirty-six percent (36%) of subjects in the ITT population reported a history of SAR only and 55% of subjects reported a history of PAR only, while 9% of subjects reported a history of both SAR and PAR (Table 6.16). A Listing of Allergy History for each subject is provided in Table

46 CONFIDENTIAL Table 6 Demographics and Baseline Characteristics (ITT Population ) ITT Population (N= 58) Growth Population (N= 53) Age (years) Mean (SD) 9.1 (1.37) 9.0 (1.39) Min-Max Gender, n (%) Female 19 (33) 18 (34) Male 39 (67) 35 (66) Race, n(%) White a 56 (97) 51 (96) Black b 0 0 Other c 2 (3) 2 (4) Height (cm) Mean (SD) (9.81) (9.69) Min-Max Weight (kg) Mean (SD) 33.3 (9.11) 33.1 (8.68) Min-Max Duration of Allergic Rhinitis, n (%) <1 year 0-1 to <3 years 26 (45) - 3 years 32 (55) - Source: Table 6.13, Table 6.14, Table 6.16 a. White is defined as those subjects who chose only the White (Arabic/North African Heritage) and/or White (White/Caucasian/European Heritage) categories; b. Black is defined as those subjects who chose only the African American/African Heritage category; c. Other is defined as those subjects who chose any other race on the CRF Other Current Medical Conditions Fifty percent (50%) of subjects reported other current medical conditions (i.e., excluding allergic rhinitis) (Table 6.18). These included respiratory, thoracic and mediastinal disorders (33%), skin and subcutaneous tissue disorders (12%), general disorders and administration site conditions (3%) gastrointestinal disorders (2%) and psychiatric disorders (2%) Other Factors Affecting Response to Therapy Routine laboratory tests were performed at Visit 1 only to assess the health of potential subjects and exclude from the study any subject with a clinically significant laboratory abnormality. Screening laboratory values are provided in Table Abnormal Screening laboratory haematology and biochemistry values are summarised in 45

47 CONFIDENTIAL Table The haematology and clinical chemistry laboratory data did not reveal any findings of clinical concern to the investigator. A Listing of Chemistry and Haematology Data for Subjects with at Least one Normal Range Abnormality is provided in Table Concomitant Medications Concomitant use of any prescription or non-prescription medication containing a corticosteroid, or any treatment that might potentially influence linear growth was not permitted during the study. The Relationship of ATC Level 1, Ingredients and Verbatim Text for concomitant medications taken during the study, is provided in Table Concomitant Medications Taken During the Run-in Period Forty-eight percent (48%) of subjects used concomitant medications during the Run-in Period (regardless of when they ceased, Table 6.23). The most common medications used concurrently during this period were allergen treatment for hyposensitisation (21%), terbutaline (10%), paracetamol (9%) and terbutaline sulphate (7%). The other medications recorded by the subjects during the Run-in Period constituted 2% incidence of concurrent use. A listing of all concomitant medications taken during the Run-in period is provided in Table Concomitant Medications Taken During the Treatment Period and Washout Regardless of when concomitant medications were commenced, 43% of subjects used concomitant medications during the fluticasone furoate 100mcg QD Treatment Period, 47% of subjects used concomitant medications during the Placebo Treatment Period and 49% of subjects used these medications during the Placebo Washout Period (Table 6.24). The most common medications used concurrently during the fluticasone furoate 100mcg QD Treatment Period, Placebo Treatment Period and Washout Period, were allergen treatment for hyposensitisation (21%, 19% and 19% of subjects, respectively), terbutaline (12%, 14% and 14% of subjects, respectively), terbutaline sulphate (7%, 9% and 9% of subjects, respectively) and paracetamol (3%, 4% and 4% of subjects, respectively). The other medications recorded by the subjects constituted 2% incidence of concurrent use. A listing of all concomitant medications taken pre-study and during the run-in, Period 1, Period 2 and Washout is provided in Table Overall, the usage of the rescue medication loratadine, a non-prescription antihistamine, was lower when subjects were receiving active medication. On average, loratadine tablets and/or loratadine syrup, was used as allergy rescue medication on 48% and 36% of study days during Treatment Period 1 and Treatment Period 2, respectively, for subjects taking Placebo, and on 33.8% and 27.4% of study days during Treatment Period 46

48 CONFIDENTIAL 1 and Treatment Period 2, respectively, for subjects taking fluticasone furoate 100mcg QD. A summary of Daily Allergy Rescue Medication is provided in Table Treatment Compliance Nasal Spray Compliance Based on Diary Card Record To confirm compliance each day during the treatment period, subjects were asked to circle a response of Yes or No to a question on the diary card that asked if they had administered two sprays into each nostril that morning. The mean rate of treatment compliance based on subject s diary record for the Growth Population was 96% for both treatment groups in both treatment sequences (Table 7). The mean rate of treatment compliance in the fluticasone furoate 100mcg and in the Placebo Treatment groups was generally unaffected by the order of the treatment sequence. Overall, the majority of subjects in both treatment groups were 90% compliant with their treatment (89% for fluticasone furoate 100mcg QD and 94% for Placebo). The dates that were entered by the site were earlier than the date the subject was screened for the study. This error was not identified by data consistency checks prior to the database being frozen. As a result, the two erroneous dates were excluded from this subject s diary card data and they were not included in any summaries of medication compliance. Compliance data from subject diaries for the ITT population is provided in Table This was similar to that reported for the Growth Population. 47

49 Table 7 Summary of Treatment Compliance Based on Diary Card Record (Growth Population ) 48 Placebo (Run-in) (N= 53 ) FF 100mcg QD/Placebo (N= 27 ) Placebo/FF 100mcg QD (N= 26 ) Overall (N= 53 ) Placebo FF Placebo FF Placebo FF Compliance Rate (%) Mean (SD) 97.9 (4.68) 96.4 (6.92) 96.8 (7.43) 98.8 (2.79) 95.8 (6.97) 97.6 (5.40) 96.3 (7.16) Min Max Compliance Category, n (%) 90% - 100% 49 (92%) 24 (89%) 25 (93) 26 (100) 22 (85) 50 (94) 47 (89) 80 - <90% 4 (8%) 2 (7) 1 (4) 0 2 (8) 2 (4) 3 (6) <80% 0 1 (4) 1 (4) 0 2 (8) 1 (2) 3 (6) Source Data: Table 6.27 CONFIDENTIAL

50 CONFIDENTIAL Nasal Spray Compliance Based on Bottle Weights Mean and median dispensed nasal spray weights were similar between the two treatments at baseline, for both treatment sequences (Table 8). The mean and median total usage based on combined weight loss for all bottles dispensed and returned for each subject was similar between the Placebo and fluticasone furoate 100mcg QD treatment groups, for both treatment sequences. Mean and median total usage overall was also similar between Placebo and fluticasone furoate 100mcg QD, as were mean and median daily usage. Research was conducted by GSK Pharmaceutical Development to determine average weight loss from baseline for ten GW685698X (fluticasone furoate) aqueous nasal spray Placebo packs after six priming sprays and 84 additional sprays (Attachment 2). The total weight loss of 84 sprays after the priming sprays was = 4.789g. The daily mean weight loss (four sprays) of a nasal spray after the priming sprays was ( )/84*4 = 0.218g, based on the benchmark data. Mean daily weight loss for both the fluticasone furoate 100mcg QD (0.20g) and the Placebo (0.22g) treatment groups was close to the estimated benchmark mean daily usage (Table 8). A summary of Study Medication Usage Based on Nasal Device Weight Reduction is provided for the ITT population in Table A listing of compliance per subject is provided in Table No subjects reported nasal spray device malfunctions (Table 6.32). 49

51 Table 8 Summary of Treatment Compliance Based on Nasal Device Weight (Growth Population ) 50 FF 100mcg QD/Placebo (N= 27 ) Placebo/FF 100mcg QD (N= 26 ) TOTAL (N= 53 ) Placebo FF Placebo FF Placebo FF Dispensed Weight (g) Mean (SD) (0.378) (0.368) (0.358) (0.238) (0.365) (0.315) Median Min Max Total usage during treatment period (g) Mean (SD) 2.80 (0.708) 2.76 (0.820) 2.98 (0.784) 2.63 (0.750) 2.89 (0.744) 2.70 (0.782) Median Min Max Daily usage during treatment period (g/day) Mean (SD) 0.21 (0.048) 0.21 (0.052) 0.22 (0.055) 0.19 (0.050) 0.22 (0.051) 0.20 (0.051) Median Min Max Data Source: Table 6.28 CONFIDENTIAL

52 CONFIDENTIAL 7. SAFETY RESULTS 7.1. Extent of Exposure The mean number of days of exposure to Placebo during the Run-in was virtually identical between the two treatment sequences (Table 9). The mean number of days of exposure for subjects in the fluticasone furoate 100mcg QD /Placebo treatment sequence was 13.3 days for fluticasone furoate 100mcg QD, 13.3 days for Placebo and 13.8 days for Placebo Washout. The mean number of days of exposure for subjects in the Placebo/ fluticasone furoate 100mcg QD treatment sequence was 13.6 for fluticasone furoate 100mcg QD, 13.7 for Placebo and 13.5 for Placebo Washout. The proportions of subjects exposed to treatment with fluticasone furoate 100mcg QD were generally unaffected by the order of the treatment sequence: 41% and 59% of subjects were exposed to 8-13 days and days treatment respectively for the fluticasone furoate 100mcg QD/Placebo treatment sequence and 38% and 54% of subjects were exposed to 8-13 and days treatment respectively for the Placebo/fluticasone furoate 100mcg QD treatment sequence. All except one subject were exposed to 11 days of study medication in each treatment period (Run-in, Period 1, Washout and Period 2) (Table 7.3). A Summary of exposure to Study Drug in the ITT population is provided in Table 7.2. This was similar to the exposure in the Growth Population. A subject Listing of Exposure to Study Drug is provided in Table

53 Table 9 Summary of Extent of Exposure to Study Medication (Growth Population ) 52 Overall Sequence: FF 100mcg QD/Placebo Sequence: Placebo/FF 100mcg QD Run-in (N= 53) Placebo (N= 27) FF 100mcg QD (N= 27) Washout (N= 27) Placebo (N= 26) FF 100mcg QD (N= 26) Washout (N= 26) Number of Subjects, n (%) 1-7 days days 14 (26) 12 (44) 11 (41) 9 (33) 9 (35) 10 (38) 10 (38) days 37 (70) 14 (52) 16 (59) 15 (56) 16 (62) 14 (54) 14 (54) >16 days 2 (4) 1 (4) 0 3 (11) 1 (4) 2 (8) 2 (8) Exposure (days) Mean SD Median Min-Max Source Data: Table 7.1 CONFIDENTIAL

54 CONFIDENTIAL 7.2. Primary Safety Results The primary safety endpoint was the mean growth rate (mm/wk) in lower-leg length, as determined by knemometry, over a two-week treatment period with fluticasone furoate nasal spray 100mcg QD versus a two-week treatment period with Placebo nasal spray. Baseline mean lower-leg growth rates were similar between the two treatment sequences (0.40mm/wk for fluticasone furoate 100mcg QD/Placebo treatment sequence and 0.38mm/wk for Placebo/fluticasone furoate 100mcg QD treatment sequence (Table 10). When treated with fluticasone furoate 100mcg QD, subjects had similar mean rates of growth, whether they were treated with fluticasone furoate 100mcg QD during Treatment Period 1 (0.44mm/wk) or during Treatment Period 2 (0.39mm/wk). Similarly, when treated with Placebo, subjects had similar rates of growth regardless of whether they were treated with Placebo during Treatment Period 1 (0.45mm/wk) or Treatment Period 2 (0.40mm/wk). Washout growth rates for the two treatment sequences were also similar (0.45mm/wk for fluticasone furoate 100mcg QD/Placebo sequence and 0.40mm/wk for the Placebo/fluticasone furoate 100 mcg QD sequence) (Table 10). Mean lower-leg growth rate was 0.40mm/wk for the fluticasone furoate 100mcg QD group and 0.42mm/wk for the Placebo group. The difference in growth rates between the fluticasone furoate 100mcg QD and Placebo treatments was mm/wk (95% CI: [-0.13, 0.10]) (Table 10). The lower limit of the 95% CI for the treatment difference was -0.13mm/wk, which was greater than the non-inferiority margin of -0.20mm/wk, therefore confirming that fluticasone furoate nasal spray 100mcg QD was non-inferior to Placebo in terms of an effect on lower-leg growth rate. Figure 2 shows a box plot of lower-leg growth rates for each treatment sequence and overall for both treatments. This plot illustrates the similarity of growth rates for the two treatments. For the Placebo/fluticasone furoate 100mcg QD treatment sequence and for the treatments overall, there was a greater spread of data around the mean in the fluticasone furoate 100mcg QD treatment group. However, the standard error of the mean (SE) for fluticasone furoate 100mcg QD for Treatment Period 2 (0.078) was similar to the sequence s Run-in period SE (0.066) (see Table 10). In addition, the range of lower-leg growth rates for Treatment Period 2 (fluticasone furoate 100mcg QD: ) was similar to those observed during the Run-in period ( ) and the Washout period ( ) (Figure 3). The distribution of growth rates, according to the percentage of subjects in each growth rate category, was generally similar between treatment groups in both sequences (Figure 4). A scatter plot of lower-leg growth rates (Treatment Period 1 vs Treatment Period 2) is provided for the Growth Population in Figure 5. This plot illustrates the relationship 53

55 CONFIDENTIAL between the lower-leg growth rate (mm/wk) and each treatment period for each subject. Each point plotted represents one subject. A listing of knemometry data is provided in Table 7.8. Histograms of lower-leg growth rate by treatment overall are presented in Figure

56 CONFIDENTIAL Table 10 Summary of Lower-Leg Growth Rate (mm/wk) (Growth Population - ) Placebo (N= 53) FF 100mcg QD (N= 53) Raw Change in Rate 1 Raw Change in Rate 1 Baseline (Run-in) n Mean (SE) 0.38 (0.066) (0.042) - Median Min Max Treatment Period 1 n Mean (SE) 0.45 (0.046) 0.07 (0.085) 0.44 (0.059) 0.04 (0.085) Median Min Max Washout n Mean (SE) 0.40 (0.059) 0.02 (0.088) 0.45 (0.065) 0.05 (0.073) Median Min Max Treatment Period 2 n Mean (SE) 0.40 (0.050) 0.00 (0.065) 0.39 (0.078) 0.01 (0.113) Median Min Max Comparison against Placebo n LS Mean (SE) 0.42 (0.04) 0.40 (0.04) LS Mean Difference p-value against Placebo 2 95% C.I , 0.10 Source Data: Table 7.4, Table Change calculated relative to baseline rate. 2. ANCOVA adjusted for baseline lower-leg growth rate, age and gender. Treatment and period included as fixed effects and subject included as a random effect. Note: for ease of reporting, washout and baseline data are both displayed under the treatment for period 1, although baseline (run-in) growth rate was used as a covariate in calculating mean growth rates in both Period 1 and Period 2. SE = Standard error; LS = Least square; CI = Confidence Interval ; LS mean Difference = LS mean Change in active LS mean Change in Placebo 55

57 Figure 2 Lower-Leg Growth Rate (mm/wk) (Growth Population ) 56 Source Data: Figure 7.7 Description of box plot: the bottom and top edges of the box represent the sample 25th and 75th percentiles. The horizontal line represents the sample median and the plus sign (+) represents the sample mean. The central vertical lines or whiskers, extend from the box as far as the data extend, to a distance of at most 1.5 inter-quartile ranges (an inter-quartile range being the distance between the 25th and the 75th sample percentiles). Any value more extreme than this, was marked with a box and labeled with the subject number. CONFIDENTIAL

58 CONFIDENTIAL Figure 3 Lower-Leg Growth Rate (mm/wk, Run-in and Washout Periods) (Growth Population ) Source Data: Figure 7. 9 Figure 4 Lower-Leg Growth Rates (mm/wk, Treatment Period 1 vs Treatment Period 2) (Growth Population ) Source Data: Figure

59 CONFIDENTIAL Figure 5 Lower-Leg Growth Rates for Each Subject (mm/wk) (Growth Population ) Source Data: Figure 7.1 An analysis of the primary safety endpoint was also performed in the ITT population. Results in the ITT population were supportive of those observed in the Growth Population (Treatment difference:-0.013mm/wk; 95% CI [-0.12, 0.10]) (Table 11). Results are illustrated in Figure 6, Figure 7 and Figure 8). Histograms of lower-leg growth rate by treatment overall and for the Run-in and Washout Periods are presented in Figure 7.4 and Figure

60 CONFIDENTIAL Table 11 Summary of Lower-Leg Growth Rate (mm/wk) (ITT Population ) Placebo (N= 57) FF 100mcg QD (N= 58) Raw Change in Rate 1 Raw Change in Rate 1 Baseline (Run-in) n Mean (SE) 0.34 (0.066) 0.40 (0.039) Median Min Max Treatment Period 1 n Mean (SE) 0.43 (0.044) 0.09 (0.078) 0.42 (0.057) 0.02 (0.080) Median Min Max Washout n Mean (SE) 0.42 (0.055) 0.08 (0.088) 0.46 (0.064) 0.06 (0.071) Median Min Max Treatment Period 2 n Mean (SE) 0.41 (0.048) 0.01 (0.063) 0.39 (0.072) 0.05 (0.109) Median Min Max Comparison against Placebo n LS Mean (SE) 0.41 (0.04) 0.40 (0.04) LS Mean Difference p-value vs. Placebo % C.I , 0.10 Source Data: Table 7.6, Table Change calculated relative to baseline rate. 2. ANCOVA adjusted for baseline lower-leg growth rate, age and gender. Treatment and period included as fixed effects and subject included as a random effect. Note: for ease of reporting, washout and baseline data are both displayed under the treatment for period 1, although baseline (run-in) growth rate was used as a covariate in calculating mean growth rates in both Period 1 and Period 2. SE = Standard error; LS = Least square; CI = Confidence Interval LS mean Difference = LS mean Change in active LS mean Change in Placebo 59

61 Figure 6 Lower-Leg Growth Rate (mm/wk) (ITT Population ) 60 Source Data: Figure 7.8 Description of box plot: the bottom and top edges of the box represent the sample 25th and 75th percentiles. The horizontal line represents the sample median and the plus sign (+) represents the sample mean. The central vertical lines or whiskers, extend from the box as far as the data extend, to a distance of at most 1.5 inter-quartile ranges (an inter-quartile range being the distance between the 25th and the 75th sample percentiles). Any value more extreme than this was marked with a box and labeled with the subject number. CONFIDENTIAL

62 CONFIDENTIAL Figure 7 Lower-Leg Growth Rate (mm/wk) (ITT Population ) Source Data: Figure 7.6 Figure 8 Plot of Lower-Leg Growth Rates (mm/wk, Treatment Period 1 vs Treatment Period 2) (ITT Population ) Source Data: Figure

63 CONFIDENTIAL 7.3. Secondary Safety Results Secondary safety endpoints were: The frequency and type of clinical adverse events experienced during treatment Nasal examinations Vital signs (systolic and diastolic blood pressure, heart rate [pulse]) Adverse Events Table 7.9 provides the Relationship of Adverse Event System Organ Classes, Preferred Term and Verbatim text for the reporting of AEs. A Listing of Subject Numbers for Individual AEs is provided in Table A Listing of all AEs occurring post-randomisation is provided in Table AEs were counted only in the treatment period during which they started Run-in Period AEs Fourteen subjects (24%) reported AEs during the run-in period (Table 7.10). The most common AEs reported were epistaxis and headache (four subjects [7%] for each event). Pyrexia was reported by two subjects (3%). No other AEs that occurred during the run-in period were reported by more than one subject Treatment Period AEs During the treatment periods, similar numbers of subjects experienced AEs whilst receiving fluticasone furoate 100mcg QD and Placebo. Ten subjects (17%) experienced at least one AE whilst receiving fluticasone furoate 100mcg QD and 10 subjects (18%) whilst receiving Placebo during the treatment periods (Table 12). This excludes AEs with onset during the washout or post-treatment periods. The most common AE was nasopharyngitis, with greater incidence for Placebo (1 subject [2%] fluticasone furoate 100mcg QD, 4 subjects [7%] Placebo) (Table 12). The only AEs more common with fluticasone furoate 100mcg QD than with Placebo were epistaxis (3 subjects [5%] fluticasone furoate 100mcg QD, none Placebo) and cough (2 subjects [3%] fluticasone furoate 100mcg QD, 1 subject [2%] Placebo). 62

64 CONFIDENTIAL All three events of epistaxis were mild in intensity, resolved by treatment end and all were deemed related to study drug (Table 7.14). Table 12 Adverse Events Reported in Two or More Subjects in any Treatment Group during the Treatment Period (ITT Population ) Number (%) of Subjects Adverse Event Placebo (N= 57) FF 100mcg QD (N= 58) Subjects with any Adverse Event 10 (18) 10 (17) Nasopharyngitis (cold syndrome) 4 (7) 1 (2) Epistaxis 0 3 (5) Headache 3 (5) 1 (2) Cough 1 (2) 2 (3) Vomiting 3 (5) 0 Diarrhoea 2 (4) 0 Source Data: Table Post-Treatment Period AEs with onset occurring during the Washout and Follow-Up Periods are summarised in Table Three subjects (5%) who received fluticasone furoate 100mcg QD in the previous treatment period and six subjects (11%) who received Placebo in the previous treatment period experienced at least one AE during the post-treatment period (Table 7.12). Epistaxis (3 subjects [5%] for Placebo) and headache (2 subjects [3%] for fluticasone furoate 100mcg QD) were the most common AEs reported. The remaining events were reported by 2% of the subjects in both treatment groups Summary of Drug-Related Adverse Events during the Study Period A drug-related AE was an event recorded by the investigator as having a reasonable possibility of being caused by the study drug. The number and incidence of drug-related AEs with onset during the treatment and post-treatment periods are presented in Table The only reported AE deemed to be drug-related by the investigator was epistaxis, which was reported by three subjects (5%) whilst being treated with fluticasone furoate 100mcg QD and one subject (2%) whilst being treated with Placebo (Washout Period). All events of epistaxis were mild in intensity and resolved by study end. A listing of the drug-related AEs is presented in Table Serious Adverse Events No fatal or non-fatal serious adverse events were reported during the Run-in and postrandomisation periods (Table 7.17 and Table 7.18). 63

65 CONFIDENTIAL Adverse Events Leading to Premature Discontinuation of Investigational Product and/or Study No AEs causing early withdrawal from the study were reported (Table 7.19 and Table 7.20) Nasal Examination The investigators performed detailed nasal examinations of the turbinates, mucosa, septum, and nasal secretions at all study visits. A summary of the nasal examinations is provided in Table As noted in Table 7.21, the nostril was patent and the septum normal for all subjects at all study visits. No subjects had mucosal crusting at any visit. Regardless of the order of the treatment sequence, similar proportions of subjects in each treatment sequence had mucosal oedema and mucosal bleeding at each visit. More subjects in the Placebo/fluticasone furoate 100mcg QD treatment sequence had secretions at randomisation (Visit 2, 17%) compared with subjects in the fluticasone furoate 100mcg QD/Placebo treatment sequence (7%). More subjects in the fluticasone furoate 100 mcg QD/Placebo treatment sequence had secretions at the start of Washout (Visit 3, 14%), at the start of Period 2 (Visit 4, 29%) and at the final Visit 5 (21%), compared with subjects in the Placebo/fluticasone furoate 100mcg QD treatment sequence (3%, 17% and 17%, respectively. No subjects had ulcers during the study. One subject had a nasal polyp at Screening (Visit 1) which was not present at subsequent visits. A summary of the nasal examination shifts from baseline to Visit 3, Visit 4 and Visit 5 is provided in Table 13, Table 14 and Table 15. No subjects developed septum or turbinate ulcers during the study. Likewise, there were no changes from baseline in nostril patency, septum, mucosal crusting and nasal polyps at any time during the study. At the end of Treatment Period 1 (start of Washout), changes in mucosal oedema, bleeding and secretions were generally similar between the groups treated with fluticasone furoate 100mcg QD or Placebo (Table 13). At the Start of Period 2 (end of Washout), changes in mucosal oedema and bleeding were similar between the groups, while a greater percentage of subjects (29%) in the fluticasone furoate 100mcg QD/Placebo treatment sequence (i.e., subjects treated with fluticasone furoate 100mcg QD in Period 1) experienced a worsening in secretions compared with subjects in the Placebo/fluticasone furoate 100mcg QD treatment sequence (10%) (i.e., subjects treated with Placebo in Period 1) (Table 14). At the final visit (end of Period 2), the percentage of subjects with a worsening in secretions (18%) continued to be higher in the fluticasone furoate 100mcg QD/Placebo treatment sequence than in the Placebo/fluticasone furoate 100mcg QD sequence (10%) (Table 15). Additionally, at the final visit, a greater proportion of subjects (14%) in the Placebo/fluticasone furoate 100mcg QD treatment sequence (i.e., subjects treated with fluticasone furoate 100mcg QD in Period 2) experienced a worsening in mucosal oedema compared with subjects in the fluticasone furoate 100mcg QD/Placebo treatment sequence (7%) (i.e., subjects treated with Placebo in Period 2). 64

66 CONFIDENTIAL A Listing of Subjects with at Least One Abnormal Nasal Examination Result Post- Randomisation is provided in Table Table 13 Summary of Nasal Examination Shifts from Baseline to Visit 3 (Start of Washout) (ITT Population ) Nasal Examination Component n (%) Number (%) of Subjects FF 100mcg QD/ Placebo (N= 29) Placebo/ FF 100mcg QD (N= 29) Nostril Patent, n Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Septum Normal, n Improved 0 0 No Change 28 (100) 29 (100) Change 0 0 Mucosa Oedema, n Improved 7 (25) 7 (24) No Change 17 (61) 19 (66) Worsened 4 (14) 3 (10) Mucosa Crusting, n Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Mucosa Bleeding, n Improved 0 1 (3) No Change 26 (93) 27 (93) Worsened 2 (7) 1 (3) Secretions, n Improved 0 5 (17) No Change 26 (93) 23 (79) Worsened 2 (7) 1 (3) Ulcer Turbinates/Septum, n Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Polyposis Turbinates/Septum, n Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Source Data: Table

67 CONFIDENTIAL Table 14 Summary of Nasal Examination Shifts from Baseline to Visit 4 (Start of Period 2) (ITT Population ) Nasal Examination Component n (%) Number (%) of Subjects FF 100mcg QD/ Placebo (N= 29) Placebo/ FF 100mcg QD (N= 29) Nostril Patent, n Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Septum Normal, n Improved 0 0 No Change 28 (100) 29 (100) Change 0 0 Mucosa Oedema, n Improved 8 (29) 7 (24) No Change 19 (68) 20 (69) Worsened 1 (4) 2 (7) Mucosa Crusting, n Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Mucosa Bleeding, n Improved 0 1 (3) No Change 28 (100) 28 (97) Worsened 0 0 Secretions, n Improved 2 (7) 3 (10) No Change 18 (64) 23 (79) Worsened 8 (29) 3 (10) Ulcer Turbinates/Septum, n Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Polyposis Turbinates/Septum, n Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Source Data: Table

68 CONFIDENTIAL Table 15 Summary of Nasal Examination Shifts from Baseline to Visit 5 (Final Visit) (ITT Population ) Nasal Examination Component n (%) Number (%) of Subjects FF 100mcg QD/ Placebo (N= 29) Placebo/ FF 100mcg QD (N= 29) Nostril Patent Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Septum Normal Improved 0 0 No Change 28 (100) 29 (100) Change 0 0 Mucosa Oedema Improved 7 (25) 7 (24) No Change 19 (68) 18 (62) Worsened 2 (7) 4 (14) Mucosa Crusting Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Mucosa Bleeding Improved 0 1 (3) No Change 28 (100) 27 (93) Worsened 0 1 (3) Secretions Improved 1 (4) 3 (10) No Change 22 (79) 23 (79) Worsened 5 (18) 3 (10) Ulcer Turbinates/Septum Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Polyposis Turbinates/Septum Improved 0 0 No Change 28 (100) 29 (100) Worsened 0 0 Source Data: Table Vital Signs Vital signs (systolic blood pressure [sbp], diastolic blood pressure [dbp], and heart rate [HR]) were assessed at all visits. A Summary of Vital Signs is provided in Table There were no noticeable differences in mean sbp, dbp and HR between subjects in the 67

69 CONFIDENTIAL two treatment sequences at Screening, Baseline, Visit 3, Visit 4 or Visit 5. A subject Listing of Vital Signs in provided in Table Safety Conclusion(s) Fluticasone furoate nasal spray 100mcg QD was shown to be non-inferior to Placebo nasal spray based on the lower bound of the 95% CI being above the pre-specified non-inferiority margin of -0.20mm/wk in lower-leg growth rate. In the Growth Population, following two weeks of treatment, mean lower-leg growth rate was 0.40mm/wk for the fluticasone furoate nasal spray 100mcg QD group and 0.42mm/wk for the Placebo group, with a treatment difference of mm/wk (95% CI: [-0.13, 0.10]). Results in the ITT population were supportive of those in the Growth Population. Lower-leg growth rates in the ITT Population were 0.40mm/wk for fluticasone furoate 100mcg QD and 0.41mm/wk for Placebo, with a treatment difference of mm/wk (95% CI: [-0.12, 0.10]). Fluticasone furoate nasal spray 100mcg QD was well tolerated and was comparable to Placebo nasal spray with respect to the AE profile. There were no safety concerns in the study population as evaluated by nasal examination. 68

70 CONFIDENTIAL 8. DISCUSSION AND CONCLUSIONS 8.1. Discussion This randomised, double-blind, placebo-controlled, two-week crossover study was conducted to evaluate for any potential effect from treatment with fluticasone furoate nasal spray 100mcg once daily on short-term lower-leg growth rate in children aged 6 to 11 years with SAR and/or PAR. Fluticasone furoate nasal spray was administered at a dosage equivalent to the proposed adult labeled dose (100mcg QD) for SAR and PAR, which is also the highest dose studied in the paediatric clinical programme. Fluticasone furoate nasal spray 100mcg once-daily was non-inferior to Placebo on short-term lowerleg growth rate of pre-pubertal children with allergic rhinitis (treatment difference = mm/wk; 95% CI: [-0.13, 0.10]) and was well tolerated. Adequate corticosteroid levels are required for the maintenance of normal growth, but an excess of or a deficiency in corticosteroids in pathological states, e.g., adrenal hyperplasia and adrenal insufficiency, can lead to a reduction in growth rate. The use of exogenous corticosteroids can also result in a reduction in growth rate. The effect on growth appears to vary with the particular corticosteroid studied and the dose and route administered. The pharmacologically-relevant systemic corticosteroid exposure is determined by factors such as bioavailability, which also varies with the route of administration and the device or formulation, relative potency, clearance, and circulating unbound fraction [Daley-Yates, 2001]. Since the effect on growth has varied with the particular corticosteroid studied, the possibility of an effect must be explored as new compounds become available. For the intranasal, inhaled and oral routes, bioavailability is the most important factor that determines the potential for growth effects [Allen, 2000; Daley-Yates, 2004b]. More recently developed intranasal corticosteroids such as fluticasone propionate and mometasone furoate have very low systemic bioavailability due to negligible absorption directly from the nose [Daley-Yates, 2004a], lower systemic absorption from the gastrointestinal tract [Crim, 2001] and higher first pass inactivation by the liver; these corticosteroids have demonstrated no effect on growth rate [Scadding, 2001; Skoner, 2003; Allen, 2002; MacKenzie, 1994; Agertoft, 1999]. Corticosteroids with higher bioavailability such as intranasal beclomethasone dipropionate and inhaled budesonide have been shown to modestly reduce growth in long-term studies using stadiometry [Skoner, 2000; Berger, 2005; Doull, 1995]. The current study used knemometry to evaluate the effects of fluticasone furoate nasal spray on short-term lower-leg growth. Knemometry is well established as the preferred method for growth studies of short duration, as a sensitive measure of systemic activity of exogenous corticosteroids [Wolthers, 1990; Wolthers, 1992b; Wolthers, 1993b; Wolthers, 1995; Agertoft, 1997; Agertoft, 1999]. With repeated measurements, the knemometer is able to detect very small changes in lower-leg length over periods as short as one week [Wales, 1987; Wit, 1987; Hermanussen, 1988]. The knemometry design used in the present study has previously been shown to be a sufficiently sensitive tool to detect short-term significant systemic effects of exogenous corticosteroids such as 69

71 CONFIDENTIAL prednisolone (oral), beclomethasone dipropionate (inhaled) and budesonide (inhaled or intranasal) [Wolthers, 1990; Wolthers, 1993a; Wolthers, 1993b; Wolthers, 1994]. With the high sensitivity of this methodology, some researchers consider that projections of future growth based on knemometry findings probably exaggerate growth effects of exogenously administered corticosteroids. However, if an effect on lower-leg growth is not detected for a corticosteroid studied by knemometry, it is considered unlikely that the study drug, administered at the same dose, will cause an adverse effect on growth when used for extended periods [Pedersen, 2001]. Following two weeks of treatment, mean lower-leg growth rate was 0.40mm/wk for the fluticasone furoate nasal spray 100mcg QD group and 0.42mm/wk for the Placebo group, with a treatment difference of mm/wk (95% CI: [-0.13, 0.10]). This is consistent with data obtained from the literature for other knemometry studies [Wolthers, 1993b; Heuck, 1997; Heuck, 1998; Schou, 2004], which have provided estimates of mean lowerleg growth rate for Placebo-treated subjects of 0.40mm/wk to 0.50mm/wk. Furthermore, a 50% or greater reduction in lower-leg growth rate is considered to represent a clinically significant effect [Skoner, 2003; Wolthers, 1990; Wolthers, 1991; Wolthers, 1992b; Wolthers, 1993a; Wolthers, 1993b]. Therefore, in the present study, fluticasone furoate 100mcg QD was considered to be non-inferior to Placebo with respect to lower-leg growth rate if the lower limit of the two-sided 95% confidence interval for the treatment difference (fluticasone furoate minus Placebo) was greater than or equal to -0.20mm/wk. This margin was chosen as it was expected to represent approximately 40-50% of the predicted Placebo growth rate (which was an accurate assumption in this study). The confidence interval for the difference in mean lower-leg growth rate between fluticasone furoate 100mcg QD and Placebo (CI: -0.13, 0.10 mm/wk) suggests that intranasal fluticasone furoate is unlikely to have a clinically relevant effect on lower-leg growth at a dosage of 100mcg QD. This study was adequately powered to detect any clinically-relevant changes in lower-leg growth. Those studies published in the literature which did demonstrate an effect on growth over a two-week period by knemometry were of similar design and sample size [Wolthers, 1990; Wolthers, 1993b; Agertoft, 1997; Pedersen, 2003]. In the present study, weekly lower-leg growth rates were similar to those observed in the literature for children of this age range (0.40 to 0.50mm/wk) [Ahmed, 1995; Wales, 1987; Wolthers, 1992a]. Baseline mean growth rate was 0.40mm/wk for children in the fluticasone furoate 100mcg QD/Placebo treatment sequence and 0.38mm/wk for children in the Placebo/fluticasone furoate 100mcg QD treatment sequence. When treated with fluticasone furoate nasal spray 100mcg QD, children had similar mean growth rates over the two-week period, whether they were treated before or after treatment with Placebo (0.44mm/wk and 0.39mm/wk, respectively). In the same way, when treated with Placebo, children had similar mean growth rates over the two-week period, whether they were treated before or after treatment with fluticasone furoate nasal spray 100mcg QD (0.45mm/wk and 0.40mm/wk, respectively). Variability in the present study was kept to a minimum by having the same technician perform all knemometry measurements. All measurements were performed in the afternoon/early evening, and within one to two hours of the Visit 1 assessment, in order 70

72 CONFIDENTIAL to minimise the diurnal variation in lower-leg length caused by changes in physical pressure on soft tissue [Hermanussen, 1988]. As in all knemometry studies, a number of outliers and negative values of lower-leg growth rate were reported in this study. When systematic influences on lower-leg length measurements such as diurnal variations, physical activity, spontaneous changes in weight and variation between observers are excluded, a day-to-day variation of up to 1.5mm may occur [Hermanussen, 1988]. The cause of this day to day variation has been suggested as due to soft tissue changes. Slight dehydration, changes in physical activity during the day and different degrees of loading of the knee immediately prior to measuring may explain some of the variability [Wales, 1987; Hermanussen, 1988]. Children 6 to 11 years of age comprised the population for this study. This range was selected because children of at least 6 years are more likely to comply with the requirements of the measuring procedure and because linear growth rate in this age range is relatively consistent [Karlberg, 2002; Liu, 2000]. The inclusion criteria in the present study permitted inclusion of children without asthma or with mild asthma only, in an effort to minimize any possible influence of poorly controlled asthma on growth, and of differential dropout rates. Indeed, no subjects discontinued the study due to asthma exacerbation. The use of the permitted rescue medication loratadine, a non-prescription antihistamine, was similar in both treatment groups for subjects in the fluticasone furoate 100mcg QD/Placebo treatment sequence (34% and 36% of study days, respectively); in the Placebo/fluticasone furoate 100mcg QD treatment sequence, it was more frequently used when subjects took Placebo (48% of study days) than when they took fluticasone furoate 100mcg QD (27% of study days). No adjustment was made in the primary analysis for rescue medication use, as loratadine is believed not to have any confounding effect on growth. Compliance to study medication was adequate as evidenced by subject diary card and bottle weight data. The secondary safety findings of this study show fluticasone furoate nasal spray 100mcg QD to be well tolerated. Epistaxis was the most common drug-related AE with a low incidence in both treatment groups. No SAEs or deaths were reported and no subjects withdrew due to AEs Conclusion The data from this study suggest that there is a very low potential for a clinically relevant effect from treatment with fluticasone furoate nasal spray 100mcg once daily on shortterm lower-leg growth rate in pre-pubertal children with allergic rhinitis. 71

73 CONFIDENTIAL 9. REFERENCES Agertoft L, Pedersen S. Short-term knemometry and urine cortisol excretion in children treated with fluticasone propionate and budesonide: a dose-response study. Eur Respir J 1997;10: Agertoft L, Pedersen S. Short-term lower-leg growth rate in children with rhinitis treated with intranasal mometasone furoate and budesonide. J Allergy Clin Immunol 1999;104: Agertoft L, Pedersen, S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;343: Ahmed SF, Wallace WHB, Kelnar CJH. Knemometry in childhood: a study to compare the precision of two different techniques. Annals of Human Biology 1995;22(3): Allen DB, Meltzer EO, Lemanske RF, Philpot E, Faris MA, Kral KM, Prillaman BA, Rickard KA. No Growth Suppression in Children Treated with the Maximum Recommended Dose of Fluticasone Propionate Aqueous Nasal Spray from one year. Allergy and Asthma Proc 2002;23: Allen DB. Systemic effects of intranasal steroids: An endocrinologist s perspective. J Allergy Clin Immunol, 2000;106:S179-S190. Berger WE. Budesonide inhalation suspension for the treatment of asthma in infants and children. Drugs, 2005;65(14): Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343: Crim C, Pierre LN, Daley-Yates PT. A review of the pharmacology and pharmacokinetics of inhaled fluticasone propionate and mometasone furoate. Clin Ther. 2001;23: Daley-Yates PT, Kunka RL, Shen Y, et al. Bioavailability of fluticasone propionate and mometasone furoate aqueous nasal sprays. Eur J Clin Pharmacol. 2004a; 60: Daley-Yates PT, Pierre LN. Pharmacokinetic and pharmacodynamic data for inhaled and intranasal corticosteroids reassessed using a physiological PK/PD model. Eur Respir J. 2001;18 (Suppl 33):147S. Abstract Daley-Yates PT, Richards DH. Relationship Between Systemic Corticosteroid Exposure and Growth Velocity: Development and Validation of a Pharmacokinetic/ Pharmacodynamic Model. Clinical Therapeutics 2004b;26(11): Doull IJM, Freezer NJ, Holgate ST. Growth of Prepubertal Children with Mild Asthma Treated with Inhaled Beclomethasone Dipropionate. Am J Respir Crit Care Med 1995;151:

74 CONFIDENTIAL GlaxoSmithKline Document Number GM2002/00324/00. Study FFR A randomised, double-blind, placebo-controlled, cross-over, dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of single and 7 days repeat intranasal doses of a micronised suspension formulation of GW685698X (50, 100, 200, 400, 800 µg) in healthy male subjects GlaxoSmithKline Document Number RM2004/00150/00. Study FFR A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multicentre, Study to Evaluate the Efficacy and Safety of Once Daily, Intranasal Administration of GW685698X Aqueous Nasal Spray 50 mcg, 100 mcg, 200 mcg, or 400 mcg for 14 days in Adult and Adolescent Subjects with Seasonal Allergic Rhinitis, 31 July GlaxoSmithKline Document Number RM2004/00454/01. Study FFR A randomized, double-blind, parallel group, placebo controlled, 6-week study of the effect of GW685698X aqueous nasal spray 100mcg QD on the hypothalamic pituitary adrenocortical (HPA) axis in children 2 to <12 years of age with perennial allergic rhinitis (PAR). GlaxoSmithKline Document Number RM2005/00272/00. Study FFR A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Safety and Efficacy of Once-Daily, Intranasal Administration of GW685698X Aqueous Nasal Spray 50mcg and 100mcg for 12 Weeks in Pediatric Subjects Ages 2 to <12 Years with Perennial Allergic Rhinitis (PAR). Global Initiative for Asthma (GINA) Guidelines, Available at Accessed September 28, Hermanussen M, Geiger-Benoit K, Burmeister J, et al. Knemometry in childhood: accuracy and standardization of a new technique of lower-leg length measurement. Ann Hum Biol 1988;15:1-16. Heuck C, Wolthers OD, Hansen M, Kollerup G. Short-term growth and collagen turnover in asthmatic adolescents treated with the inhaled glucocorticoid budesonide. Steroids 1997;62: Heuck C, Wolthers OD, Kollerup G, Hansen M, Teisner B. Adverse effects of inhaled budesonide (800µg) on growth and collagen turnover in children with asthma: a double blind comparison of once-daily versus twice-daily administration. J Ped 1998;133: Karlberg J. Secular Trends in Pubertal Development. Horm Res 2002;57(suppl 2): Liu YX, Albertsson-Wikland K, Karlberg J. New reference for the age at childhood onset of growth and secular trend in the timing of puberty in Swedish. Acta Paediatr 2000;89: MacKenzie C Knemometry 88(A):

75 CONFIDENTIAL Pedersen S, Agertoft L, Lee T, Staudinger H. Lower-leg growth in children with asthma during treatment with inhaled corticosteroids [abstract]. J Allergy Clin Immunol 2003;111(suppl):S269. Pedersen S. Do inhaled corticosteroids inhibit growth in children? Am J Respir Crit Care Med 2001;164: Scadding GK. Corticosteroids in the treatment of paediatric allergic rhinitis. J Allergy Clin Immunol 2001; 108;S Schenkel EJ, Skoner DP, Bronsky EA et al. Absence of Growth Retardation in Children With Perennial Allergic Rhinitis After One Year of Treatment With Mometasone Furoate Aqueous Nasal Spray. Pediatrics 2000;105(2). Schou AJ, AM Plomgaard, K Thomsen, Wolthers OD. Suppression of lower leg growth in children treated with inhaled glucocorticoids is not accompanied by reduced thickness of cutis or subcutis. Acta Paediatr 2004; 93 (5): Skoner DP, Gentile D, Angelini B, et al. The effects of triamcinolone acetonide and intranasal fluticasone propionate on short-term bone growth and HPA axis in children with allergic rhinitis. Ann Allergy Asthma Immunol 2003;90: Skoner DP, Rachelefsky GS, Meltzer EO, et al. Detection of growth suppression in children during treatment with intranasal beclomethasone dipropionate. Pediatrics [electronic pages] 105:e23, Tanner JM and Davies PS. Clinical longitudinal standards for height and height rate for North American Children, Journal of Pediatrics, 107: Task Force on Allergic Disorders. American Academy of Allergy, Asthma, and Immunology. The Allergy Report. Available at Accessed July 23, Wales JKH, Milner RDG. Knemometry in the assessment of linear growth. Arch Dis Child 1987;62: Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomised controlled trials. BMJ 1998;317: Wit JM, Kalsbeek EJ, Wijk-Hoek, et al. Assessment of the usefulness of weekly knemometric measurements in growth studies. Acta Paediatr Scand 1987;76: Wolthers OD, Konstantin-Hansen Karen, Pedersen S, Petersen K. Knemometry in the Assessement of Short-Term Linear Growth in a Population of Healthy School Children. Horm Res 1992a;37: Wolthers OD, Pedersen S. Controlled study of linear growth in asthmatic children during treatment with inhaled glucocorticosteroids. Pediatrics 1992b;

76 CONFIDENTIAL Wolthers OD, Pedersen S. Knemometric assessment of systemic activity of once daily intranasal dry-power budesomine in children. Allergy 1994;49: Wolthers OD, Pedersen S. Short-term growth during treatment with inhaled fluticasone propionate and beclomethasone dipropionate. Arch Dis Child, 1993b;68: Wolthers OD, Pedersen S. Growth of asthmatic children during treatment with budesonide: a double-blind trial. BMJ, 1991;303: Wolthers OD, Pedersen S. Measures of systemic activity of inhaled glucocorticoids in children: a comparison of urine cortisol excretion and knemometry. Respir Med 1995;89: Wolthers OD, Pedersen S. Short-term growth in children with allergic rhinitis treated with oral antihistamine, depot and intranasal glucocorticosteroids. Acta Paedriatr 1993a;82: Wolthers OD, Pedersen S. Short-term linear growth in asthmatic children during treatment with prednisolone. BMJ 1990; 301(6744): Wolthers OD. Methodological aspects of short-term knemometry in the assessment if exogenous glucocorticosteroid-induced growth suppression in children. Annals of Human Biology 1997; 24(6):

77 CONFIDENTIAL Study Population Data Source Tables Page Table 6.1 Summary of Screening Subject Disposition (All Subjects Screened Population) Table 6.2 Listing of Reasons for Screening Failure (All Subjects Screened Population) Table 6.3 Summary of End of Study Record (Intent-to-Treat Population) Table 6.4 Listing of End of Study Record (Intent-to-Treat Population) Table 6.5 Summary of Number of Subjects at Each Visit (Intent-to-Treat Population) Table 6.6 Summary of Inclusion/Exclusion Criteria Deviations (Intent-to-Treat Population) Table 6.7 Listing of Subjects with Inclusion/Exclusion Criteria Deviations (Intent-to-Treat Population) Table 6.8 Summary of Visit Spacing Relative to Protocol Specification (Intent-to-Treat Population) Table 6.9 Listing of Subjects for Whom the Treatment Blind was Broken During the Study (Intent-to-Treat Population) Table 6.10 Listing of Reasons for Exclusion from the Intent-to-Treat Population ( All Subjects Screened Population) Table 6.11 Listing of Reasons for Exclusion from the Growth Population (Intent-to-Treat Population) Table 6.12 Listing of Population Membership and Treatment Sequence Allocation (All Subjects Screened Population) Table 6.13 Summary of Demographic Characteristics Growth Population (Growth Population) Table 6.14 Summary of Demographic Characteristics Intent-to-Treat Population (Intent-to-Treat Population) Table 6.15 Listing of Demographic Characteristics (Intent-to-Treat Population) Table 6.16 Summary of Allergy History (Intent-to-Treat Population) Table 6.17 Listing of Allergy History (Intent-to-Treat Population)

78 CONFIDENTIAL Table 6.18 Summary of Current Medical Conditions (Intent-to-Treat Population) Table 6.19 Summary of Screening Laboratory Values (Intent-to-Treat Population) Table 6.20 Summary of Screening Abnormal Laboratory Values (Intent-to-Treat Population) Table 6.21 Listing of Screening Laboratory Data for Subjects with at Least one Normal Range Abnormality (Intent-to-Treat Population) Table 6.22 Relationship Between ATC Level 1, Ingredient and Verbatim Text (Intent-to-Treat Population) Table 6.23 Summary of Concomitant Medications During the Run-in Period by Ingredient and Ingredient Combination (Intent-to-Treat Population) Table 6.24 Summary of Concomitant Medications During the Treatment Period by Ingredient and Ingredient Combination (Intent-to-Treat Population) Table 6.25 Listing of Concomitant Medications (Intent-to-Treat Population). 231 Table 6.26 Summary of Daily Allergy Rescue Medication (Percentage of Days Used) (Intent-to-Treat Population) Table 6.27 Summary of Treatment Compliance on Nasal Spray Study Medication Based on Subject Diary Record Growth Population (Growth Population) Table 6.28 Summary of Study Medication Usage Based on Nasal Device Weight Growth Population (Growth Population) Table 6.29 Summary of Treatment Compliance on Nasal Spray Study Medication Based on Subject Diary Record Intent-to-Treat Population (Intent-to-Treat Population) Table 6.30 Summary of Study Medication Usage Based on Nasal Device Weight Intent-to-Treat Population (Intent-to-Treat Population) Table 6.31 Listing of Compliance (Intent-to-Treat Population) Table 6.32 Listing of Subjects with Nasal Spray Device Malfunction (Intent-to-Treat Population)

79 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: All Subjects Screened Table 6.1 Summary of Screening Subject Disposition Total (N=61) Subjects who were randomized Randomized and received at least one dose of study drug (ITT) 58(95%) Subjects who were screened but not randomized 3 (5%) Subject decided to withdraw from study 1 (2%) Did not fulfill eligibility criteria 2 (3%) CONFIDENTIAL 78

80 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: All Subjects Screened Table 6.2 Listing of Reasons for Screening Failure Inv. Subject Age (yr) Sex Ethnicity Reason This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 79

81 80 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.3 Summary of End of Study Record Total (N=58) Completion Status Completed 57 (98%) Prematurely withdrawn 1 (2%) Reason for Premature Withdrawal Adverse event 0 Lost to follow-up 0 Protocol violation 1 (2%) Subject decided to withdraw from the study 0 Lack of efficacy 0 Sponsor terminated study 0 Non-compliance 0 Did not meet treatment eligibility criteria 0 Investigation decision 0 Other 0 CONFIDENTIAL

82 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.4 Listing of End of Study Record Treatment at Date of Treatment Time of Premature Study Reason for Premature Inv. Subj. Sequence Period Withdrawal Withdrawal Day Withdrawal This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 81

83 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.5 Summary of Number of Subjects at Each Visit Total (N=58) Screening (Visit 1) 58 (100%) Randomization (Visit 2) 58 (100%) Visit 3 57 (98%) Visit 4 57 (98%) Visit 5 (Final Visit) 57 (98%) Early Withdrawal 1 (2%) Unscheduled Visit 1 (2%) CONFIDENTIAL 82

84 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.6 Summary of Inclusion/Exclusion Criteria Deviations No data to report CONFIDENTIAL 83

85 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.7 Listing of Subjects with Inclusion/Exclusion Criteria Deviations No data to report CONFIDENTIAL 84

86 85 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.8 Summary of Visit Spacing Relative to Protocol Specification Total Visit / Specified Window Actual (N=58) Randomization (Visit 2) / days after Screening Visit Early 0 (0%) On Target 57 (98%) Late 1 (2%) Visit 3 / days after Visit 2 Discontinued 1 (2%) Early 0 (0%) On Target 57 (98%) Late 0 (0%) Visit 4 / days after Visit 3 Discontinued 1 (2%) Early 0 (0%) On Target 57 (98%) Late 0 (0%) Visit 5 / days after Visit 4 Discontinued 1 (2%) Early 0 (0%) On Target 57 (98%) Late 0 (0%) CONFIDENTIAL

87 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.9 Listing of Subjects for Whom the Treatment Blind was Broken During the Study No data to report CONFIDENTIAL 86

88 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: All Subjects Screened Table 6.10 Listing of Reasons for Exclusion from the Intent-to-Treat Population Inv. Subject Age (yrs) [1] Sex Race Reason This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. 87 [1]: Age (yrs) calculated at Screening visit CONFIDENTIAL

89 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.11 Listing of Reasons for Exclusion from the Growth Population Inv. Subject Deviation text This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 88

90 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 4 Population: All Subjects Screened Table 6.12 Listing of Population Membership and Treatment Sequence Allocation Inv./ Member of Population? Subj./ Treatment Rand. Sequence All Subjects Number Allocation Screened Screen Failure Intent-to-Treat Growth This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 89

91 93 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Growth Table 6.13 Summary of Demographic Characteristics Growth Population Total (N=53) Age (yrs) n 53 Mean 9.0 SD 1.39 Median 9.0 Min. 6 Max. 11 Sex n 53 Female 18 (34%) Male 35 (66%) Race n 53 American Hispanic 1 (2%) Arabic/North African 0 Black 0 East & South East Asian 0 Japanese 0 South Asian 0 White/Caucasian 51 (96%) Other 1 (2%) Height (cm) n 53 Mean SD 9.69 Median Min. 113 Max. 155 CONFIDENTIAL

92 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 2 Population: Growth Table 6.13 Summary of Demographic Characteristics Growth Population Total (N=53) Weight (kg) n 53 Mean 33.1 SD 8.68 Median 32.2 Min. 19 Max. 54 CONFIDENTIAL 94

93 95 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Intent-to-Treat Table 6.14 Summary of Demographic Characteristics Intent-to-Treat Population Total (N=58) Age (yrs) n 58 Mean 9.1 SD 1.37 Median 9.0 Min. 6 Max. 11 Sex n 58 Female 19 (33%) Male 39 (67%) Race n 58 American Hispanic 1 (2%) Arabic/North African 0 Black 0 East & South East Asian 0 Japanese 0 South Asian 0 White/Caucasian 56 (97%) Other 1 (2%) Height (cm) n 58 Mean SD 9.81 Median Min. 113 Max. 157 CONFIDENTIAL

94 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 2 Population: Intent-to-Treat Table 6.14 Summary of Demographic Characteristics Intent-to-Treat Population Total (N=58) Weight (kg) n 58 Mean 33.3 SD 9.11 Median 32.0 Min. 19 Max. 59 CONFIDENTIAL 96

95 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 6 Population: Intent-to-Treat Table 6.15 Listing of Demographic Characteristics Treatment Assessment Date of Age Height Weight Inv. Subj. Sequence Date Birth (yrs) Sex Ethnicity Race (cm) (kg) This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 97

96 103 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.16 Summary of Allergy History Total (N=58) Duration of Disease n 58 < 1 year 0 >= 1 year to < 3 years 26 (45%) >= 3 years 32 (55%) History of SAR? n 58 No 32 (55%) Yes 26 (45%) History of PAR? n 58 No 21 (36%) Yes 37 (64%) History of Both? n 58 No 53 (91%) Yes 5 (9%) CONFIDENTIAL

97 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Intent-to-Treat Table 6.17 Listing of Allergy History Diagnosis of Rhinitis Inv. Subject Duration of Rhinitis SAR PAR This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 104

98 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.18 Summary of Current Medical Conditions Total Classification (N=58) Any condition 29 (50%) Psychiatric disorders 1 (2%) Respiratory, thoracic and mediastinal disorders 19 (33%) Skin and subcutaneous tissue disorders 7 (12%) General disorders and administration site conditions 2 (3%) Gastrointestinal disorders 1 (2%) CONFIDENTIAL 106

99 107 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Intent-to-Treat Table 6.19 Summary of Screening Laboratory Values Planned Lab Test N Relative Time n Mean SD Median Min. Max Albumin (G/L) 58 Screening Alkaline Phosphatase 58 Screening (IU/L) Alanine Amino Transferase 58 Screening (IU/L) Aspartate Amino 58 Screening Transferase (IU/L) Total Bilirubin (UMOL/L) 58 Screening Calcium (MMOL/L) 58 Screening Creatinine (UMOL/L) 58 Screening Glucose (MMOL/L) 58 Screening Potassium (MMOL/L) 58 Screening Sodium (MMOL/L) 58 Screening Total Protein (G/L) 58 Screening Urea (MMOL/L) 58 Screening Basophils (GI/L) 58 Screening Basophils (percentage) 58 Screening (%) CONFIDENTIAL

100 108 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 2 Population: Intent-to-Treat Table 6.19 Summary of Screening Laboratory Values Planned Lab Test N Relative Time n Mean SD Median Min. Max Eosinophils (GI/L) 58 Screening Eosinophils (percentage) 58 Screening (%) Hemoglobin (G/L) 58 Screening Hematocrit 58 Screening Lymphocytes (GI/L) 58 Screening Lymphocytes (percentage) 58 Screening (%) Monocytes (GI/L) 58 Screening Monocytes (percentage) 58 Screening (%) Segmented Neutrophils 58 Screening (GI/L) Total Neutrophils 58 Screening (percentage) (%) Platelet count (GI/L) 58 Screening Red Blood Cell Count 58 Screening (TI/L) White Blood Cell Count 58 Screening (GI/L) CONFIDENTIAL

101 109 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 5 Population: Intent-to-Treat Table 6.20 Summary of Screening Abnormal Laboratory Values Planned Normal Range Total Lab Test Relative Time Indicator (N=58) Albumin (G/L) Screening n 56 High 9 (16%) Normal 47 (84%) Low 0 Alkaline Phosphatase (IU/L) Screening n 56 High 0 Normal 56 (100%) Low 0 Alanine Amino Transferase (IU/L) Screening n 56 High 1 (2%) Normal 55 (98%) Low 0 Aspartate Amino Transferase (IU/L) Screening n 56 High 0 Normal 56 (100%) Low 0 Total Bilirubin (UMOL/L) Screening n 56 High 0 Normal 56 (100%) Low 0 Calcium (MMOL/L) Screening n 56 High 4 (7%) Normal 52 (93%) Low 0 CONFIDENTIAL

102 110 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 5 Population: Intent-to-Treat Table 6.20 Summary of Screening Abnormal Laboratory Values Planned Normal Range Total Lab Test Relative Time Indicator (N=58) Creatinine (UMOL/L) Screening n 56 High 0 Normal 56 (100%) Low 0 Glucose (MMOL/L) Screening n 56 High 3 (5%) Normal 53 (95%) Low 0 Potassium (MMOL/L) Screening n 56 High 0 Normal 56 (100%) Low 0 Sodium (MMOL/L) Screening n 56 High 1 (2%) Normal 55 (98%) Low 0 Total Protein (G/L) Screening n 56 High 0 Normal 56 (100%) Low 0 Urea (MMOL/L) Screening n 56 High 2 (4%) Normal 54 (96%) Low 0 CONFIDENTIAL

103 111 Protocol: (Fluticasone Furoate Nasal Spray) Page 3 of 5 Population: Intent-to-Treat Table 6.20 Summary of Screening Abnormal Laboratory Values Planned Normal Range Total Lab Test Relative Time Indicator (N=58) Basophils (GI/L) Screening n 55 High 0 Normal 55 (100%) Low 0 Basophils (percentage) (%) Screening n 55 High 0 Normal 55 (100%) Low 0 Eosinophils (GI/L) Screening n 55 High 21 (38%) Normal 34 (62%) Low 0 Eosinophils (percentage) (%) Screening n 55 High 36 (65%) Normal 19 (35%) Low 0 Hemoglobin (G/L) Screening n 56 High 0 Normal 54 (96%) Low 2 (4%) Hematocrit Screening n 56 High 0 Normal 51 (91%) Low 5 (9%) CONFIDENTIAL

104 112 Protocol: (Fluticasone Furoate Nasal Spray) Page 4 of 5 Population: Intent-to-Treat Table 6.20 Summary of Screening Abnormal Laboratory Values Planned Normal Range Total Lab Test Relative Time Indicator (N=58) Lymphocytes (GI/L) Screening n 55 High 3 (5%) Normal 52 (95%) Low 0 Lymphocytes (percentage) (%) Screening n 55 High 1 (2%) Normal 51 (93%) Low 3 (5%) Monocytes (GI/L) Screening n 55 High 0 Normal 48 (87%) Low 7 (13%) Monocytes (percentage) (%) Screening n 55 High 0 Normal 55 (100%) Low 0 Segmented Neutrophils (GI/L) Screening n 55 High 1 (2%) Normal 52 (95%) Low 2 (4%) Total Neutrophils (percentage) (%) Screening n 55 High 10 (18%) Normal 45 (82%) Low 0 CONFIDENTIAL

105 113 Protocol: (Fluticasone Furoate Nasal Spray) Page 5 of 5 Population: Intent-to-Treat Table 6.20 Summary of Screening Abnormal Laboratory Values Planned Normal Range Total Lab Test Relative Time Indicator (N=58) Platelet count (GI/L) Screening n 56 High 6 (11%) Normal 50 (89%) Low 0 Red Blood Cell Count (TI/L) Screening n 56 High 0 Normal 54 (96%) Low 2 (4%) White Blood Cell Count (GI/L) Screening n 56 High 0 Normal 54 (96%) Low 2 (4%) CONFIDENTIAL

106 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 111 Population: Intent-to-Treat Table 6.21 Listing of Screening Laboratory Data for Subjects with at Least one Normal Range Abnormality Age(y)/ Planned NR Inv./ Sex/ Relative Study Converted Data Flag Subj. Race Lab Test (units) Time Date Day Value Normal Range [1] This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. 114 [1] NR for Normal Range flag; H=Above range, L=Below range CONFIDENTIAL

107 225 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 3 Population: Intent-to-Treat Table 6.22 Relationship Between ATC Level 1, Ingredient and Verbatim Text ATC level 1 text Ingredient Verbatim Text ALIMENTARY TRACT AND METABOLISM BUDESONIDE Pulmicort Rhinocort Spirocort HYDROCORTISONE BUTYRATE Locoid creme ANTIINFECTIVES FOR SYSTEMIC USE FUSIDATE SODIUM fucidin CARDIOVASCULAR SYSTEM NICOMOL Dexophan DERMATOLOGICALS BUDESONIDE Pulmicort Rhinocort Spirocort FLUTICASONE PROPIONATE Flixotide FUSIDATE SODIUM fucidin HYDROCORTISONE BUTYRATE MOMETASONE FUROATE Locoid creme Elocon Nasonex GENITO URINARY SYSTEM AND SEX IBUPROFEN Ibumetin HORMONES Ibuprofen MUSCULO-SKELETAL SYSTEM IBUPROFEN Ibumetin Ibuprofen TOLFENAMIC ACID Migea Retard NERVOUS SYSTEM IBUPROFEN Ibumetin Ibuprofen METHYLPHENIDATE HYDROCHLORIDE Ritalin PARACETAMOL Paracetamol pamol panodil CONFIDENTIAL

108 226 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 3 Population: Intent-to-Treat Table 6.22 Relationship Between ATC Level 1, Ingredient and Verbatim Text ATC level 1 text Ingredient Verbatim Text RESPIRATORY SYSTEM BUDESONIDE Pulmicort Rhinocort Spirocort FEXOFENADINE HYDROCHLORIDE Telfast FLUTICASONE PROPIONATE Flixotide MOMETASONE FUROATE Elocon Nasonex SALBUTAMOL Ventoline TERBUTALINE Bricanyl TERBUTALINE SULFATE Bricanyl Turbohaler Terbasmin Turbohaler XYLOMETAZOLINE HYDROCHLORIDE Zymelin SENSORY ORGANS FUSIDATE SODIUM fucidin XYLOMETAZOLINE HYDROCHLORIDE Zymelin SYSTEMIC HORMONAL PREPARATIONS, BUDESONIDE Pulmicort EXCL. SEX HORMONES Rhinocort Spirocort HYDROCORTISONE BUTYRATE Locoid creme VARIOUS ALLERGENS (NOS) Alk 108 Betula verruco 1ml Q6W-Q8W Alk 108 Betula verruco, 1ml Q6W to Q8W Alk 108 Betula verruco, 1ml Q6W-Q8W Alk 225 Phleum pratense 1ml Q6W-Q8W Alk 225 Phleum pratense, 1ml Q6W-Q8W Alk 225 Pleum pratens, 1ml Q6W-Q8W Alk 225 Pleum pratense 0,5ml Q6W-Q8W Alk 225 Pleum pratense 1ml. Q6W-Q8W CONFIDENTIAL

109 227 Protocol: (Fluticasone Furoate Nasal Spray) Page 3 of 3 Population: Intent-to-Treat Table 6.22 Relationship Between ATC Level 1, Ingredient and Verbatim Text ATC level 1 text Ingredient Verbatim Text VARIOUS ALLERGENS (NOS) Alk 225 Pleum pratense, 1ml Q6W-Q8W Alk 225 pleum pratense, 1ml Q6W-Q8W Alk 312 Artenisia vulg, 1ml Q6W-Q8W Alk 503 Dermatoph. Pte. 1ml Q6W-Q8W Alk 503 Dermatoph.Pte.1ml Q6W-Q8W Alk 503 Dermatophagoides Pteronyssinus,1ml Q6W-Q8W Alk 504 Dermatoph.fa, 1ml Q6W-Q8W Alk 553 hair from dogs, 1ml Q6W-Q8W Alk 555 hair from cats, 1ml Q6W-Q8W Alk Betula verrucu, 1ml Q6W-Q8W Alk pleum pratense, 1ml Q6W-Q8W CONFIDENTIAL

110 228 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.23 Summary of Concomitant Medications During the Run-in Period by Ingredient and Ingredient Combination ATC Level 1 Total Ingredient (N=58) Any Medication 28 (48%) VARIOUS Any Medication 12 (21%) ALLERGENS (NOS) 12 (21%) RESPIRATORY SYSTEM Any Medication 11 (19%) TERBUTALINE 6 (10%) TERBUTALINE SULFATE 4 (7%) SALBUTAMOL 1 (2%) NERVOUS SYSTEM Any Medication 6 (10%) PARACETAMOL 5 (9%) IBUPROFEN 1 (2%) METHYLPHENIDATE HYDROCHLORIDE 1 (2%) MUSCULO-SKELETAL SYSTEM Any Medication 2 (3%) IBUPROFEN 1 (2%) TOLFENAMIC ACID 1 (2%) CARDIOVASCULAR SYSTEM Any Medication 1 (2%) NICOMOL 1 (2%) GENITO URINARY SYSTEM AND SEX HORMONES Any Medication 1 (2%) IBUPROFEN 1 (2%) Note: A medication may be included in more than one ATC level category and appear more than once. CONFIDENTIAL

111 229 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Intent-to-Treat Table 6.24 Summary of Concomitant Medications During the Treatment Period by Ingredient and Ingredient Combination ATC Level 1 Placebo FF 100mcg QD Washout Ingredient (N=57) (N=58) (N=57) Any Medication 27 (47%) 25 (43%) 28 (49%) RESPIRATORY SYSTEM Any Medication 14 (25%) 13 (22%) 14 (25%) TERBUTALINE 8 (14%) 7 (12%) 8 (14%) TERBUTALINE SULFATE 5 (9%) 4 (7%) 5 (9%) SALBUTAMOL 1 (2%) 1 (2%) 1 (2%) XYLOMETAZOLINE HYDROCHLORIDE 1 (2%) 0 1 (2%) BUDESONIDE 0 1 (2%) 0 VARIOUS Any Medication 11 (19%) 12 (21%) 11 (19%) ALLERGENS (NOS) 11 (19%) 12 (21%) 11 (19%) NERVOUS SYSTEM Any Medication 3 (5%) 2 (3%) 3 (5%) PARACETAMOL 2 (4%) 2 (3%) 2 (4%) METHYLPHENIDATE HYDROCHLORIDE 1 (2%) 1 (2%) 1 (2%) IBUPROFEN 1 (2%) 0 0 DERMATOLOGICALS Any Medication 1 (2%) 1 (2%) 1 (2%) BUDESONIDE 0 1 (2%) 0 FUSIDATE SODIUM 1 (2%) 0 0 HYDROCORTISONE BUTYRATE (2%) ALIMENTARY TRACT AND METABOLISM Any Medication 0 1 (2%) 1 (2%) BUDESONIDE 0 1 (2%) 0 Note: A medication may be included in more than one ATC level category, appear more than once and appear in more than one treatment group. CONFIDENTIAL

112 230 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 2 Population: Intent-to-Treat Table 6.24 Summary of Concomitant Medications During the Treatment Period by Ingredient and Ingredient Combination ATC Level 1 Placebo FF 100mcg QD Washout Ingredient (N=57) (N=58) (N=57) HYDROCORTISONE BUTYRATE (2%) MUSCULO-SKELETAL SYSTEM Any Medication 2 (4%) 1 (2%) 1 (2%) TOLFENAMIC ACID 1 (2%) 1 (2%) 1 (2%) IBUPROFEN 1 (2%) 0 0 SENSORY ORGANS Any Medication 2 (4%) 0 1 (2%) XYLOMETAZOLINE HYDROCHLORIDE 1 (2%) 0 1 (2%) FUSIDATE SODIUM 1 (2%) 0 0 SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES Any Medication 0 1 (2%) 1 (2%) BUDESONIDE 0 1 (2%) 0 HYDROCORTISONE BUTYRATE (2%) ANTIINFECTIVES FOR SYSTEMIC USE Any Medication 1 (2%) 0 0 FUSIDATE SODIUM 1 (2%) 0 0 GENITO URINARY SYSTEM AND SEX HORMONES Any Medication 1 (2%) 0 0 IBUPROFEN 1 (2%) 0 0 Note: A medication may be included in more than one ATC level category, appear more than once and appear in more than one treatment group. CONFIDENTIAL

113 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 36 Population: Intent-to-Treat Table 6.25 Listing of Concomitant Medications ATC Level 1/ Dose/ Start Stop Inv./ Ingredient/ Units/ Date/ Date/ Started Ongoing Subj./ Period of Verbatim Text/ Freq/ Study Day/ Study Day/ Pre- Medi- Seq. Onset Indication Route Period Day Period Day Trial? cation? This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 231

114 267 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.26 Summary of Daily Allergy Rescue Medication (Percentage of Days Used) Placebo FF 100mcg QD Total (N=57) (N=58) (N=58) Run-in N 17 Mean (SD) 31.0 (30.69) Median 14.3 Min - Max Treatment Period 1 N Mean (SD) 48.0 (47.62) 33.8 (36.53) 38.9 (39.60) Median Min - Max Washout N 15 Mean (SD) 38.7 (33.49) Median 25.0 Min - Max Treatment Period 2 N Mean (SD) 36.0 (36.80) 27.4 (35.91) 32.8 (35.51) Median Min - Max CONFIDENTIAL

115 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Growth Table 6.27 Summary of Treatment Compliance on Nasal Spray Study Medication Based on Subject Diary Record Growth Population Compliance Rate for Placebo FF 100mcg QD Total Treatment Sequence Nasal Spray (%) (N=53) (N=53) (N=53) Placebo(Run-in) n 53 Mean (SD) 97.9 (4.68) Median Min - Max <80% 0 >=80%-<90% 4 (8%) >=90%-100% 49 (92%) GW685698X 100mcg QD/ n Placebo Mean (SD) 96.4 (6.92) 96.8 (7.43) 96.6 (6.62) Median Min - Max <80% 1 (4%) 1 (4%) 1 (4%) >=80%-<90% 2 (7%) 1 (4%) 1 (4%) >=90%-100% 24 (89%) 25 (93%) 25 (93%) CONFIDENTIAL

116 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 2 Population: Growth Table 6.27 Summary of Treatment Compliance on Nasal Spray Study Medication Based on Subject Diary Record Growth Population Compliance Rate for Placebo FF 100mcg QD Total Treatment Sequence Nasal Spray (%) (N=53) (N=53) (N=53) Placebo/ n GW685698X 100mcg QD Mean (SD) 98.8 (2.79) 95.8 (6.97) 97.3 (3.98) Median Min - Max <80% 0 2 (8%) 0 >=80%-<90% 0 2 (8%) 3 (12%) >=90%-100% 26 (100%) 22 (85%) 23 (88%) Overall (2 active n treatment periods) Mean (SD) 97.6 (5.40) 96.3 (7.16) 96.9 (5.45) Median Min - Max <80% 1 (2%) 3 (6%) 1 (2%) >=80%-<90% 2 (4%) 3 (6%) 4 (8%) >=90%-100% 50 (94%) 47 (89%) 48 (91%) CONFIDENTIAL

117 270 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 3 Population: Growth Table 6.28 Summary of Study Medication Usage Based on Nasal Device Weight Growth Population Treatment Sequence: FF 100mcg QD/ Placebo Placebo FF 100mcg QD Total (N=27) (N=27) (N=27) Dispensed Weight (g) No. of Devices Mean (SD) (0.378) (0.368) (0.547) Median Min - Max Total Usage During Treatment Period (g) No. of Devices Mean (SD) 2.80 (0.708) 2.76 (0.820) 2.78 (0.759) Median Min - Max Daily Usage During Treatment Period (g/day) No. of Devices Mean (SD) 0.21 (0.048) 0.21 (0.052) 0.21 (0.049) Median Min - Max CONFIDENTIAL

118 271 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 3 Population: Growth Table 6.28 Summary of Study Medication Usage Based on Nasal Device Weight Growth Population Treatment Sequence: Placebo/ FF 100mcg QD Placebo FF 100mcg QD Total (N=26) (N=26) (N=26) Dispensed Weight (g) No. of Devices Mean (SD) (0.358) (0.238) (0.572) Median Min - Max Total Usage During Treatment Period (g) No. of Devices Mean (SD) 2.98 (0.784) 2.63 (0.750) 2.81 (0.779) Median Min - Max Daily Usage During Treatment Period (g/day) No. of Devices Mean (SD) 0.22 (0.055) 0.19 (0.050) 0.21 (0.054) Median Min - Max CONFIDENTIAL

119 272 Protocol: (Fluticasone Furoate Nasal Spray) Page 3 of 3 Population: Growth Table 6.28 Summary of Study Medication Usage Based on Nasal Device Weight Growth Population Overall (2 active treatment periods) Placebo FF 100mcg QD Total (N=53) (N=53) (N=53) Dispensed Weight (g) No. of Devices Mean (SD) (0.365) (0.315) (0.557) Median Min - Max Total Usage During Treatment Period (g) No. of Devices Mean (SD) 2.89 (0.744) 2.70 (0.782) 2.79 (0.765) Median Min - Max Daily Usage During Treatment Period (g/day) No. of Devices Mean (SD) 0.22 (0.051) 0.20 (0.051) 0.21 (0.051) Median Min - Max CONFIDENTIAL

120 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Intent-to-Treat Table 6.29 Summary of Treatment Compliance on Nasal Spray Study Medication Based on Subject Diary Record Intent-to-Treat Population Compliance Rate for Placebo FF 100mcg QD Total Treatment Sequence Nasal Spray (%) (N=57) (N=58) (N=58) Placebo(Run-in) n 57 Mean (SD) 98.0 (4.54) Median Min - Max <80% 0 >=80%-<90% 4 (7%) >=90%-100% 53 (93%) GW685698X 100mcg QD/ n Placebo Mean (SD) 96.5 (6.82) 97.1 (7.21) 96.8 (6.44) Median Min - Max <80% 1 (4%) 1 (3%) 1 (3%) >=80%-<90% 2 (7%) 1 (3%) 1 (3%) >=90%-100% 25 (89%) 27 (93%) 27 (93%) CONFIDENTIAL

121 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 2 Population: Intent-to-Treat Table 6.29 Summary of Treatment Compliance on Nasal Spray Study Medication Based on Subject Diary Record Intent-to-Treat Population Compliance Rate for Placebo FF 100mcg QD Total Treatment Sequence Nasal Spray (%) (N=57) (N=58) (N=58) Placebo/ n GW685698X 100mcg QD Mean (SD) 99.0 (2.66) 96.2 (6.71) 97.6 (3.85) Median Min - Max <80% 0 2 (7%) 0 >=80%-<90% 0 2 (7%) 3 (10%) >=90%-100% 29 (100%) 25 (86%) 26 (90%) Overall (2 active n treatment periods) Mean (SD) 97.8 (5.24) 96.6 (6.92) 97.2 (5.27) Median Min - Max <80% 1 (2%) 3 (5%) 1 (2%) >=80%-<90% 2 (4%) 3 (5%) 4 (7%) >=90%-100% 54 (95%) 52 (90%) 53 (91%) CONFIDENTIAL

122 275 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 3 Population: Intent-to-Treat Table 6.30 Summary of Study Medication Usage Based on Nasal Device Weight Intent-to-Treat Population Treatment Sequence: FF 100mcg QD/ Placebo Placebo FF 100mcg QD Total (N=28) (N=29) (N=29) Dispensed Weight (g) No. of Devices Mean (SD) (0.377) (0.360) (0.550) Median Min - Max Total Usage During Treatment Period (g) No. of Devices Mean (SD) 2.88 (0.813) 2.93 (1.076) 2.90 (0.948) Median Min - Max Daily Usage During Treatment Period (g/day) No. of Devices Mean (SD) 0.22 (0.066) 0.22 (0.070) 0.22 (0.068) Median Min - Max CONFIDENTIAL

123 276 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 3 Population: Intent-to-Treat Table 6.30 Summary of Study Medication Usage Based on Nasal Device Weight Intent-to-Treat Population Treatment Sequence: Placebo/ FF 100mcg QD Placebo FF 100mcg QD Total (N=29) (N=29) (N=29) Dispensed Weight (g) No. of Devices Mean (SD) (0.341) (0.229) (0.574) Median Min - Max Total Usage During Treatment Period (g) No. of Devices Mean (SD) 3.08 (1.002) 2.71 (0.830) 2.89 (0.930) Median Min - Max Daily Usage During Treatment Period (g/day) No. of Devices Mean (SD) 0.23 (0.060) 0.20 (0.056) 0.21 (0.059) Median Min - Max CONFIDENTIAL

124 277 Protocol: (Fluticasone Furoate Nasal Spray) Page 3 of 3 Population: Intent-to-Treat Table 6.30 Summary of Study Medication Usage Based on Nasal Device Weight Intent-to-Treat Population Overall (2 active treatment periods) Placebo FF 100mcg QD Total (N=57) (N=58) (N=58) Dispensed Weight (g) No. of Devices Mean (SD) (0.357) (0.306) (0.560) Median Min - Max Total Usage During Treatment Period (g) No. of Devices Mean (SD) 2.98 (0.910) 2.82 (0.959) 2.90 (0.935) Median Min - Max Daily Usage During Treatment Period (g/day) No. of Devices Mean (SD) 0.22 (0.063) 0.21 (0.063) 0.22 (0.063) Median Min - Max CONFIDENTIAL

125 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 12 Population: Intent-to-Treat Table 6.31 Listing of Compliance Nasal Spray Inv./ Treatment Treatment Pack Treatment Treatment Weight (g) Subj. Sequence Period Number Start Date Stop Date Dispensed Returned Change This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 278

126 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 6.32 Listing of Subjects with Nasal Spray Device Malfunction No data to report CONFIDENTIAL 290

127 CONFIDENTIAL Safety Data Source Figures and Tables Page Figure 7.1 Plot of Lower Leg Growth Rates (mm/wk) Treatment Period 1 vs Treatment Period 2 Growth Population Figure 7.2 Plot of Lower Leg Growth Rates (mm/wk) Treatment Period 1 vs Treatment Period 2 Intent-to-Treat Population Figure 7.3 Histogram of Lower Leg Growth Rate by Treatment Growth Population Figure 7.4 Histogram of Lower Leg Growth Rate by Treatment Intent-to-Treat Population Figure 7.5 Histogram of Lower Leg Growth Rate (mm/wk) by Treatment Sequence and Treatment Growth Population Figure 7.6 Histogram of Lower Leg Growth Rate (mm/wk) by Treatment Sequence and Treatment Intent-to-Treat Population Figure 7.7 Boxplot of Lower Leg Growth (mm/wk) Growth Population Figure 7.8 Boxplot of Lower Leg Growth (mm/wk) Intent-to-Treat Population 300 Figure 7.9 Histogram of Lower Leg Growth Rate for Run-in and Washout Periods Figure 7.10 Histogram of Lower Leg Growth Rate for Run-in and Washout Periods Table 7.1 Summary of Exposure to Study Drug Growth Population (Growth Population) Table 7.2 Summary of Exposure to Study Drug Intent-to-Treat Population (Intent-to-Treat Population) Table 7.3 Listing of Exposure to Study Drug (Intent-to-Treat Population) Table 7.4 Summary of Mean Lower Leg Growth Rate (mm/wk) Growth Population (Growth Population) Table 7.5 Analysis of Mean Lower Leg Growth Rate (mm/wk) Growth Population (Growth Population) Table 7.6 Summary of Mean Lower Leg Growth Rate (mm/wk) Intent-to-Treat Population (Intent-to-Treat Population) Table 7.7 Analysis of Mean Lower Leg Growth Rate (mm/wk) Intent-to-Treat Population (Intent-to-Treat Population)

128 CONFIDENTIAL Table 7.8 Listing of Knemometry Data (Intent-to-Treat Population) Table 7.9 Relationship of Adverse Event System Organ Classes, Preferred Term and Verbatim Text (Intent-to-Treat Population) Table 7.10 Summary of All Adverse Events During The Run-In Period (Intent-to-Treat Population) Table 7.11 Summary of All Adverse Events During The Treatment Period (Intent-to-Treat Population) Table 7.12 Summary of All Adverse Events During The Post-Treatment Periods (Intent-to-Treat Population) Table 7.13 Listing of Subject Numbers for Individual Adverse Events (Intent-to-Treat Population) Table 7.14 Listing of All Adverse Events (Intent-to-Treat Population) Table 7.15 Summary of Drug Related Adverse Events Post Randomization (Intent-to-Treat Population) Table 7.16 Listing of Drug Related Adverse Events Post Randomization (Intent-to-Treat Population) Table 7.17 Listing of Serious Adverse Events During The Screen Period (Screen Failure Population) Table 7.18 Listing of Serious Adverse Events (Intent-to-Treat Population) Table 7.19 Summary of Adverse Events Causing Withdrawal From the Study (Intent-to-Treat Population) Table 7.20 Listing of Adverse Events Causing Withdrawal From The Study (Intent-to-Treat Population) Table 7.21 Summary of Nasal Examinations (Intent-to-Treat Population) Table 7.22 Summary of Nasal Examination Shifts from Baseline (Intent-to-Treat Population) Table 7.23 Listing of Subjects With at Least One Abnormal Nasal Examination Result Post-Randomization (Intent-to-Treat Population) Table 7.24 Summary of Vital Signs (Intent-to-Treat Population) Table 7.25 Listing of Vital Signs (Intent-to-Treat Population)

129 CONFIDENTIAL 293

130 CONFIDENTIAL 294

131 CONFIDENTIAL 295

132 CONFIDENTIAL 296

133 CONFIDENTIAL 297

134 CONFIDENTIAL 298

135 This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 299

136 This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 300

137 CONFIDENTIAL 301

138 CONFIDENTIAL 302

139 303 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 3 Population: Growth Table 7.1 Summary of Exposure to Study Drug Growth Population Treatment Sequence: FF 100mcg QD/ Placebo Run-in Placebo FF 100mcg QD Washout (N=27) (N=27) (N=27) (N=27) Number of subjects n (%) n days days 6 (22%) 12 (44%) 11 (41%) 9 (33%) days 20 (74%) 14 (52%) 16 (59%) 15 (56%) 17+ days 1 (4%) 1 (4%) 0 3 (11%) Exposure (days) n Mean SD Median Min Max CONFIDENTIAL

140 304 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 3 Population: Growth Table 7.1 Summary of Exposure to Study Drug Growth Population Treatment Sequence: Placebo/ FF 100mcg QD Run-in Placebo FF 100mcg QD Washout (N=26) (N=26) (N=26) (N=26) Number of subjects n (%) n days days 8 (31%) 9 (35%) 10 (38%) 10 (38%) days 17 (65%) 16 (62%) 14 (54%) 14 (54%) 17+ days 1 (4%) 1 (4%) 2 (8%) 2 (8%) Exposure (days) n Mean SD Median Min Max CONFIDENTIAL

141 305 Protocol: (Fluticasone Furoate Nasal Spray) Page 3 of 3 Population: Growth Table 7.1 Summary of Exposure to Study Drug Growth Population Overall (2 active treatment periods) Run-in Placebo FF 100mcg QD Washout (N=53) (N=53) (N=53) (N=53) Number of subjects n (%) n days days 14 (26%) 21 (40%) 21 (40%) 19 (36%) days 37 (70%) 30 (57%) 30 (57%) 29 (55%) 17+ days 2 (4%) 2 (4%) 2 (4%) 5 (9%) Exposure (days) n Mean SD Median Min Max CONFIDENTIAL

142 306 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 3 Population: Intent-to-Treat Table 7.2 Summary of Exposure to Study Drug Intent-to-Treat Population Treatment Sequence: FF 100mcg QD/ Placebo Run-in Placebo FF 100mcg QD Washout (N=29) (N=28) (N=29) (N=28) Number of subjects n (%) n days days 6 (21%) 13 (46%) 11 (38%) 9 (32%) days 22 (76%) 14 (50%) 18 (62%) 16 (57%) 17+ days 1 (3%) 1 (4%) 0 3 (11%) Exposure (days) n Mean SD Median Min Max CONFIDENTIAL

143 307 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 3 Population: Intent-to-Treat Table 7.2 Summary of Exposure to Study Drug Intent-to-Treat Population Treatment Sequence: Placebo/ FF 100mcg QD Run-in Placebo FF 100mcg QD Washout (N=29) (N=29) (N=29) (N=29) Number of subjects n (%) n days days 8 (28%) 10 (34%) 10 (34%) 12 (41%) days 19 (66%) 17 (59%) 17 (59%) 15 (52%) 17+ days 2 (7%) 2 (7%) 2 (7%) 2 (7%) Exposure (days) n Mean SD Median Min Max CONFIDENTIAL

144 308 Protocol: (Fluticasone Furoate Nasal Spray) Page 3 of 3 Population: Intent-to-Treat Table 7.2 Summary of Exposure to Study Drug Intent-to-Treat Population Overall (2 active treatment periods) Run-in Placebo FF 100mcg QD Washout (N=58) (N=57) (N=58) (N=57) Number of subjects n (%) n days days 14 (24%) 23 (40%) 21 (36%) 21 (37%) days 41 (71%) 31 (54%) 35 (60%) 31 (54%) 17+ days 3 (5%) 3 (5%) 2 (3%) 5 (9%) Exposure (days) n Mean SD Median Min Max CONFIDENTIAL

145 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 11 Population: Intent-to-Treat Table 7.3 Listing of Exposure to Study Drug Date Date Treatment Treatment Duration Subj. Tmt Seq. Period Dispensed Returned Start Date Stop Date (days) This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 309

146 320 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Growth Table 7.4 Summary of Mean Lower Leg Growth Rate (mm/wk) Growth Population Placebo FF 100mcg QD (N=53) (N=53) Change in Change in Raw Rate Rate [1] Raw Rate Rate [1] Baseline (Run-in) n Mean (Std Err) 0.38 (0.066) 0.40 (0.042) Median Min - Max Treatment Period 1 n Mean (Std Err) 0.45 (0.046) 0.07 (0.085) 0.44 (0.059) 0.04 (0.085) Median Min - Max Washout n Mean (Std Err) 0.40 (0.059) 0.02 (0.088) 0.45 (0.065) 0.05 (0.073) Median Min - Max Treatment Period 2 n Mean (Std Err) 0.40 (0.050) 0.00 (0.065) 0.39 (0.078) 0.01 (0.113) Median Min - Max Note: Washout and baseline data are both displayed under the treatment for period 1 [1] Change calculated relative to baseline rate CONFIDENTIAL

147 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Growth Table 7.5 Analysis of Mean Lower Leg Growth Rate (mm/wk) Growth Population Placebo FF 100mcg QD (N=53) (N=53) n LS Mean (Std Err) 0.42 (0.04) 0.40 (0.04) LS Mean Difference p-value vs. Placebo % C.I. (-0.13, 0.10) 321 Analysis of covariance adjusted for baseline lower leg growth rate, age and gender. Treatment and period included as fixed effects and subject included as a random effect. CONFIDENTIAL

148 322 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 7.6 Summary of Mean Lower Leg Growth Rate (mm/wk) Intent-to-Treat Population Placebo FF 100mcg QD (N=57) (N=58) Change in Change in Raw Rate Rate [1] Raw Rate Rate [1] Baseline (Run-in) n Mean (Std Err) 0.34 (0.066) 0.40 (0.039) Median Min - Max Treatment Period 1 n Mean (Std Err) 0.43 (0.044) 0.09 (0.078) 0.42 (0.057) 0.02 (0.080) Median Min - Max Washout n Mean (Std Err) 0.42 (0.055) 0.08 (0.088) 0.46 (0.064) 0.06 (0.071) Median Min - Max Treatment Period 2 n Mean (Std Err) 0.41 (0.048) 0.01 (0.063) 0.39 (0.072) 0.05 (0.109) Median Min - Max Note: Washout and baseline data are both displayed under the treatment for period 1 [1] Change calculated relative to baseline rate CONFIDENTIAL

149 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 7.7 Analysis of Mean Lower Leg Growth Rate (mm/wk) Intent-to-Treat Population Placebo FF 100mcg QD (N=57) (N=58) n LS Mean (Std Err) 0.41 (0.04) 0.40 (0.04) LS Mean Difference p-value vs. Placebo % C.I. (-0.12, 0.10) 323 Analysis of covariance adjusted for baseline lower leg growth rate, age and gender. Treatment and period included as fixed effects and subject included as a random effect. CONFIDENTIAL

150 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 29 Population: Intent-to-Treat Table 7.8 Listing of Knemometry Data Planned Inv./ Relative Period/ Raw Measurements (mm) Period Growth Subj. Time Treatment Average Rate (mm/wk) This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 324

151 353 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Intent-to-Treat Table 7.9 Relationship of Adverse Event System Organ Classes, Preferred Term and Verbatim Text System Organ Class Preferred Term Verbatim Text Ear and labyrinth disorders Ear pain Ear-ache Gastrointestinal disorders Abdominal pain upper Stomach-ache stomach-ache Diarrhoea Diarrhoea Toothache Toothache Vomiting Vomit throwing up General disorders and Pyrexia Fever administration site conditions fever Infections and infestations Furuncle Influenza Nasopharyngitis Viral rash furunculus Flue Common Cold Common cold common cold Exanthema due to virus Injury, poisoning and Limb injury Hurt the big toe procedural complications Musculoskeletal and Neck pain Pain in the right side of neck connective tissue disorders Pain in extremity pain in both lower legs pain in the legs in the evenings Nervous system disorders Dizziness Dizzy Headache Headache Headeche headache CONFIDENTIAL

152 354 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 2 Population: Intent-to-Treat Table 7.9 Relationship of Adverse Event System Organ Classes, Preferred Term and Verbatim Text System Organ Class Preferred Term Verbatim Text Reproductive system and Penile discharge purulent secretion from the breast disorders preputium Respiratory, thoracic and Asthma asthma mediastinal disorders Cough Cough cough Dyspnoea Dyspnoe Epistaxis Nosebleeding epistaxis nosebleeding Rhinorrhoea runny nose Sneezing Sneeze Throat irritation scratch in the throat Skin and subcutaneous tissue Eczema disorders Eczema eczema in the elbow flexures CONFIDENTIAL

153 355 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 7.10 Summary of All Adverse Events During The Run-In Period System Organ Class Run-in Preferred Term (N=58) ANY EVENT 14 (24%) Respiratory, thoracic and mediastinal disorders Any event 8 (14%) Epistaxis 4 (7%) Asthma 1 (2%) Cough 1 (2%) Rhinorrhoea 1 (2%) Sneezing 1 (2%) Nervous system disorders Any event 4 (7%) Headache 4 (7%) General disorders and administration site conditions Any event 2 (3%) Pyrexia 2 (3%) Gastrointestinal disorders Any event 1 (2%) Vomiting 1 (2%) Infections and infestations Any event 1 (2%) Nasopharyngitis 1 (2%) Musculoskeletal and connective tissue disorders Any event 1 (2%) Pain in extremity 1 (2%) CONFIDENTIAL

154 356 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Intent-to-Treat Table 7.11 Summary of All Adverse Events During The Treatment Period System Organ Class Placebo FF 100mcg QD Preferred Term (N=57) (N=58) ANY EVENT 10 (18%) 10 (17%) Respiratory, thoracic and mediastinal disorders Any event 1 (2%) 6 (10%) Cough 1 (2%) 2 (3%) Epistaxis 0 3 (5%) Dyspnoea 1 (2%) 0 Throat irritation 0 1 (2%) Infections and infestations Any event 4 (7%) 2 (3%) Nasopharyngitis 4 (7%) 1 (2%) Furuncle 0 1 (2%) Nervous system disorders Any event 3 (5%) 1 (2%) Headache 3 (5%) 1 (2%) Gastrointestinal disorders Any event 3 (5%) 1 (2%) Vomiting 3 (5%) 0 Abdominal pain upper 1 (2%) 1 (2%) Diarrhoea 2 (4%) 0 General disorders and administration site conditions Any event 1 (2%) 1 (2%) Pyrexia 1 (2%) 1 (2%) Musculoskeletal and connective tissue disorders Excludes adverse events started during washout or post-treatment CONFIDENTIAL

155 357 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 2 Population: Intent-to-Treat Table 7.11 Summary of All Adverse Events During The Treatment Period System Organ Class Placebo FF 100mcg QD Preferred Term (N=57) (N=58) Any event 1 (2%) 1 (2%) Neck pain 1 (2%) 0 Pain in extremity 0 1 (2%) Ear and labyrinth disorders Any event 1 (2%) 0 Ear pain 1 (2%) 0 Injury, poisoning and procedural complications Any event 0 1 (2%) Limb injury 0 1 (2%) Reproductive system and breast disorders Any event 1 (2%) 0 Penile discharge 1 (2%) 0 Skin and subcutaneous tissue disorders Any event 1 (2%) 0 Eczema 1 (2%) 0 Excludes adverse events started during washout or post-treatment CONFIDENTIAL

156 358 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Intent-to-Treat Table 7.12 Summary of All Adverse Events During The Post-Treatment Periods System Organ Class Placebo FF 100mcg QD Preferred Term (N=57) (N=58) ANY EVENT 6 (11%) 3 (5%) Respiratory, thoracic and mediastinal disorders Any event 4 (7%) 0 Epistaxis 3 (5%) 0 Cough 1 (2%) 0 Gastrointestinal disorders Any event 1 (2%) 2 (3%) Abdominal pain upper 1 (2%) 0 Toothache 0 1 (2%) Vomiting 0 1 (2%) Nervous system disorders Any event 1 (2%) 2 (3%) Headache 0 2 (3%) Dizziness 1 (2%) 0 General disorders and administration site conditions Any event 1 (2%) 1 (2%) Pyrexia 1 (2%) 1 (2%) Infections and infestations Any event 1 (2%) 1 (2%) Influenza 1 (2%) 0 Nasopharyngitis 0 1 (2%) Viral rash 1 (2%) 0 Skin and subcutaneous tissue disorders Includes adverse events started during washout or post-treatment CONFIDENTIAL

157 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 2 Population: Intent-to-Treat Table 7.12 Summary of All Adverse Events During The Post-Treatment Periods System Organ Class Placebo FF 100mcg QD Preferred Term (N=57) (N=58) Any event 1 (2%) 0 Eczema 1 (2%) Includes adverse events started during washout or post-treatment CONFIDENTIAL

158 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 3 Population: Intent-to-Treat Table 7.13 Listing of Subject Numbers for Individual Adverse Events No. System Organ Class with Preferred Term Treatment Group Event Subject Numbers This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 360

159 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 17 Population: Intent-to-Treat Table 7.14 Listing of All Adverse Events Outcome/ Onset Date/ Resolve Date/ Maximum Action Inv./ Treat Age(y)/ Duration/ Intensity/ Taken/ Subj./ ment/ Sex/ Preferred Term/ Onset Study Serious/ Relation to Seq. Period Race/ VERBATIM TEXT Day Withdrawal Study Drug This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 363

160 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 7.15 Summary of Drug Related Adverse Events Post Randomization System Organ Class Placebo FF 100mcg QD Preferred Term (N=57) (N=58) ANY EVENT 1 (2%) 3 (5%) Respiratory, thoracic and mediastinal disorders Any event 1 (2%) 3 (5%) Epistaxis 1 (2%) 3 (5%) CONFIDENTIAL 380

161 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 7.16 Listing of Drug Related Adverse Events Post Randomization Outcome/ Onset Date/ Resolve Date/ Maximum Action Inv./ Treat Age(y)/ Duration/ Intensity/ Taken/ Subj./ ment/ Sex/ Preferred Term/ Onset Study Serious/ Relation to Seq. Period Race/ VERBATIM TEXT Day Withdrawal Study Drug This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 381

162 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Screen Failure Table 7.17 Listing of Serious Adverse Events During The Screen Period No data to report CONFIDENTIAL 382

163 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 7.18 Listing of Serious Adverse Events No data to report CONFIDENTIAL 383

164 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 7.19 Summary of Adverse Events Causing Withdrawal From the Study No data to report CONFIDENTIAL 384

165 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 1 Population: Intent-to-Treat Table 7.20 Listing of Adverse Events Causing Withdrawal From The Study No data to report CONFIDENTIAL 385

166 386 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 9 Population: Intent-to-Treat Table 7.21 Summary of Nasal Examinations FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Visit (N=29) (N=29) Nostril Patent? Screening (Visit 1) n None 0 0 One Yes 0 0 Both Yes 29 (100%) 29 (100%) Randomization (Visit 2) n None 0 0 One Yes 0 0 Both Yes 29 (100%) 29 (100%) Start of Washout (Visit 3) n None 0 0 One Yes 0 0 Both Yes 28 (100%) 29 (100%) Start of Period 2 (Visit 4) n None 0 0 One Yes 0 0 Both Yes 28 (100%) 29 (100%) Final Visit (Visit 5) n None 0 0 One Yes 0 0 Both Yes 28 (100%) 29 (100%) CONFIDENTIAL

167 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 9 Population: Intent-to-Treat Table 7.21 Summary of Nasal Examinations FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Visit (N=29) (N=29) Nostril Patent? Early Withdrawal n 1 0 None 0 One Yes 0 Both Yes 1 (100%) 387 Septum Normal? Screening (Visit 1) n Yes 29 (100%) 29 (100%) No 0 0 Randomization (Visit 2) n Yes 29 (100%) 29 (100%) No 0 0 Start of Washout (Visit 3) n Yes 28 (100%) 29 (100%) No 0 0 Start of Period 2 (Visit 4) n Yes 28 (100%) 29 (100%) No 0 0 Final Visit (Visit 5) n Yes 28 (100%) 29 (100%) No 0 0 CONFIDENTIAL

168 Protocol: (Fluticasone Furoate Nasal Spray) Page 3 of 9 Population: Intent-to-Treat Table 7.21 Summary of Nasal Examinations FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Visit (N=29) (N=29) Septum Normal? Early Withdrawal n 1 0 Yes 1 (100%) No Mucosa Oedema? Screening (Visit 1) n Absent 18 (62%) 16 (55%) Present 11 (38%) 13 (45%) Randomization (Visit 2) n Absent 14 (48%) 17 (59%) Present 15 (52%) 12 (41%) Start of Washout (Visit 3) n Absent 16 (57%) 21 (72%) Present 12 (43%) 8 (28%) Start of Period 2 (Visit 4) n Absent 20 (71%) 22 (76%) Present 8 (29%) 7 (24%) Final Visit (Visit 5) n Absent 18 (64%) 20 (69%) Present 10 (36%) 9 (31%) CONFIDENTIAL

169 Protocol: (Fluticasone Furoate Nasal Spray) Page 4 of 9 Population: Intent-to-Treat Table 7.21 Summary of Nasal Examinations FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Visit (N=29) (N=29) Mucosa Oedema? Early Withdrawal n 1 0 Absent 1 (100%) Present Mucosa Crusting? Screening (Visit 1) n Absent 29 (100%) 29 (100%) Present 0 0 Randomization (Visit 2) n Absent 29 (100%) 29 (100%) Present 0 0 Start of Washout (Visit 3) n Absent 28 (100%) 29 (100%) Present 0 0 Start of Period 2 (Visit 4) n Absent 28 (100%) 29 (100%) Present 0 0 Final Visit (Visit 5) n Absent 28 (100%) 29 (100%) Present 0 0 CONFIDENTIAL

170 Protocol: (Fluticasone Furoate Nasal Spray) Page 5 of 9 Population: Intent-to-Treat Table 7.21 Summary of Nasal Examinations FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Visit (N=29) (N=29) Mucosa Crusting? Early Withdrawal n 1 0 Absent 1 (100%) Present Mucosa Bleeding? Screening (Visit 1) n Absent 28 (97%) 29 (100%) Present 1 (3%) 0 Randomization (Visit 2) n Absent 29 (100%) 28 (97%) Present 0 1 (3%) Start of Washout (Visit 3) n Absent 26 (93%) 28 (97%) Present 2 (7%) 1 (3%) Start of Period 2 (Visit 4) n Absent 28 (100%) 29 (100%) Present 0 0 Final Visit (Visit 5) n Absent 28 (100%) 28 (97%) Present 0 1 (3%) CONFIDENTIAL

171 Protocol: (Fluticasone Furoate Nasal Spray) Page 6 of 9 Population: Intent-to-Treat Table 7.21 Summary of Nasal Examinations FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Visit (N=29) (N=29) Mucosa Bleeding? Early Withdrawal n 1 0 Absent 1 (100%) Present Secretions? Screening (Visit 1) n Absent 26 (90%) 28 (97%) Present 3 (10%) 1 (3%) Randomization (Visit 2) n Absent 27 (93%) 24 (83%) Present 2 (7%) 5 (17%) Start of Washout (Visit 3) n Absent 24 (86%) 28 (97%) Present 4 (14%) 1 (3%) Start of Period 2 (Visit 4) n Absent 20 (71%) 24 (83%) Present 8 (29%) 5 (17%) Final Visit (Visit 5) n Absent 22 (79%) 24 (83%) Present 6 (21%) 5 (17%) CONFIDENTIAL

172 Protocol: (Fluticasone Furoate Nasal Spray) Page 7 of 9 Population: Intent-to-Treat Table 7.21 Summary of Nasal Examinations FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Visit (N=29) (N=29) Secretions? Early Withdrawal n 1 0 Absent 1 (100%) Present Ulcer Turbinates/Septum? Screening (Visit 1) n None 29 (100%) 29 (100%) Small/Large 0 0 Randomization (Visit 2) n None 29 (100%) 29 (100%) Small/Large 0 0 Start of Washout (Visit 3) n None 28 (100%) 29 (100%) Small/Large 0 0 Start of Period 2 (Visit 4) n None 28 (100%) 29 (100%) Small/Large 0 0 Final Visit (Visit 5) n None 28 (100%) 29 (100%) Small/Large 0 0 CONFIDENTIAL

173 Protocol: (Fluticasone Furoate Nasal Spray) Page 8 of 9 Population: Intent-to-Treat Table 7.21 Summary of Nasal Examinations FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Visit (N=29) (N=29) Ulcer Turbinates/Septum? Early Withdrawal n 1 0 None 1 (100%) Small/Large Polyposis Turbinates/Septum? Screening (Visit 1) n None 28 (97%) 29 (100%) Small/Large 1 (3%) 0 Randomization (Visit 2) n None 29 (100%) 29 (100%) Small/Large 0 0 Start of Washout (Visit 3) n None 28 (100%) 29 (100%) Small/Large 0 0 Start of Period 2 (Visit 4) n None 28 (100%) 29 (100%) Small/Large 0 0 Final Visit (Visit 5) n None 28 (100%) 29 (100%) Small/Large 0 0 CONFIDENTIAL

174 Protocol: (Fluticasone Furoate Nasal Spray) Page 9 of 9 Population: Intent-to-Treat Table 7.21 Summary of Nasal Examinations FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Visit (N=29) (N=29) Polyposis Turbinates/Septum? Early Withdrawal n 1 0 None 1 (100%) Small/Large 0 CONFIDENTIAL 394

175 395 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 6 Population: Intent-to-Treat Table 7.22 Summary of Nasal Examination Shifts from Baseline FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Shifts from Baseline to Visit 3 (Start of Washout) (N=29) (N=29) Nostril Patent [1] Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Septum Normal Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Mucosa Oedema Improved 7 (25%) 7 (24%) No Change 17 (61%) 19 (66%) Worsened 4 (14%) 3 (10%) Mucosa Crusting Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Mucosa Bleeding Improved 0 1 (3%) No Change 26 (93%) 27 (93%) Worsened 2 (7%) 1 (3%) Improved=Shift from present for any nostril at baseline to absent for both nostrils at endpoint Worsened=Shift from absent for both nostrils at baseline to present for any nostril at endpoint [1] Improved=Increase in number patencies; Worsened=Decrease in number of patencies CONFIDENTIAL

176 396 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 6 Population: Intent-to-Treat Table 7.22 Summary of Nasal Examination Shifts from Baseline FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Shifts from Baseline to Visit 3 (Start of Washout) (N=29) (N=29) Secretions Improved 0 5 (17%) No Change 26 (93%) 23 (79%) Worsened 2 (7%) 1 (3%) Ulcer Turbinates/Septum Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Polyposis Turbinates/Septum Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Improved=Shift from present for any nostril at baseline to absent for both nostrils at endpoint Worsened=Shift from absent for both nostrils at baseline to present for any nostril at endpoint [1] Improved=Increase in number patencies; Worsened=Decrease in number of patencies CONFIDENTIAL

177 397 Protocol: (Fluticasone Furoate Nasal Spray) Page 3 of 6 Population: Intent-to-Treat Table 7.22 Summary of Nasal Examination Shifts from Baseline FF 100mcg QD/ Placebo/ Shifts from Baseline to Visit 4 (Start of Period Placebo FF 100mcg QD 2) (N=29) (N=29) Nostril Patent [1] Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Septum Normal Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Mucosa Oedema Improved 8 (29%) 7 (24%) No Change 19 (68%) 20 (69%) Worsened 1 (4%) 2 (7%) Mucosa Crusting Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Mucosa Bleeding Improved 0 1 (3%) No Change 28 (100%) 28 (97%) Worsened 0 0 Improved=Shift from present for any nostril at baseline to absent for both nostrils at endpoint Worsened=Shift from absent for both nostrils at baseline to present for any nostril at endpoint [1] Improved=Increase in number patencies; Worsened=Decrease in number of patencies CONFIDENTIAL

178 398 Protocol: (Fluticasone Furoate Nasal Spray) Page 4 of 6 Population: Intent-to-Treat Table 7.22 Summary of Nasal Examination Shifts from Baseline FF 100mcg QD/ Placebo/ Shifts from Baseline to Visit 4 (Start of Period Placebo FF 100mcg QD 2) (N=29) (N=29) Secretions Improved 2 (7%) 3 (10%) No Change 18 (64%) 23 (79%) Worsened 8 (29%) 3 (10%) Ulcer Turbinates/Septum Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Polyposis Turbinates/Septum Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Improved=Shift from present for any nostril at baseline to absent for both nostrils at endpoint Worsened=Shift from absent for both nostrils at baseline to present for any nostril at endpoint [1] Improved=Increase in number patencies; Worsened=Decrease in number of patencies CONFIDENTIAL

179 399 Protocol: (Fluticasone Furoate Nasal Spray) Page 5 of 6 Population: Intent-to-Treat Table 7.22 Summary of Nasal Examination Shifts from Baseline FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Shifts from Baseline to Visit 5 (Final Visit) (N=29) (N=29) Nostril Patent [1] Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Septum Normal Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Mucosa Oedema Improved 7 (25%) 7 (24%) No Change 19 (68%) 18 (62%) Worsened 2 (7%) 4 (14%) Mucosa Crusting Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Mucosa Bleeding Improved 0 1 (3%) No Change 28 (100%) 27 (93%) Worsened 0 1 (3%) Improved=Shift from present for any nostril at baseline to absent for both nostrils at endpoint Worsened=Shift from absent for both nostrils at baseline to present for any nostril at endpoint [1] Improved=Increase in number patencies; Worsened=Decrease in number of patencies CONFIDENTIAL

180 400 Protocol: (Fluticasone Furoate Nasal Spray) Page 6 of 6 Population: Intent-to-Treat Table 7.22 Summary of Nasal Examination Shifts from Baseline FF 100mcg QD/ Placebo/ Placebo FF 100mcg QD Shifts from Baseline to Visit 5 (Final Visit) (N=29) (N=29) Secretions Improved 1 (4%) 3 (10%) No Change 22 (79%) 23 (79%) Worsened 5 (18%) 3 (10%) Ulcer Turbinates/Septum Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Polyposis Turbinates/Septum Improved 0 0 No Change 28 (100%) 29 (100%) Worsened 0 0 Improved=Shift from present for any nostril at baseline to absent for both nostrils at endpoint Worsened=Shift from absent for both nostrils at baseline to present for any nostril at endpoint [1] Improved=Increase in number patencies; Worsened=Decrease in number of patencies CONFIDENTIAL

181 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 85 Population: Intent-to-Treat Table 7.23 Listing of Subjects With at Least One Abnormal Nasal Examination Result Post-Randomization Treatment Sequence: FF 100mcg QD/ Placebo Inv./ Subj./ Age (y)/ Race/ Planned Relative Left Right Sex Ethnicity Time Parameter Result Result Result This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 401

182 486 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 2 Population: Intent-to-Treat Table 7.24 Summary of Vital Signs Treatment Planned Sequence N Relative Time n Mean SD Median Min. Max Systolic BP FF 100mcg Screening (Visit 1) (mmhg) QD/ Placebo 29 Randomization (Visit 2) Visit Visit Visit 5 (Final Visit) Early Withdrawal Placebo/ FF Screening (Visit 1) mcg QD 29 Randomization (Visit 2) Visit Visit Visit 5 (Final Visit) Diastolic BP FF 100mcg Screening (Visit 1) (mmhg) QD/ Placebo 29 Randomization (Visit 2) Visit Visit Visit 5 (Final Visit) Early Withdrawal Placebo/ FF Screening (Visit 1) mcg QD 29 Randomization (Visit 2) Visit Visit Visit 5 (Final Visit) CONFIDENTIAL

183 487 Protocol: (Fluticasone Furoate Nasal Spray) Page 2 of 2 Population: Intent-to-Treat Table 7.24 Summary of Vital Signs Treatment Planned Sequence N Relative Time n Mean SD Median Min. Max Heart rate FF 100mcg Screening (Visit 1) (beats/min) QD/ Placebo 29 Randomization (Visit 2) Visit Visit Visit 5 (Final Visit) Early Withdrawal Placebo/ FF Screening (Visit 1) mcg QD 29 Randomization (Visit 2) Visit Visit Visit 5 (Final Visit) CONFIDENTIAL

184 Protocol: (Fluticasone Furoate Nasal Spray) Page 1 of 25 Population: Intent-to-Treat Table 7.25 Listing of Vital Signs Systolic Diastolic Age(y)/ Planned Blood Blood Heart Inv./ Sex/ Treatment/ Relative Actual Study Pressure Pressure Rate Height Weight Subj. Race Period Time Date Day (mmhg) (mmhg) (bpm) (cm) (kg) This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register. CONFIDENTIAL 488

185 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 The GlaxoSmithKline group of companies Division: World Wide Development Retention Category: GRS019 Information Type: Reporting and Analysis Plan Title: Reporting and Analysis Plan for. A Randomized, Double-blind, Placebo-controlled, 2-Week Crossover, Knemometric Assessment of the Effect of Once Daily GW685698X Aqueous Nasal Spray 100 mcg on Short Term Growth in Children Ages 6 11 Years with Seasonal and/or Perennial Allergic Rhinitis Compound Number: GW685698X Effective Date: 01-JUL-2005 Description: This study is a double blind, randomized, placebo-controlled, crossover trial and will be conducted at one site in Denmark. The primary objective of the study is to determine the effect on lower leg growth of once-daily treatment with 100 mcg of intranasal GW685698X aqueous nasal spray versus placebo nasal spray in children ages 6 to 11 years with seasonal allergic rhinitis (SAR) and/or perennial allergic rhinitis (PAR). Males < 12 and pre-menarcheal females < 11 years of age who exhibit either a current level of symptoms that warrant treatment with an intranasal corticosteroid and/or expected symptoms during a majority of the study period will be eligible for the study. The primary safety endpoint will be the mean growth velocity (mm/wk) in lower leg growth, as determined by knemometry, over a 2-week treatment period with intranasal GW685698X aqueous nasal spray versus a 2-week treatment with placebo nasal spray. The secondary safety endpoints will be the frequency and type of clinical adverse events experienced during treatment, physical examination including gross nasal examination, and vital signs (systolic and diastolic blood pressure, pulse). Identifier/Version Number: GM2005/00115/00 Subject: Allermist, GW685698, rhinitis, growth, knemometry, paediatrics Author s Name, Title and Functional Area: Senior Statistician, BDS Statistics and Programming 1 513

186 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 The GlaxoSmithKline group of companies Approved by: Senior Statistician BDS Statistics and Programming, Respiratory Date Biostatistics and Programming Manager BDS Statistics and Programming, Respiratory Date Director Clinical Development MDC Clinical Respiratory EU Date Copyright 2005 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited

187 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 TABLE OF CONTENTS PAGE ABBREVIATIONS INTRODUCTION STUDY OBJECTIVE(S) AND ENDPOINT(S) Study Objective(s) Study Endpoint(s) Primary Safety Endpoint Secondary Safety Endpoints Statistical Hypotheses STUDY DESIGN PLANNED ANALYSES Interim Analyses Final Analysis SAMPLE SIZE CONSIDERATIONS ANALYSIS POPULATIONS Intent-To-Treat Population Growth Population All Subjects Screened Population Screen Failure Population TREATMENT COMPARISONS Data Display Treatment and Other Sub-group Descriptors GENERAL CONSIDERATIONS FOR DATA ANALYSES Multicentre Studies Other Strata and Covariates Examination of Subgroups Multiple Comparisons and Multiplicity DATA HANDLING CONVENTIONS Premature Withdrawal and Missing Data Derived and Transformed Data Calculation of Days On Treatment Calculation of percentage of days where allergy rescue medication is used Calculation of Lower Leg Growth Velocity Calculation of Treatment Compliance from Diary Card Calculation of Study Medication Usage Based on Nasal Spray Weight Extent of Exposure Assessment Windows Safety Data Adverse Events

188 CONFIDENTIAL CONFIDENTIAL GM2005/00115/ Values of Clinical Concern STUDY POPULATION Disposition of Subjects Protocol Deviations Demographic and Baseline Characteristics Concurrent Medications Treatment Compliance SAFETY ANALYSES Extent of Exposure Primary Safety Endpoint Adverse Events Deaths and Serious Adverse Events Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events Pregnancies Other Safety Measures Nasal Examination Vital Signs REFERENCES ATTACHMENTS Table of Contents for Data Display Specifications Study Population Safety Data Display Specifications

189 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 ABBREVIATIONS AE ANCOVA ATC CSR DBF DBR ecrf GSK ICH IDSL ITT RAP mcg MedDRA mm mm/wk PAR PT QD RAMOS SAE SAR SOC Adverse Event Analysis of Covariance Anatomic Therapeutic Chemical Clinical Study Report Database Freeze Database Release Electronic Case Report Form GlaxoSmithKline International Conference on Harmonisation International Data Standards Library Intent-To-Treat Reporting and Analysis Plan Micrograms Medical Dictionary for Regulatory Activities Millimeters Millimeters per week Perennial allergic rhinitis Preferred Term Once Daily Randomisation And Medication Ordering System Serious Adverse Event Seasonal allergic rhinitis System Organ Class Trademark Information Trademarks of the GlaxoSmithKline group of companies Trademarks not owned by the GlaxoSmithKline group of companies 5 517

190 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 1. INTRODUCTION This Reporting and Analysis Plan (RAP) describes in detail the statistical methods that will be used to summarise and analyse the demographic, safety and compliance data from the study for the purposes of submission to the relevant regulatory authorities. This RAP is provided for use by the project team members within GlaxoSmithKline (GSK). All decisions regarding analysis, as defined in this document, have been made prior to the unblinding of the study data. All study results will be included in a Clinical Study Report (CSR). 2. STUDY OBJECTIVE(S) AND ENDPOINT(S) 2.1. Study Objective(s) The primary objective of this study is to determine the effect on lower leg growth of treatment with 100mcg of intranasal GW685698X aqueous nasal spray once daily (QD) versus placebo nasal spray QD in children aged 6 to 12 years with seasonal allergic rhinitis (SAR) and/or perennial allergic rhinitis (PAR). The objective is to show that GW685698X 100mcg QD is non-inferior to placebo with respect to lower leg growth velocity Study Endpoint(s) Primary Safety Endpoint The primary safety endpoint is the mean growth velocity (mm/wk) in lower leg growth, as determined by knemometry, over a 2 week treatment period with intranasal GW685698X aqueous nasal spray versus a 2 week treatment period with placebo nasal spray Secondary Safety Endpoints Secondary safety endpoints will be: The frequency and type of clinical adverse events (AE) experienced during treatment Nasal examination Vital signs (systolic and diastolic blood pressure and heart rate [pulse]) 2.3. Statistical Hypotheses This study is designed to show that GW685698X 100mcg QD is non-inferior to placebo with respect to lower leg growth velocity

191 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 The hypotheses that correspond to this comparison are as follows: H 0 : µ µ PBO δ H 1 : µ µ PBO > δ Where µ 100 and µ PBO represent the mean growth velocity (mm/wk) over a 2 week treatment period for GW685698X 100mcg QD aqueous nasal spray and placebo treatment groups respectively. The pre-specified non-inferiority margin (δ) is mm/wk. Non-inferiority will be demonstrated if the lower limit of the confidence interval (1-sided 2.5% significance level) for mean difference in lower leg growth velocity of GW685698X versus placebo is greater than mm/wk. This confidence interval approach to the non-inferiority comparison is illustrated in Figure 1. Figure 1 Confidence Interval Approach to Non-inferiority Comparison of Mean Lower Leg Growth Velocity (mm/wk) GW685698X non-inferior to placebo GW685698X not noninferior to placebo Placebo δ 0 GW685698X Better Better Difference in mean lower leg growth rate (mm/wk) (GW685698X - Placebo) 3. STUDY DESIGN This is a randomised, double-blind, two period cross-over study comparing GW685698X 100mcg QD aqueous nasal spray with placebo. Full details of the study design, including all planned assessments, can be found in Section 4 of the Protocol [GlaxoSmithKline Document Number ZM2004/00069/00] and Protocol Amendment [GlaxoSmithKline Document Number ZM2004/00069/01]. Following a two week run-in period, during which subjects will receive single-blind (the investigator is unblended to the run-in and wash-out periods) placebo nasal spray QD, 7 519

192 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 subjects will be randomised at the baseline clinic visit (Visit 2) to one of the following treatment sequences: Double Blind Treatment Period 1 (2 weeks, Visit 2 Visit 3) Single Blind Wash-out period (2 weeks, Visit 3 Visit 4) Double Blind Treatment Period 2 (2 weeks, Visit 4 - Visit 5) Sequence A Sequence B GW685698X 100mcg aqueous nasal spray QD Placebo aqueous nasal spray QD Placebo aqueous nasal spray QD Placebo aqueous nasal spray QD GW685698X 100mcg aqueous nasal spray QD The randomisation was performed using the GSK randomisation system, RANDALL, employing an appropriate block size to try to ensure equal numbers of subjects are allocated to each sequence. 4. PLANNED ANALYSES A data look will be performed when between 30% and 70% of the data are available for analysis. This will be performed on blinded data using dummy treatment groups, and as such will not carry with it multiplicity issues. The purpose of the data look is to review the data displays to ensure that all necessary information will be available to write the CSR Interim Analyses No interim analysis is planned Final Analysis All planned analyses detailed in this RAP will be performed following unblinding of study treatments, which will follow database freeze (DBF). In line with the International Conference on Harmonisation (ICH) Guideline E9, Statistical Principles for Clinical Trials [European Agency for the Evaluation of Medicinal Products, 1998], membership of the analysis populations (see Section 6) will be determined using the rules set out in this document prior to unblinding the treatment sequence allocation

193 CONFIDENTIAL 5. SAMPLE SIZE CONSIDERATIONS CONFIDENTIAL GM2005/00115/00 The study randomisation is planned for equal allocation of subjects between two treatment sequences, as described in Section 3. Data from previous GSK studies and the literature for other knemometry studies gave estimates of mean lower leg growth velocity for placebo-treated subjects of 0.40 mm/wk to 0.50 mm/wk, and an estimate of the standard deviation of 0.30 mm/wk. As described in Section 2.3, GW685698X 100mcg QD is considered to be non-inferior to placebo with respect to lower leg growth velocity if the lower limit of the 1-sided 2.5% confidence interval for the treatment difference (GW685698X minus placebo) is greater than or equal to mm/wk (roughly 40-50% of the placebo growth velocity). Assuming normally distributed data and a true treatment difference (GW685698X minus placebo) of 0.0 mm/wk, 50 completed subjects (25 subjects per group) will provide at least 90% power. In anticipation of a drop-out rate of 10%, approximately 56 subjects will be randomised to achieve completion of at least 50 subjects. 6. ANALYSIS POPULATIONS The population used in each summary and/or analysis will be noted in the upper left hand corner of each data display, as per International Data Standards Library (IDSL) standards Intent-To-Treat Population The analysis of all safety data will be performed on the Intent-To-Treat (ITT) population, defined as all randomised subjects who receive at least one dose of study medication. Note that randomisation does not occur until Visit 2, so subjects who take the placebo spray during the run-in but are not subsequently randomised or take study medication will not be included in the ITT population. Unless otherwise specified, analyses based on the ITT population will include all available data for these subjects. This population will be the basis for all summaries, analyses, listings and figures of demographic and safety data. Subject profiles of all safety data will be produced for any subjects who inadvertently received the wrong study treatment at any point during the study. Prior to DBF and unblinding, treatment pack numbers as recorded in the electronic Case Report Form (ecrf) for each subject will be reconciled against records in the Randomisation and Medication Ordering System (RAMOS). If any subjects are found to have received an incorrect treatment pack then following unblinding the contents of the incorrect pack will be checked against what they were supposed to receive at that point in the study to determine whether an incorrect treatment was taken

194 CONFIDENTIAL CONFIDENTIAL GM2005/00115/ Growth Population The analysis of the primary endpoint will also be performed on the Growth population in addition to the ITT population. The Growth population will be of primary interest for this endpoint and the ITT used as supportive. The Growth population is defined to exclude from the ITT population subjects who do not have sufficient or reliable lower leg growth data in order to provide an estimate of lower leg growth velocity for both 2 week treatment periods (GW685698X and placebo), or subjects who have received any protocol prohibited medications that may affect short term growth (e.g. systemic or inhaled corticosteroid medications that have confounding effects on the interpretation of growth velocity). The Growth population is defined as the ITT population excluding subjects who have any one of the following: 1. Did not fulfil the inclusion, exclusion and randomisation criteria that are growth specific. Inclusion and exclusion criteria can be found in Section 5.2 of the protocol [GlaxoSmithKline Document Number ZM2004/00069/00] and protocol amendment 1 [GlaxoSmithKline Document Number ZM2004/00069/01]. Inclusion criteria deemed to be growth specific are criteria 1, 2, 3 and 5. Exclusion criteria deemed to be growth specific are criteria 1, 3, 6, 8, 9, 10 and Did not have growth assessment(s) by knemometry at any protocol planned assessment time point (e.g. lower leg growth velocity cannot be estimated for at least one treatment period). This includes any subjects who have at least one study visit which falls outside of the protocol defined visit windows (see Section 9.3). 3. Withdrawal from the study due to AE s related to major trauma to the legs, major surgery or severe dehydration. A by-subject listing of all adverse events experienced during the study will be reviewed to identify subjects in breach of this criterion prior to unblinding. 4. Received protocol prohibited medications (other than the study medication) prior to randomisation and during the study. See Section 8.2 of the protocol [GlaxoSmithKline Document Number ZM2004/00069/00] and protocol amendment 1 [GlaxoSmithKline Document Number ZM2004/00069/01] for the list of protocol prohibited medications. A by-subject listing of all concomitant medications taken during the study will be reviewed to identify subjects in breach of this criterion prior to unblinding. 5. A change in Tanner stage during the study. 6. Received incorrect study treatment at any point during the study. The Growth population will be used for summaries of demographic and baseline characteristics and summaries, figures and analysis of the primary safety endpoint. If the ITT population and the Growth population are identical then all outputs will only produced for the Intent-to-Treat population

195 CONFIDENTIAL 6.3. All Subjects Screened Population CONFIDENTIAL GM2005/00115/00 The All Subjects Screened population is defined as all subjects who are screened for inclusion in the study and assigned a subject number in Inform. Subject disposition will be summarised for this population Screen Failure Population The Screen Failure population is defined as all subjects screened for inclusion in the study who are discontinued from the study prior to randomisation, or subjects who are misrandomised and receive no administration of study drug. The reasons for withdrawal prior to randomisation and serious adverse events (SAE) during the screening period will be listed for this population. 7. TREATMENT COMPARISONS The primary comparison will be the non-inferiority comparison made on the mean lower leg growth velocity as measured by knemometry over the two week treatment periods, between GW685698X 100mcg QD and placebo. The Growth population will be of primary interest for this comparison and the ITT population used as supportive. The 95% confidence interval for the treatment difference (GW685698X minus placebo), derived from the model detailed in Section 11.2, will be used for the non-inferiority comparison (as described in Section 2.3). As the non-inferiority comparison is made by looking at the lower limit of the confidence interval only, the use of the 95% confidence interval for the treatment difference is equivalent to performing the non-inferiority comparison at a 1-sided 2.5% confidence level Data Display Treatment and Other Sub-group Descriptors Treatment groups will be labelled as follows: GW685698X 100mcg QD for the GW685698X 100mcg aqueous nasal spray treatment Placebo for the vehicle placebo treatment 8. GENERAL CONSIDERATIONS FOR DATA ANALYSES 8.1. Multicentre Studies This study is being conducted in one site in Denmark so there will be no need to group centres or adjust for centre in summaries and analyses

196 CONFIDENTIAL 8.2. Other Strata and Covariates CONFIDENTIAL GM2005/00115/00 The analysis of mean lower leg growth velocity will be adjusted for covariates of baseline lower leg growth velocity measured by knemometry (calculated based on knemometric measurements at Visits 1 and 2), age and gender, all of which are thought to have an influence on lower leg growth velocity. Period will be included in the model as a fixed effect to confirm the assumption of no period effect. Subject will be included in the model as a random effect. Due to the study design the washout period growth velocity is likely to be affected by carry-over from the first treatment period. As such the baseline lower leg growth velocity will be used as the covariate for both treatment periods. The analysis result on the primary endpoint will be based on the analysis model without carry over effect, a formal statistical test for carry-over will not be performed. In this type of two period cross-over design it is not possible to statistically distinguish carryover effect from a treatment-by-period interaction, meaning that any true carry-over effect cannot be reliably detected [Senn, 1993]. The tests for carry-over and the treatment-by-period interaction also lack power because the corresponding contrast is between subject. [European Agency for the Evaluation of Medicinal Products, 1998] The study has been designed to include a two week washout period between active treatment periods which previous studies have shown is sufficient for complete elimination of drug effect on lower leg growth by the start of the second treatment period Examination of Subgroups It is not planned to perform any subgroup summaries or analyses for this study Multiple Comparisons and Multiplicity As there is a single primary endpoint and no statistical testing is to be performed on the secondary endpoints no adjustments for multiple comparisons or multiplicity are required. 9. DATA HANDLING CONVENTIONS 9.1. Premature Withdrawal and Missing Data For any subject who prematurely withdraws from the study, all available data up to the time of discontinuation will be included in the ITT population. Any subject who has insufficient knemometry data to provide estimates of lower leg growth velocity for either of the two treatment periods will be excluded from the Growth population. As a model with subject as a random effect will be used to analyse mean lower leg growth velocity, no imputation will be required for missing data for the analysis on the ITT population

197 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 When knemometry data is available at an unscheduled visit which is within the visit window for a scheduled study visit, the unscheduled visit knemometry data may be used if the data is missing at the scheduled clinic visit. This applies to both the ITT and Growth Populations Derived and Transformed Data Calculation of Days On Treatment When calculating the number of days relative to the date of randomisation the date of Visit 2 (the randomisation visit) will be counted as Day 1. Days on treatment will be calculated as: Days on treatment = date of the event date of Visit When calculating the number of days relative to the start of a treatment period the treatment start date of the treatment taken during that period will be counted as Day 1. Period day will be calculated as: Period day = date of event treatment start date Calculation of percentage of days where allergy rescue medication is used For each period for each subject the percentage of days on which they use allergy rescue medication, as recorded on the DRC, will be calculated as: Allergy rescue medication = usage per period (%) # of days on which allergy rescue medication is used end date - start date of the period (days) Calculation of Lower Leg Growth Velocity 100 For each subject the lower leg growth velocity (millimetres per week (mm/wk)) is estimated as change in the lower leg length (millimetres (mm)) from beginning to end of each 2-week period of the study, divided by the time interval (number of days) between the two measurements, multiplied by 7, as follows: Change in lower leg length (mm) Lower leg growth rate (mm per week) = 7 end date - start date of the period (days) For each visit the lower leg length is defined as the average of 3 repeated knemometry measurements. If fewer than 3 knemometry measurements are available at a visit then the mean will not be calculated and the growth velocity for that period will therefore be missing

198 CONFIDENTIAL CONFIDENTIAL GM2005/00115/ Calculation of Treatment Compliance from Diary Card The number of doses of study drug taken during each of the double-blind 2-week treatment periods will be estimated based on information recorded by the subject on the diary card. Subjects will document their study medication compliance on the diary card by answering the question Did you spray 2 sprays of your medication in each nostril today?. Each occurrence of Yes in response to this question will count as one dose of study medication. Percent treatment compliance will be calculated for each subject as follows: number of doses used in period % treatment compliance = 100 expected # of doses used in period Where the number of doses used in a period is the number of Yes responses to the question Did you spray 2 sprays of your medication in each nostril today? across the days on-treatment in the period, i.e. missing reponses will be assumed to be No. Subjects are instructed to take the first dose of study medication for each period the day after the visit at which it is dispensed. The final dose of study medication is taken on the morning of the visit marking the end of the period. Treatment start and stop dates are collected in the ecrf for each period. As such the expected number of doses taken in a period is calculated as follow: Expected # of doses used in period = (treatment stop date treatment start date) Calculation of Study Medication Usage Based on Nasal Spray Weight The difference in the recorded weight will be utilized to gain a gross determination of study medication usage. For each subject, the total amount of study medication (nasal spray) used during each treatment period is defined as the total weight reduction (g) from all nasal spray(s) that have been dispensed to this subject during the period and returned to the site for weighing. If any dispense or return weights are missing for any nasal spray(s), the total weight reduction will be set to missing for that treatment period. The daily usage is defined as the total usage during the period divided by the treatment duration in days (i.e. treatment stop date treatment start date +1) Extent of Exposure Extent of exposure to study medication will be calculated for each subject and period as the expected number of doses used in each period (see Section 9.2.4) If the treatment stop date is missing for any nasal spray then the visit date of the study visit which marked the end of the period where it should have been returned will be used as the treatment stop date. If the treatment stop date for the last nasal spray dispensed is

199 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 missing then the study discontinuation/completion date will be used for the treatment sto date. If the necessary visit date or the study discontinuation/completion date is also missing then the extent of exposure will be set to missing for that period. If treatment start date is missing for any nasal spray the date of the visit where it was dispensed will be used for treatment start date Assessment Windows Assessment windows for the scheduled study visits are as follows: Visit 1 (Screening), 14 ± 3 days prior to Visit 2 (Randomisation) Visit 2 (Randomisation), Day 1 Visit 3 (Day 15), 14 ± 3 days after Visit 2 Visit 4 (Day 29), 14 ± 3 days after Visit 3 Visit 5 (Day 43), 14 ± 3 days after Visit 4 Follow-up phone call (Day 46 to 50), 3 7 days after Visit 5 Individual assessment collected outside of the scheduled window for scheduled visits will be included in all analyses without adjustment. Knemometry data collected on the scheduled visit screens of the ecrf will be used for analysis. If any visits are missing this assessment, but there is an unscheduled visit within the window for the scheduled visit, then knemometry data collected at the unscheduled visit may be used for analysis for both the ITT and Growth populations. Any other data collected at unscheduled clinic visits will be summarised separately according to when the data was collected, i.e. between Visits 1 and 2, between Visits 2 and 3 etc Safety Data Adverse Events The following rules will be applied in order to determine if the adverse event started prior to active treatment (during run-in), during treatment or after treatment stopped. If the date of onset of the adverse event is before the active treatment start date then the event will be assigned as pre-treatment. If the date of onset of the adverse event is on or after the active treatment start date then the event will be assigned as during treatment. If the date of onset is after the active treatment stop date plus one day then the event will be assigned as post-treatment. If onset date is complete then : If onset date < active treatment start then PRE-TREATMENT

200 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 Else If onset date greater than or equal to active treatment start and less than or equal to treatment stop then DURING TREATMENT Else if onset date > active treatment stop + 1 then POST TREATMENT If onset date partial (??/MMM/YYYY) then: If onset date MMM/YYYY < MMM/YYYY of active treatment start then PRE- TREATMENT Else if onset date MMM/YYYY greater than or equal to MMM/YYYY of active treatment start and MMM/YYYY less than or equal to MMM/YYYY of active treatment stop then DURING TREATMENT Else if onset date MMM/YYYY > MMM/YYYY + 1 day of active treatment stop then POST TREATMENT If onset date partial (??/???/YYYY) then: If onset date YYYY < YYYY of active treatment start then PRE-TREATMENT Else if onset date YYYY greater than or equal to YYYY of active treatment start and YYYY less than or equal to YYYY of active treatment stop then DURING TREATMENT Else if onset date YYYY > YYYY + 1 day of active treatment stop the POST TREATMENT Time to onset of an adverse event is defined as: onset date treatment start date + 1 Duration of an adverse event is defined as: (stop date onset date) + 1. If it is not clear from the onset date during which period of the study an AE began then it will be included in all possible washout / treatment periods during which it might have begun Values of Clinical Concern There are no values of clinical concern. 10. STUDY POPULATION With the exception of the disposition of subjects screened and the reasons for withdrawal prior to randomisation, all summaries of study population data will be provided for the ITT population. Some summaries, specified below, will also be produced for the Growth population if it is different to the ITT population Disposition of Subjects The disposition of subjects screened for this study, including reason for screening failure, will be summarised for the All Subjects Screened Population. A listing of screened subjects who are excluded from the ITT Population and the reason(s) for exclusion will be provided for the Screen Failure Population

201 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 A listing will be prepared indicating treatment sequence allocation and membership of the various populations. The disposition of subjects at the end of the study, including early withdrawal from the study by major reason will be summarised by treatment being taken at time of withdrawal. A listing of subjects withdrawn early from the study and the withdrawal reasons will also be provided Protocol Deviations Any inclusion / exclusion / randomisation criteria not met at Visit 1 (Screening) or Visit 2 (Randomisation) will be summarised by treatment group. A listing of ITT subjects who are excluded from the Growth Population and the reason(s) for exclusion will be provided for the ITT Population. Reasons for exclusion from the Growth Population are as detailed in Section Demographic and Baseline Characteristics As this is a crossover study demographic and baseline characteristics will be summarised for all subjects and not by treatment group. Demographic characteristics including race, ethnicity and sex, will be summarised for all subjects using descriptive statistics and frequencies as appropriate. Age will be calculated based on the date of randomisation (Visit 2). Summaries will be provided for both the ITT and Growth populations. For the ITT population, summaries of race and racial combinations will also be provided. Diagnosis of SAR / PAR, duration of disease and medical conditions will be summarised. For each laboratory analyte, normal ranges as determined by the central laboratory will be displayed. Laboratory data (haematology, chemistry and electrolytes) will be collected at Visit 1 (Screening) only. The number and percentage of subjects with laboratory values outside the normal range will be summarised for each laboratory analyte. No further laboratory tests will be performed after Visit 1 so changes from baseline will not be examined Concurrent Medications Any concurrent medication taken by a subject during the study will defined as falling into the following categories for tabulation purposes: Medications taken during the run-in period (regardless of when they ceased) Medications taken during active treatment i.e. after the run-in (regardless of when they commenced). These will be presented separately for each treatment and

202 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 washout period between treatments. Concurrent medications spanning more than one treatment/washout period should be summarised in all treatment/washout periods in which they were taken. All medication verbatim text will be coded using the GSKDrug dictionary to obtain the appropriate ATC classification and preferred term. A summary of the number and percentage of subjects with concomitant medications will be produced using a method which presents multi-ingredient medications according to their combination ATC classification rather than the classifications of the ingredients. This display will also include single-ingredient medications. Multi-ingredient medications will be labeled according to the sum of their ingredients, e.g., Tylenol Cold and Flu would appear as CHLORPHENAMINE MALEATE + DEXTROMETHORPHAN HYDROBROMIDE + PARACETAMOL + PSEUDOEPHEDRINE HYDROCHLORIDE under the ATC headings for Nervous System and Respiratory System (the combination s ATC classifications). A multiingredient drug s component ingredients will not be summarized separately. The methods for dealing with partial drug start and stop dates will be the same for all medications and are as follows: If drug start date partial (??/MMM/YYYY) then: If drug start date MMM/YYYY < MMM/YYYY of active treatment start (i.e. during Run-In) then started PRE-TREATMENT Else if drug start date MMM/YYYY greater than or equal to MMM/YYYY of active treatment start and MMM/YYYY less than or equal to MMM/YYYY of active treatment stop then started DURING TREATMENT Else if drug start date MMM/YYYY > MMM/YYY Y of active treatment stop then started POST TREATMENT If drug start date partial (??/???/YYYY) then: If onset date YYYY < YYYY of active treatment start (i.e. during Run-In) then started PRE-TREATMENT Else if onset date YYYY greater than or equal to YYYY of active treatment start and YYYY less than or equal to YYYY of active treatment stop then started DURING TREATMENT Else if onset date YYYY > YYYY of active treatment stop then started POST TREATMENT If drug stop date partial (??/MMM/YYYY) then: If drug started pre-treatment and drug stop date MMM/YYYY < MMM/YYYY of active treatment start then drug NOT taken during treatment Else if drug started pre-treatment and drug stop date MMM/YYYY greater than or equal to MMM/YYYY of active treatment start then drug taken DURING TREATMENT

203 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 If drug stop date partial (??/???/YYYY) then: If drug started pre-treatment and drug stop date YYYY < YYYY of active treatment start then drug NOT taken during treatment Else if drug started pre-treatment and onset date YYYY YYYY of active treatment start then drug taken DURING TREATMENT. Concurrent medications taken pre-treatment will be summarised for all subjects and not by treatment group due to the crossover design of the study. For drugs classified as taken during treatment, if it is not clear in which period they were taken they will be included in all possible treatment/washout periods during which it was possible they may have been taken. The relationship between ATC Level 1, ingredient and verbatim text will be listed. Daily allergy rescue medication use recorded on subject diary card will be summarized in terms of the percentage of days on which allergy rescue medication was taken, calculated as described in Section Treatment Compliance Subject-reported compliance with the dosing regimen will be summarised by treatment as a percentage for the double-blind treatment periods. Data for each treatment will be combined across the periods. Treatment compliance percentages will be calculated for each subject based on the information recorded by the subject on the DRC (see Section 9.2.4). Compliance based on the weights of nasal sprays (calculated as described in Section 9.2.5) will also be summarised. These summaries will be provided for both the ITT and Growth population. 11. SAFETY ANALYSES Extent of Exposure Extent of exposure to study treatment (i.e. number of days on treatment) will be summarised for the double-blind treatment periods by treatment group for both the Growth and ITT populations using the mean, standard deviation, median, minimum and maximum Primary Safety Endpoint The primary safety endpoint is the mean lower leg growth velocity (mm/wk) measured by knemometry. All summary and analysis tables, as well as graphs, will be provided for both the Growth Population (of primary interest) and the ITT Population (as supportive)

204 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 The primary analysis method will be the comparison of the treatment groups (GW685698X 100mcg QD vs placebo) using analysis of covariance (ANCOVA) adjusting for baseline lower leg growth velocity as measured by knemometry, age and gender. Treatment will be included as a fixed effect in the model, and subject as a random effect. Period effect will be considered as a fixed effect. Individual subject lower leg growth rates (mm/wk) for each of the two treatment periods will be plotted against each other. The distribution of the lower leg growth rates will be illustrated by treatment via histogram. Summary statistics will be provided for the lower leg growth velocity as measured by knemometry during each of the two treatment periods as well as the washout period. From the ANCOVA model the least squares mean lower leg growth velocity for each treatment period will be summarised and compared. The least squares treatment mean difference (GW685698X 100mcg QD vs placebo) will be presented along with the corresponding 95% confidence interval and p-value Adverse Events Adverse events during the screening period, each of the two double-blind treatment periods, the wash-out period between the two double-blind treatment periods, and the post treatment period will be summarized and displayed. The onset date of the adverse events relative to the clinic visit dates will be used to determine in which period an adverse event occurs, as described in Section The verbatim texts for adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will be reported using the primary System Organ Class (SOC) and Preferred Term (PT). Preferred Terms will be summarized within the primary SOC. The relationship of primary SOC, preferred terms, and verbatim text will be listed. The number of subjects with one or more events of any type will be calculated. Results will be displayed in the order of decreasing frequency, both across primary SOC and within primary SOC. Adverse events will also be listed. Demographic details (e.g., age, sex, and race), as well as details of the individual adverse events, will be included in these listings. Listings will be sorted within subject by the adverse event date of onset. Similar summaries and listings will be provided for drug-related adverse events. A listing will be provided for adverse events leading to withdrawal from study Deaths and Serious Adverse Events All serious adverse events will be listed. Any deaths and serious adverse events reported during this study will also be summarized in case narratives written by Global Clinical Safety and Pharmacovigilance personnel

205 CONFIDENTIAL CONFIDENTIAL GM2005/00115/ Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events Adverse events causing withdrawal from the study will be summarised and listed Pregnancies Any pregnancies reported during this study will also be summarized in case narratives written by Global Clinical Safety and Pharmacovigilance personnel Other Safety Measures Nasal Examination Nasal examinations will be performed at each visit, and will include assessments of patency, septum deviation, mucosa, secretions, ulcers, and polyposis. Nasal examination results will be summarized by visit for each of the 6 examination parameters listed above. At all visits, frequencies of classifications (yes/no, absent/present) will be calculated. Shift from baseline (defined as examination results from Visit 2) to end of the treatment (Visit 5), as well as from beginning to end of each period (Visit 2 to Visit 3 and Visit 3 to Visit 4) will also be summarized for each individual nasal examination parameter. All nasal examination results will be listed for those subjects with at least one abnormal nasal examination result post baseline Vital Signs Number of subjects, mean, standard deviation, median, minimum, and maximum will be used to summarise vital signs (heart rate, systolic blood pressure, and diastolic blood pressure) by visit

206 CONFIDENTIAL CONFIDENTIAL GM2005/00115/ REFERENCES Committee for Proprietary Medicinal Products (CPMP) Points to Consider (PtC) on Switching Between Superiority and Non-inferiority, (CPMP/EWP/482/99), 27 July 2000 European Agency for the Evaluation of Medicinal Products, Notes for Guidance on Statistical Principals for Clinical Trials, ICH Topic E9, (CPMP/ICH/363/96), 18 March 1998 GlaxoSmithKline Document Number ZM2004/00069/00, Study ID. A Randomized, Double-blind, Placebo-controlled, 2-Week Crossover, Knemometric Assessment of the Effect of Once Daily GW685698X Aqueous Nasal Spray 100 mcg on Short Term Growth in Children Ages 6 11 Years with Seasonal and/or Perennial Allergic Rhinitis GlaxoSmithKline Document Number ZM2004/00069/01, Study ID. Amendment 1: A Randomized, Double-blind, Placebo-controlled, 2-Week Crossover, Knemometric Assessment of the Effect of Once Daily GW685698X Aqueous Nasal Spray 100 mcg on Short Term Growth in Children Ages 6 11 Years with Seasonal and/or Perennial Allergic Rhinitis Senn, S.J. Cross-over Trials in Clinical Research. John Wiley & Sons Ltd.;

207 CONFIDENTIAL CONFIDENTIAL GM2005/00115/ ATTACHMENTS Table of Contents for Data Display Specifications Study Population Table 6.1 Table 6.2 Table 6.3 Table 6.4 Table 6.5 Table 6.6 Table 6.7 Table 6.8 Table 6.9 Summary of Screening Subject Disposition All Subjects Screened Population Listing of Screening Subject Disposition All Subjects Screened Population Summary of End of Study Record Intent-to-Treat Population Listing of End Of Study Record Intent-to-Treat Population Summary of the Number of Subjects At Each Visit Intent-to-Treat Population Summary of Inclusion / Exclusion Criteria Deviations Intent-to-Treat Population Listing of Subjects With Inclusion / Exclusion Criteria Deviations Intentto-Treat Population Summary of Visit Spacing Relative to Protocol Specifications Intent-to- Treat Population Listing of Subjects for Whom the Treatment Blind was Broken During the Study Intent-to-Treat Population Table 6.10 Listing of Reasons for Exclusion from the Intent-to-Treat Population Table 6.11 Listing of Reasons for Exclusion from the Growth Population Table 6.12 Listing of Population Membership and Treatment Sequence Allocation All Subjects Screened Population Table 6.13 Summary of Demographic Characteristics Intent-to-Treat Population Table 6.14 Summary of Demographic Characteristics Growth Population Table 6.15 Summary of Race and Racial Combinations Intent-to-Treat Population Table 6.16 Summary of Race and Racial Combination Details Intent-to-Treat Population Table 6.17 Listing of Demographic Characteristics Intent-to-Treat Population Table 6.18 Summary of Allergy History Intent-to-Treat Population

208 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 Table 6.19 Listing of Allergy History Intent-to-Treat Population Table 6.20 Summary of Current Medical Conditions Intent-to-Treat Population Table 6.21 Summary of Baseline Laboratory Values Intent-to-Treat Population Table 6.22 Summary of Baseline Abnormal Laboratory Values Intent-to-Treat Population Table 6.23 Listing of Laboratory Data for Subjects with at Least One Abnormal Value Intent-to-Treat Population Table 6.24 Relationship of ATC Level, Ingredients and Verbatim Text Intent-to-Treat Population Table 6.25 Summary of Concomitant Medications During the Run-In Period By Ingredient And Ingredient Combination Intent-to-Treat Population Table 6.26 Summary of Concomitant Medications During the Treatment Period By Ingredient and Ingredient Combination Intent-to-Treat Population Table 6.27 Listing of Concomitant Medications Intent-to-Treat Population Table 6.28 Summary of Daily Allergy Rescue Medication (Percentage of Days Used) Intent-to-Treat Population Table 6.29 Summary of Treatment Compliance on Nasal Spray Study Medication Based on Subject Diary Record Intent-to-Treat Population Table 6.30 Summary of Study Medication Usage Based on Nasal Device Weight Intent-to-Treat Population Table 6.31 Summary of Treatment Compliance on Nasal Spray Study Medication Based on Subject Diary Record Growth Population Table 6.32 Summary of Study Medication Usage Based on Nasal Device Weight Growth Population Table 6.33 Listing of Compliance Intent-to-Treat Population

209 CONFIDENTIAL CONFIDENTIAL GM2005/00115/ Safety Figures Figure 7.1 Plot of lower leg growth rates (mm/wk) Treatment Period 1 vs Treatment Period 2 Intent-to-Treat Population Figure 7.2 Plot of lower leg growth rates (mm/wk) Treatment Period 1 vs Treatment Period 2 - Growth Population Figure 7.3 Histogram of Lower Leg Growth Rate (mm/wk) Distribution by Treatment Intent-to-Treat Population Figure 7.4 Histogram of Lower Leg Growth Rate (mm/wk) by Treatment Growth Population Figure 7.5 Histogram of Lower Leg Growth Rate (mm/wk) by Treatment Sequence and Treatment Intent-to-Treat Population Figure 7.6 Histogram of Lower Leg Growth Rate (mm/wk) by Treatment Sequence and Treatment Growth Population Figure 7.7 Boxplot of Lower Leg Growth Rate (mm/wk) by Treatment Group Intentto-Treat Population Figure 7.8 Boxplot of Lower Leg Growth Rate (mm/wk) by Treatment Group Growth Population

210 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 Tables Table 7.1 Table 7.2 Table 7.3 Table 7.4 Table 7.5 Table 7.6 Table 7.7 Table 7.8 Table 7.9 Summary of Exposure to Study Drug Intent-to-Treat Population Summary of Exposure to Study Drug Growth Population Listing of Exposure to Study Drug Intent-to-Treat Population Summary of Lower Leg Growth Velocity (mm/wk) Intent-to-Treat Population Analysis of Lower Leg Growth Velocity (mm/wk) Intent-to-Treat Population Summary of Lower Leg Growth Velocity (mm/wk) Growth Population Analysis of Lower Leg Growth Velocity (mm/wk) Growth Population Listing of Knemometry Data Intent-to-Treat Population Relationship of Adverse Event System Organ Class, Preferred Term and Verbatim Text Intent-to-Treat Population Table 7.10 Summary of All Adverse Events During The Run-In Period Intent-to-Treat Population Table 7.11 Summary of All Adverse Events During The Treatment Period Intent-to- Treat Population Table 7.12 Summary of All Adverse Events During The Post-Treatment Period Intentto-Treat Population Table 7.13 Listing of Subject Numbers for Individual Adverse Events Intent-to-Treat Population Table 7.14 Listing of All Adverse Events During The Study Period Intent-to-Treat Population Table 7.15 Summary of Drug-Related Adverse Events During The Study Period Intent-to-Treat Population Table 7.16 Listing of Drug-Related Adverse Events During The Study Period Intentto-Treat Population Table 7.17 Listing of Serious Adverse Events During The Screening Period Screen Failure Population Table 7.18 Listing of Serious Adverse Events During The Study Period Intent-to-Treat Population

211 CONFIDENTIAL CONFIDENTIAL GM2005/00115/00 Table 7.19 Summary of Adverse Events Causing Withdrawal From The Study Intentto-Treat Population Table 7.20 Listing of Adverse Events Causing Withdrawal From The Study Intent-to- Treat Population Table 7.21 Summary of Nasal Examinations Intent-to-Treat Population Table 7.22 Summary of Nasal Examination Shifts Intent-to-Treat Population Table 7.23 Listing of Subjects With at Least One Abnormal Nasal Examination Result Post Baseline Table 7.24 Summary of Vital Signs Intent-to-Treat Population Table 7.25 Listing of Vital Signs Intent-to-Treat Population Table 7.26 Individual Subject Profile for Subject Who Took The Wrong Treatment During The Study Intent-to-Treat Population

212 CONFIDENTIAL CONFIDENTIAL GM2005/00115/ Data Display Specifications Available on Request

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218 ZM2004/00069/02 CONFIDENTIAL The GlaxoSmithKline group of companies Title: A Randomized, Double-blind, Placebo-controlled, 2-Week Crossover, Knemometric Assessment of the Effect of Once Daily GW685698X Aqueous Nasal Spray 100 mcg on Short Term Growth in Children Ages 6 11 Years with Seasonal and/or Perennial Allergic Rhinitis Document Number: ZM2004/00069/02 Study Identifier: GSK Compound Number: GW685698X Issue Date: 14 Jun 2005 Protocol Amendment Number: 02 Author(s): MDC, Respiratory MDC, Respiratory/Allergy GCSP, Respiratory MDC, Respiratory/Allergy MDC, Respiratory/Allergy BDS Statistics and Programming BDS Statistics and Programming Revision Chronology: ZM2004/00069/ Dec-06 Original ZM2004/00069/ Feb-18 Amendment No. 01 The inclusion and exclusion criteria are numbered. Additional detail is provided on the volume and retention period for the blood sample drawn at Visit 1 and for the blood sample drawn for a serum pregnancy test, if required, at the Early Withdrawal Visit. C- Reactive Protein (CRP) is deleted from the list of chemistry and hematology analyses. 1

219 ZM2004/00069/02 CONFIDENTIAL The GlaxoSmithKline group of companies ZM2004/00069/ Jun-14 Amendment No.2: Protocol has been amended to change the exclusionary period for intranasal and inhaled corticosteroids from 4 to 2 weeks prior to visit 1; to allow for the use of study provided loratadine syrup as well as loratadine tablets; to remove physical examination as a safety endpoint. (NB new abnormalities found during physical examination are recorded as clinical adverse events, an existing safety endpoint) Copyright 2005 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 2

220 ZM2004/00069/02 CONFIDENTIAL The GlaxoSmithKline group of companies 3

221 ZM2004/00069/02 CONFIDENTIAL SPONSOR INFORMATION PAGE Title: Study Identifier: A Randomized, Double-blind, Placebo-controlled, 2-Week Crossover, Knemometric Assessment of the Effect of Once Daily GW685698X Aqueous Nasal Spray 100 mcg on Short Term Growth in Children Ages 6 11 Years with Seasonal and/or Perennial Allergic Rhinitis GlaxoSmithKline Greenford Road Greenford, Middlesex, UB6 0HE, UK Telephone: Sponsor Contact Information: Telephone: MB, ChB, MFPM IND Number: 48,647 4

222 ZM2004/00069/02 CONFIDENTIAL INVESTIGATOR AGREEMENT PAGE I agree: To assume responsibility for the proper conduct of the study at this site. To conduct the study in compliance with this protocol amendment and with any other study conduct procedures provided by GlaxoSmithKline (GSK). Not to implement this protocol amendment without agreement from the sponsor and prior submission to and written approval from (where required) the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), except when necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements). Note to implement any other changes to the protocol without agreement from the sponsor and prior review and written approval from the IRB or IEC, except where necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements). That I am thoroughly familiar with the appropriate use of the investigational product(s), as described herein, and any other information provided by the sponsor including, but not limited to, the following: the current Investigator s Brochure (IB) or equivalent document, IB supplement (if applicable), and approved product label (if the product is marketed in this country and the label is not already provided as an equivalent to an IB). That I am aware of, and will comply with, good clinical practices (GCP) and all applicable regulatory requirements. To ensure that all persons assisting me with the study are adequately informed about the GSK investigational product(s) and of their study-related duties and functions as described herein. That I have been informed that certain regulatory authorities require the Sponsor to obtain and supply, as necessary, details about the investigator s ownership interest in the Sponsor or the investigational product, and more generally about his/her financial ties with the Sponsor. GSK will use and disclose the information solely for the purpose of complying with regulatory requirements. Hence I: Agree to supply GSK with any necessary information regarding ownership interest and financial ties (including those of my spouse and dependent children); Agree to promptly update this information if any relevant changes occur during the course of the study and for 1 year following completion of the study; and Agree that GSK may disclose any information it has about such ownership interests and financial ties to regulatory authorities. 5

223 ZM2004/00069/02 CONFIDENTIAL Investigator Name: Investigator Signature Date The following co-signature is required only when the investigator is not a insert the appropriate text such as physician or dentist Physician Name: Physician Signature Date 6

224 ZM2004/00069/02 CONFIDENTIAL TABLE OF CONTENTS Page ABBREVIATIONS PROTOCOL SUMMARY INTRODUCTION Background Rationale OBJECTIVE(S) ENDPOINT(S) Primary Safety Endpoint Secondary Safety Endpoints STUDY DESIGN STUDY POPULATION Number of Subjects Eligibility Criteria Inclusion Criteria Randomization Criteria Exclusion Criteria Other Eligibility Criteria Considerations STUDY ASSESSMENTS AND PROCEDURES Knemometry Assessments Diary Cards Study Visits and Follow-Up Screening Visit (Visit 1) Randomization Randomization Visit (Visit 2) Interim Visit (Visit 3) Interim Visit (Visit 4) Final Visit (Visit 5) Follow-up phone call Early withdrawal visit Safety Physical examination Nasal examination Vital signs

225 ZM2004/00069/02 CONFIDENTIAL Clinical Laboratory Tests Pregnancy Efficacy Compliance Assessment INVESTIGATIONAL PRODUCT(S) Description of Investigational Product Dosage and Administration Dose Rationale Blinding Treatment Assignment Packaging and Labeling Treatment Pack Allergy Rescue Medication Preparation Handling and Storage Product Accountability Assessment of Compliance Treatment of Investigational Product Overdose Occupational Safety CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES Permitted Medications Allergy rescue medication Prohibited Medications Medical Devices SUBJECT COMPLETION AND WITHDRAWAL Subject Completion Subject Withdrawal Subject Withdrawal from Study Subject Withdrawal from Investigational Product Extension Study Screen and Baseline Failures ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) Definition of an AE Definition of a SAE Lack of Efficacy Clinically Abnormal Assessments as AEs and SAEs

226 ZM2004/00069/02 CONFIDENTIAL Time Period, Frequency, and Method of Detecting AEs and SAEs Recording of AEs and SAEs Evaluating AEs and SAEs Assessment of Intensity Assessment of Causality Follow-Up of AEs and SAEs Prompt Reporting of SAEs to GSK Timeframes for Submitting SAE Reports to GSK Completion and Transmission of the SAE Reports Regulatory Reporting Requirements For SAEs Post-study AEs and SAEs SAEs Related to Study Participation DATA ANALYSIS AND STATISTICAL CONSIDERATIONS Hypotheses Primary Comparison of Interest Interim Analysis Sample Size Considerations Sample Size Assumptions Sample Size Sensitivity Sample Size Re-estimation Analysis Populations General Considerations for Data Analysis Withdrawal Missing Data Derived and Transformed Data Assessment Windows Treatment Compliance Efficacy Analyses Safety Analyses Primary Safety Analysis Extent of Exposure Adverse Events Deaths and Serious Adverse Events Nasal Examination Vital Signs STUDY ADMINISTRATION Regulatory and Ethical Considerations

227 ZM2004/00069/02 CONFIDENTIAL Regulatory Authority Approval Ethical Conduct of the Study and Ethics Approval Informed Consent Investigator Reporting Requirements Study Monitoring Quality Assurance Study and Site Closure Records Retention Provision of Study Results and Information to Investigators Information Disclosure and Inventions Data Management REFERENCES APPENDICES Appendix 1: Time and Events Table Appendix 2: Study Schematic Diagram Appendix 3: Country Specific Requirements Appendix 4: Laboratory Assessments Appendix 5: History of Change

228 ZM2004/00069/02 CONFIDENTIAL ABBREVIATIONS AE AM CIB CRF EISR FDA GCP GCSP GSK IB IEC IND ITT IRB IVRS LLQ PAR PR QC QD RAMOS SAE SAR US Adverse Event Morning Clinical Investigator Brochure Case report form Expedited Investigator Safety Report Food and Drug Administration Good Clinical Practice Global Clinical Safety and Pharmacovigilance GlaxoSmithKline Investigator s Brochure Independent ethics committee Investigational New Drug Intent to treat Institutional review board Interactive voice response system Lower limit of quantitation Perennial allergic rhinitis Perennial rhinitis Quality control Once daily Registration and Medication Ordering System Serious adverse event Seasonal allergic rhinitis United States 11

229 ZM2004/00069/02 CONFIDENTIAL PROTOCOL SUMMARY Rationale Rhinitis is defined as inflammation of the membranes lining the nose and is characterized by the nasal symptoms of itching, sneezing, rhinorrhea, and nasal congestion. Intranasal corticosteroids are considered a highly effective treatment for these symptoms of rhinitis, both in children and adults. For this reason, they are recommended as first-line treatment in expert guidelines, specifically when congestion is a major component of the patient s presentation. From a general perspective, intranasally administered corticosteroids have been shown to demonstrate a low incidence of systemic adverse effects [Scadding, 2001]. Certain systemic effects however, remain an important consideration, even for intranasal formulations. One concern in children has been the potential for intranasal corticosteroids to affect growth. For example, intranasal and inhaled forms of the corticosteroid budesonide have demonstrated transient effects on growth velocity although the effect on final height was insignificant [Agertoft, 2000; Agertoft, 1999; Childhood Asthma Management Program Research Group, 2000]. Studies with other intranasal corticosteroids moieties have found no effect [Skoner, 2003]. Since the effect on growth has varied with the particular corticosteroid studied, the possibility of an effect must be explored as new agents become available. One of the methodologies that has been used to evaluate and predict an effect by intranasal corticosteroids on longitudinal growth in children is knemometry. The instrument used, called a knemometer, measures the distance between the knee and the heel of a seated subject. The length of the lower leg is electronically calculated based on the maximum distance detected between a footplate and a knee-level measuring board. With repeated measurements, the instrument is able to detect very small changes in length with an accuracy of 0.09 to 0.16 mm over periods as short as one week [Wales, 1987; Wit, 1987; Hermanussen, 1988]. Knemometry is currently the preferred method for growth studies of short duration. With the high sensitivity of this methodology, some researchers feel projections of future growth based on knemometry findings probably exaggerate growth-stunting effects of exogenously administered corticosteroids [Pedersen, 2001]. However, if an effect on lower leg growth is not detected for a corticosteroid studied by knemometry, most believe it is unlikely that the study drug, administered at the same dose, will cause an adverse effect on growth when used for extended periods. Children 6 to 11 years of age will comprise the population for this study. This range was selected because children of at least 6 years are more likely to comply with the requirements of the measuring procedure and because most boys < 12 and girls < 11 years of age are prepubertal. GW685698X, the investigational drug for this study, is a novel corticosteroid with potent glucocorticoid activity. In a 7-day, intranasal study of 24 healthy adult males using once daily doses of 50, 100, 200, 400, and 800 mcg, all doses demonstrated low systemic 12

230 ZM2004/00069/02 CONFIDENTIAL bioavailability with no significant effects on serum cortisol at any of the administered doses and no significant safety findings. In a 2-week dose ranging study of 641 subjects with seasonal allergic rhinitis, approximately 5% of blood samples had measurable plasma concentrations of GW685698X, generally no more than 3 times the lower limit of quantitation (LLQ = 10 pg/ml). Of the doses investigated in this study (GW685698X 50, 100, 200, and 400 mcg), 100 mcg once daily was determined to be the optimal adult and adolescent dose. Thus, since 100 mcg QD is the maximal dose of GW685698X to be prescribed, this dose is being evaluated in a pediatric population, ages 6 11 years, using knemometry to assess any effect on growth. Objective(s) The primary objective of the study is to determine the effect on lower leg growth of treatment with 100 mcg of intranasal GW685698X aqueous nasal spray QD versus placebo nasal spray QD in children ages 6 to 11 years with seasonal allergic rhinitis (SAR) and/or perennial allergic rhinitis (PAR). Endpoint(s) Primary Safety Endpoint The primary safety endpoint will be the mean growth velocity (mm/wk) in lower leg growth, as determined by knemometry, over a 2-week treatment period with intranasal GW685698X 100 mcg aqueous nasal spray versus a 2-week treatment with placebo nasal spray. Secondary Safety Endpoints Secondary safety assessments will be: the frequency and type of clinical adverse events (AEs) experienced during treatment nasal examination vital signs (systolic and diastolic blood pressure, heart rate [pulse]) Study Design This study is a double-blind, randomized, placebo-controlled, crossover trial. The study will be conducted at one site in Denmark and will randomize 56 subjects. After entering a 2-week, single-blind, placebo run-in period, each child will be randomly allocated to a double-blind treatment sequence to receive intranasal GW685698X aqueous nasal spray 100 mcg or placebo nasal spray. Each treatment will be administered for 2 weeks and the two double-blind treatment periods will be separated by a 2-week, washout period during which time single-blind, placebo nasal spray will be administered. A follow-up phone call will be made one week after completing the last 13

231 ZM2004/00069/02 CONFIDENTIAL treatment for the collection of post-treatment AEs. See Appendix 2 for a schematic of the study. Proper use of the study drug device will be demonstrated at the screening visit (Visit 1) to the parent(s)/guardian(s) and, if deemed appropriate by the investigator, to the subjects using a placebo nasal spray device. However, due to the visit occurring in the afternoon, the first dose will not be administered until the following morning after Visit 1. Subjects will record any medical conditions experienced and any concomitant medications taken on a daily diary card. Compliance will be assessed by the subjects completion of a diary card acknowledging whether the daily dose was taken. Compliance will also be assessed by the amount of medication used as determined by the weights of each nasal spray device at the beginning and end of each study period. All subjects will be outpatients. Clinic visits will be scheduled to occur at the following intervals: Visit 1 (Screening; 14 ± 3 days prior to randomization) Visit 2 (Randomization, Day 1) Visit 3 (14 ± 3 days after Visit 2, Day 15) Visit 4 (14 ± 3 days after Visit 3, Day 29) Visit 5 (14 ± 3 days after Visit 4, Day 43) Follow-up Phone Call (3-7 days after Visit 5, Day 46) Study Population Fifty-six subjects with SAR and/or PAR will be randomized to double-blind study treatment to ensure completion of 50 subjects, assuming a 10% drop-out rate after randomization. Study Assessments and Procedures Study assessments and procedures will take place according to the Time and Events Schedule in Appendix 1: Time and Events Table. Safety Assessments knemometry measurements the frequency and type of clinical AEs experienced during treatment physical examination, including gross nasal examination vital signs (systolic and diastolic blood pressure, heart rate [pulse]) Efficacy Assessment No efficacy assessments will be performed. 14

232 ZM2004/00069/02 CONFIDENTIAL Investigational Product(s) GW685698X Nasal Spray will be manufactured as a preserved, aqueous suspension containing 0.05% w/w of micronized GW685698X. The preservative system consists of benzalkonium chloride and disodium edetate. Each nasal spray bottle will contain a volume of suspension sufficient to deliver a minimum of 120 actuations. Each spray of the suspension will contain approximately 25 mcg of GW685698X. The matching placebo nasal spray is comprised of the GW685698X vehicle. Spray devices must be primed according to the subject instruction leaflet for proper functioning. Demonstration devices will be made available to allow site staff to demonstrate proper administration. 15

233 ZM2004/00069/02 CONFIDENTIAL 1. INTRODUCTION 1.1. Background Anti-inflammatory therapy is a well-accepted component of the management of rhinitis. To date, corticosteroids offer the only therapeutic option with proven anti-inflammatory activity. GW685698X, the investigational drug for this study, is a novel corticosteroid with potent glucocorticoid activity. GW685698X aqueous nasal spray has already demonstrated the ability to reduce the symptoms of seasonal allergic rhinitis (SAR) in one large, multi-center study of adults and adolescent rhinitis patients. Since the GW685698X aqueous nasal spray clinical development program also includes studies to secure an indication for use in children, it is important to examine those aspects of glucocorticoid therapy that could pose a risk to this population. Since an effect on longitudinal growth by corticosteroids administered via other routes, specifically oral and inhaled routes, has been seen, it is important to establish the safety of this new rhinitis treatment in regards to growth [Wolthers, 1992; Wolthers, 1990]. This study will evaluate the potential for effects of GW685698X aqueous nasal spray on longitudinal growth in this group Rationale Rhinitis is defined as inflammation of the membranes lining the nose and is characterized by the nasal symptoms of itching, sneezing, rhinorrhea, and nasal congestion. Intranasal corticosteroids are considered a highly effective treatment for these symptoms of rhinitis, both in children and adults. For this reason, they are recommended as a first-line treatment in expert guidelines, specifically when congestion is a major component of the patient s presentation [Task Force on Allergic Disorders, 2004]. In support of this treatment guideline, a meta-analyses of 16 randomized, controlled trials found intranasal corticosteroids significantly more effective at relieving nasal congestion, discharge, itch, and postnasal drip than oral antihistamines, the most prescribed treatment for allergic rhinitis [Weiner, 1998]. From a general perspective, intranasally administered corticosteroids have been shown to demonstrate a low incidence of systemic adverse effects. Certain systemic effects however, remain an important consideration, even for intranasal formulations. One concern in children has been the nasal corticosteroids' effects on growth. For example, intranasal and inhaled forms of the corticosteroid budesonide have demonstrated transient effects on growth velocity although the effect on final height was insignificant [Agertoft, 2000; Agertoft, 1999; Childhood Asthma Management Program Research Group, 2000]. Studies with other intranasal corticosteroids moieties have found no effect [Scadding, 2001; Skoner, 2003]. Since the effect on growth has varied with the particular corticosteroid studied, the possibility of an effect must be explored as new agents become available. One of the methodologies that have been used to evaluate and predict an effect by intranasal corticosteroids on longitudinal growth in children is knemometry. The instrument used, called a knemometer, measures the distance between the knee and the 16

234 ZM2004/00069/02 CONFIDENTIAL heel of a seated subject. The length of the lower leg is electronically calculated based on the maximum distance detected between a footplate and a knee-level measuring board. With repeated measurements, the instrument is able to detect very small changes in length with an accuracy of 0.09 to 0.16 mm over periods as short as one week [Wales, 1987; Wit, 1987; Hermanussen, 1988]. It is currently the preferred method for growth studies of short duration. With the high sensitivity of this methodology, some researchers feel projections of future growth based on knemometry findings probably exaggerate growth-stunting effects of exogenously administered corticosteroids. However, if an effect on lower leg growth is not detected for a corticosteroid studied by knemometry, most believe it is unlikely that the study drug, administered at the same dose, will cause an adverse effect on growth when used for extended periods [Pedersen, 2001]. Children 6 to 11 years of age will comprise the population for this study. This range was selected because children of at least 6 years are more likely to comply with the requirements of the measuring procedure and because most boys < 12 and girls <11 years of age are prepubertal. GW685698X, the investigational drug for this study, is a novel corticosteroid with potent glucocorticoid activity. In a 7-day, intranasal study of 24 healthy adult males using once daily doses of 50, 100, 200, 400, and 800 mcg, all doses demonstrated low systemic bioavailability with no significant effects on serum cortisol at any of the administered doses and no significant safety findings. In a 2-week dose ranging study of 641 subjects with seasonal allergic rhinitis, approximately 5% of blood samples had measurable plasma concentrations of GW685698X, generally no more than 3 times the lower limit of quantitation (LLQ = 10 pg/ml). Of the doses investigated in this study (GW685698X 50, 100, 200, and 400 mcg), 100 mcg once daily was determined to be the optimal adult and adolescent dose. Thus, as the maximal dose to be prescribed, GW685698X 100 mcg once daily, is being evaluated in a pediatric population, ages 6 11 years, to assess any effect on growth. 2. OBJECTIVE(S) The primary objective of the study is to determine the effect on lower leg growth of oncedaily treatment with 100 mcg of intranasal GW685698X aqueous nasal spray versus placebo nasal spray in children ages 6 to 11 years with SAR and/or PAR. 3. ENDPOINT(S) 3.1. Primary Safety Endpoint The primary safety endpoint will be the mean growth velocity (mm/wk) in lower leg growth, as determined by knemometry, over a 2-week treatment period with intranasal GW685698X aqueous nasal spray versus a 2-week treatment with placebo nasal spray. 17

235 ZM2004/00069/02 CONFIDENTIAL 3.2. Secondary Safety Endpoints Secondary safety endpoints will be: the frequency and type of clinical adverse events experienced during treatment nasal examination vital signs (systolic and diastolic blood pressure, heart rate [pulse]) 4. STUDY DESIGN This study is a double blind, randomized, placebo-controlled, crossover trial. The study will be conducted at one site in Denmark and will randomize 56 subjects. The study will be conducted over approximately 60 days. After entering a 2-week, placebo run-in period, each child will be randomly allocated to a treatment sequence to receive intranasal GW685698X aqueous nasal spray 100 mcg QD and placebo. Each treatment will be administered for 2 weeks and the two treatment periods will be separated by a 2-week placebo washout period. A follow-up phone call will be made 3 to 7 days after completing the last treatment to assess for adverse events. Rescue medication (loratadine 10 mg/day) will be permitted throughout the study. Use of the nasal spray device will be demonstrated on the screening day (Visit 1) to the parent(s)/guardian(s) and, if deemed appropriate by the investigator, to the subjects. Subjects will record medical conditions experienced and any concomitant medications taken on a diary throughout the study. Compliance will be assessed by the subjects acknowledgment on the diary card that the daily dose was taken. Compliance will also be assessed by the amount of medication used as determined by the weights of each nasal spray device at the beginning and end of each study period. All subjects will be outpatients. Clinic visits will be scheduled to occur at the following intervals relative to the day of randomization: Visit 1 (Screening Day, 14 ± 3 days prior to randomization) Visit 1 is the screening visit and the beginning of the single-blind, placebo runin period. Visit 2 (Randomization, Day 1) Visit 2 is the day of randomization. Subjects will be dispensed double-blind study medication at this visit and will begin the first day of double-blind treatment the morning after randomization. Visit 3 (14 ± 3 days after Visit 2, Day 15) Visit 3 is the end of first double-blind treatment period. Subjects will begin the single-blind, placebo wash-out period the morning after Visit 3. 18

236 ZM2004/00069/02 CONFIDENTIAL Visit 4 (14 ± 3 days after Visit 3, Day 29) Visit 4 is the end of the single-blind, placebo washout period. Subjects will begin the first day of the alternate double-blind treatment the morning after Visit 4. Visit 5 (14 ± 3 days after Visit 4, Day 43) Visit 5 is the end of the alternate double-blind treatment period and the last day of the study. Follow-up Phone Call (3-7 days after Visit 5, Day 46 to 50) 5. STUDY POPULATION 5.1. Number of Subjects Fifty-six subjects with seasonal and/or perennial allergic rhinitis will be randomized to double-blind study treatment to ensure completion of 50 subjects, assuming a 10% dropout rate after randomization Eligibility Criteria Inclusion Criteria A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. Pre-menarcheal female subjects who are 6 years to less than 11 years of age at the time of randomization 2. Male subjects who are 6 years to less than 12 years of age at the time of randomization 3. Tanner Stage 1 4. Documented clinical history of SAR or PAR of at least one year prior to study entry with (in the opinion of the investigator): a. a current level of allergic rhinitis symptoms that warrant treatment with an intranasal corticosteroid and/or b. expected symptoms during a majority of the study period Diagnosis must be confirmed by a positive skin test (by skin prick method) to an appropriate seasonal or perennial allergen within 12 months prior to Visit 1 or at Visit 1. A positive skin test is defined as a wheal 3 mm larger than the diluent control for prick testing. In vitro tests for specific IgE (such as RAST, PRIST) will also be permitted as confirmation for a diagnosis of SAR or PAR if performed within the last 12 months or at Visit 1. For these tests, 5mls of blood will be collected to determine 19

237 ZM2004/00069/02 CONFIDENTIAL allergenicity. Following analysis, the blood sample will be held for 2 weeks and then destroyed. (This sample will be drawn in conjunction with the blood required for the clinical laboratory tests such that only one venepuncture will be required at this visit.) 5. Normal current growth as reflected by baseline height within the 5 th and 95 th percentiles of normal for their age and gender as determined by stadiometry and Danish longitudinal standard charts 6. Subjects must be willing and able to comply with study procedures 7. Written informed consent must be provided by the parent or guardian Randomization Criteria 1. Subject has completed at least 80% of responses to the diary compliance questions during the 2 week, single-blind, placebo run-in period Exclusion Criteria A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1. History of abnormal growth or gross malnutrition 2. Findings of a clinically significant laboratory abnormality (Section 6.4.4) 3. History of any condition that may have substantially affected growth 4. Subjects with historical or current evidence of clinically significant, uncontrolled disease of any body system (in addition to allergic rhinitis), such as uncontrolled, epilepsy, active tuberculosis, attention deficit hyperactive disorder, psychological disorders or eczema, will not be eligible. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or which would confound the interpretation of the study results if the disease/condition exacerbated during the study 5. Any asthma other than mild, intermittent asthma controlled by short-acting, β- agonists [GINA, 2003] 6. Recent major surgery and/or trauma to the legs 7. Current or history of glaucoma and/or cataracts or ocular herpes simplex 8. History of adrenal insufficiency 9. Current or prior treatment with any medication that may have a potential for an ongoing effect on linear growth 10. Use of corticosteroids, defined as: Inhaled and intranasal corticosteroids within 2 weeks prior to Visit 1 Corticosteroids by all other routes (eg oral, intramuscular, intravenous, dermatological, ocular, otic) within 4 weeks prior to Visit 1 20

238 ZM2004/00069/02 CONFIDENTIAL 11. Any nasal condition or deformity that would impair nasal breathing or deposition of medication (i.e., nasal polyps, marked septal deviation) 12. Physical impairment that would affect the subject s ability to participate in the study 13. Documented evidence of acute or significant chronic sinusitis 14. Upper or lower respiratory or sinus infection during the 7 days before screening 15. Clinical evidence of a nasal or oropharyngeal Candida infection 16. Rhinitis medicamentosa 17. Severe dehydration 18. Use of any medications that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazole 19. Subjects with known hypersensitivity to any excipients in the study medications 20. Previous clinical trial experience with GW685698X aqueous nasal spray 21. Exposure to clinical trial/experimental medication within 30 days of Visit Affiliation with investigational site such that the subject is an immediate family member of any site personnel 23. Chickenpox or measles infections A subject is not eligible if he/she currently has chickenpox or measles, or has been exposed to chickenpox or measles during the last 3 weeks and is non-immune. If a subject develops chickenpox or measles during the study, he/she will be withdrawn from the study. If a non-immune subject is exposed to chickenpox or measles during the study, his/her continuation in the study will be at the discretion of the investigator, taking into consideration the likelihood of developing active disease Other Eligibility Criteria Considerations To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: GSK Document RM2004/00130/00, Investigator s Brochure for GW685698X. 6. STUDY ASSESSMENTS AND PROCEDURES The Time and Events Schedule details the time frame in which visits should occur and procedures should be performed at each study visit (Appendix 1: Time and Events Table) Knemometry Assessments At every visit, knemometry is carried out by a trained observer who will perform the measurements according to detailed guidelines available at the centre. Visits will occur 21

239 ZM2004/00069/02 CONFIDENTIAL at approximately 2-week intervals during the hours of 13:00 to 19:00 with each subsequent visit occurring within +/- 2 hours of the Visit 1 time. The child and the parent(s)/guardian(s) will be instructed that the subject must not participate in heavy exercises 3 hours prior to the visit at the centre. For the measurement, the child will be dressed in underwear. Five minutes prior to the measurements in the knemometer, the subject must rest in a chair. The observer will then measure the lower leg using digital parameters and without reference to previous measurements. Four measurements will be taken of the right leg at each visit and the final three measurements will be recorded in the case report form (CRF). Each measurement will be performed by the investigator or trained site personnel throughout the study and the knemometer will be calibrated prior to each visit. The same person should perform all measurements on a subject if possible Diary Cards Subjects will be provided with a diary card on which to document that they took their dose each morning. Additionally, subjects will record any medical problem (other than allergic rhinitis) they experience and any concomitant medications and/or rescue medications taken in the designated area on the diary card Study Visits and Follow-Up Screening Visit (Visit 1) Subjects who meet the entry criteria at Visit 1 will enter a 2-week, single-blind, placebo run-in period. The purpose of this 2-week period is to obtain a treatment-free, growth rate assessment that will be used for comparison of growth following active treatment. The following procedures/assessments will be performed and recorded during Visit Obtain written informed consent. Written informed consent is to be obtained prior to the implementation of any study procedures or to withholding any medication. An appropriately signed and dated assent must be obtained from the child and written informed consent from the parents or guardian. ONLY THEN can each subject be evaluated to determine if the subject selection criteria have been met (Section 5.2). The informed consent process should be documented in the subjects source documents with a statement that the subject is being enrolled into the study. 2. Obtain the medical history. The medical history must include the subject s rhinitis history including: duration of disease, onset/offset of disease, diagnosis of type of allergic rhinitis. All information pertaining to the history is recorded in the medical record and CRF, as appropriate. 22

240 ZM2004/00069/02 CONFIDENTIAL 3. Assess concomitant medication use and compliance with required exclusion periods, as specified in the exclusion criteria. The subject must have withheld relevant medications for the required exclusion periods as indicated in Section Past medication use over the six months prior to visit 1 for inhaled, oral, intranasal or dermatological corticosteroids will be recorded in the CRF as appropriate. 4. Verification of inclusion/exclusion criteria. (Section 5.2) 5. Assign the subject number. A subject number will be used to identify individual subjects during the course of the study. The clinic site will be given a specific range of possible subject numbers from which to assign each subject who has provided informed consent. Subject numbers will be assigned sequentially in ascending order. Please Note! Randomization numbers are not the same as subject numbers. In addition to subject number, subjects will also be assigned a randomization number by the GSK IVRS system, Randomization and Medication Ordering System (RAMOS), at Visit 2 to those subjects who meet the randomization criteria. More information on assigning randomization numbers is given in Section Call RAMOS and register the subject. 7. Assess height/weight and vital signs 8. Assess for current medical conditions/concurrent medications 9. Perform physical examination 10. Perform Tanner staging assessment 11. Perform nasal examination 12. Educate subjects regarding the procedures and their responsibilities when the observer is making measurements with the knemometer 13. Perform knemometry measurements. 14. Perform skin prick/in vitro test for pertinent allergen(s) if allergy test is undocumented per Section Obtain an 8 ml blood sample for clinical laboratory tests. (This sample will be drawn in conjunction with the 5mls of blood needed for the in vitro test for specific IgE, if required to determine allergy, such that only one venipuncture will be required at this visit.) 16. Dispense diary card. Explain the diary card and instruct the subject to answer the compliance question each morning after taking their dose. The patient should also be instructed to record any medical problem experienced or concomitant medication taken in the designated section of the diary card. 23

241 ZM2004/00069/02 CONFIDENTIAL 17. Demonstrate the use of the device using a placebo nasal spray device and establish that the subject s parent(s)/guardian(s) and, if deemed appropriate by the investigator, the subject have adequate understanding of the administration technique for the nasal spray device. If the investigator and parent(s)/guardian(s) agree the subject understands the proper administration procedure and is capable of administering the medication, the subject may administer the medication under adult supervision to ensure proper use and proper dose. A copy of the Subject Instruction Leaflet should be given to the parent(s)/guardian(s) to take with them so they may reference the correct administration procedure if necessary. 18. Prime the placebo nasal spray device to be dispensed then weigh it. All nasal spray devices must be primed prior to dispensing. Personnel trained in the use of the weighing device should perform the weighing procedure. 19. Dispense the single-blind, placebo nasal spray device and remind the subject to return the device and the diary card at the next visit. 20. Instruct subject/parent/guardian to administer the first dose of study medication at home the following morning. Subjects/parents/guardians must always administer the daily dose in the morning Randomization At Visit 2, subjects will be randomly assigned in a blinded fashion to a study treatment sequence. The subject will receive GW685698X aqueous nasal spray or placebo nasal spray for two weeks then be crossed over to the alternate study treatment for two weeks following a 2-week, placebo wash-out period Randomization Visit (Visit 2) The following assessments will be performed at Visit 2: 1. Collect diary card and the placebo nasal spray device. 2. Assess subject for concomitant medication use, medical problems, and adverse events. 3. Assess whether subject has met randomization criteria outlined in Section of the protocol. 4. Perform nasal examination. IF SUBJECT QUALIFIES FOR RANDOMIZATION, THE FOLLOWING ASSESSMENTS/PROCEDURES SHOULD THEN BE PERFORMED: 1. Call RAMOS and obtain randomization number. Randomization numbers are assigned to those subjects who meet the randomization criteria. The randomization number corresponds to one of the two possible treatment 24

242 ZM2004/00069/02 CONFIDENTIAL arms. Each subject will be dispensed double-blind treatment with a unique container number at this visit determined by the treatment arm assignment. 2. Perform vital signs. 3. Perform knemometry measurements. 4. Dispense diary card. 5. Weigh the single-blind, placebo nasal spray device returned. Prime the double-blind, treatment nasal spray device to be dispensed and weigh it. Record these weights in the CRF. 6. Dispense the double-blind, treatment nasal spray device and remind the subject to return the device and the diary card at the next visit. 7. Instruct subject/parent/guardian to administer the first dose of study medication at home the following morning. Subjects will always administer their daily dose in the morning Interim Visit (Visit 3) Beginning at Visit 3, subjects will enter a 2-week, single-blind, placebo wash-out period. The following assessments will be performed at Visit 3: 1. Collect the diary card and the double-blind, treatment nasal spray device. 2. Assess subject for concomitant medication use, medical problems, and adverse events. 3. Perform knemometry measurements. 4. Perform vital signs. 5. Perform nasal examination. 6. Dispense a diary card. Re-educate the parent(s)/guardian(s)/subject as needed regarding completion of the card. 7. Weigh the double-blind, treatment nasal spray device returned. Prime the singleblind, placebo nasal spray device to be dispensed at this visit and weigh it. Record these weights in the CRF. 8. Dispense single-blind, placebo nasal spray device and remind the subject to return the device and the diary card at the next visit. 9. Instruct subject/parent/guardian to continue to administer the study medication each morning Interim Visit (Visit 4) The following assessments will be performed at Visit 4: 1. Collect the diary card and the placebo nasal spray device. 25

243 ZM2004/00069/02 CONFIDENTIAL 2. Assess subject for concomitant medication use, medical problems, and adverse events. 3. Perform knemometry measurements 4. Perform vital signs. 5. Perform nasal examination. 6. Dispense a diary card. Re-educate the parent(s)/guardian(s)/subject as needed regarding completion of the card. 7. Weigh the single-blind, placebo nasal spray device returned. Prime the double-blind, treatment nasal spray device to be dispensed and weigh it. 8. Dispense the double-blind, treatment nasal spray device and remind the subject to return the device and the diary card at the next visit. Remind the subject/parent(s)/guardian(s) to continue to administer the study medication each morning Final Visit (Visit 5) The following assessments will be performed at Visit 5: 1. Collect the diary card and the double-blind, treatment nasal spray device. 2. Assess subject for concomitant medication use, medical problems, and adverse events. 3. Perform knemometry measurement. 4. Assess vital signs. 5. Perform physical examination. 6. Perform Tanner staging assessment. 7. Perform nasal examination. 8. Weigh the returned double-blind, treatment nasal spray device and record the weight in the CRF Follow-up phone call Site staff should perform a follow-up phone call to all subjects to assess for posttreatment adverse events 3 to 7 days after study completion or Early Withdrawal Early withdrawal visit In the event a randomized subject must be discontinued from the study, all assessments and procedures performed during Visit 5 (Final Visit) should be performed during the Early Withdrawal visit. The reason for early withdrawal must be documented in the source documents and CRF. If a subject is prematurely discontinued during a regularly scheduled visit, that visit will become the Early Withdrawal visit. Any procedures 26

244 ZM2004/00069/02 CONFIDENTIAL already performed should not be repeated and all procedures should be recorded on the Early Withdrawal CRF pages Safety Safety will be assessed by monitoring of adverse events, vital signs (blood pressure, heart rate [pulse]), physical examination, and nasal examination Physical examination A physical examination will be conducted at Visit 1 (Screening) and Visit 5/Early Withdrawal by the investigator, nurse practitioner, or physician s assistant listed on the FDA Form Physical examination results will be documented in the source documents only. Any unfavourable changes from the Visit 1 assessment will be recorded as an adverse event, documenting the start and stop dates of the adverse event. At each study visit, subjects will also be clinically assessed by the investigator with regard to the status of concurrent asthma (if present). A patient will be withdrawn if he or she demonstrates any deterioration in asthma that warrants introduction of inhaled or oral corticosteroid therapy Nasal examination A detailed nasal examination of the turbinates, mucosa, septum, and secretions will be performed by the investigator at all visits (Visits 1 through 5 or Early Withdrawal) and the findings recorded on the nasal examination CRF page. This examination will include an evaluation of nasal patency and the size of any polyps and ulcers that may be present. Any unfavorable changes that are not reflective of the symptoms of allergic rhinitis from the Visit 1 assessment will be recorded as an adverse event, documenting the start and stop dates of the adverse event. The same practitioner should perform the nasal examinations for a given subject at all visits when possible for consistency. Should the investigator recognize symptoms of a nasal fungal infection, a fungal culture should be performed. Culture kits will be provided for testing by a local laboratory and reported in the case report form. A diagnosis of nasal candidiasis should be reported as an adverse event Vital signs Vital signs (heart rate [pulse], systolic and diastolic blood pressure) will be measured at all visits with the subject in the seated position. The subject must be seated at least five minutes before these measurements are done. A single set of values for heart rate [pulse] and blood pressure (systolic and diastolic) will be determined and recorded in the CRF Clinical Laboratory Tests Routine laboratory tests (Appendix 4: Laboratory Assessments) will be performed at Visit 1. An 8 ml blood sample will be drawn at this visit to help assess the health of 27

245 ZM2004/00069/02 CONFIDENTIAL potential subjects. Following analysis, the blood sample will be held for 2 weeks and then destroyed. Subjects will not be required to fast prior to collection of the laboratory specimens. Quest Diagnostics, a central laboratory, will provide a manual to each site containing detailed instructions for collecting all specimens. Results of the laboratory tests will be transmitted electronically to GSK. A printout from the central laboratory of the results will be maintained at the site and will be signed and dated by the investigator confirming review. In cases of emergency when another laboratory other than the central lab is utilized, the investigator will supply GSK with the name, address of the laboratory, a copy of the certification, certification number, date of certification, and a list of normal values for all laboratory tests required by the protocol. Updated versions of these documents must be provided to GSK as appropriate. GSK will provide the above documentation for the central laboratory for this study, Quest Diagnostics, to the Principal Investigator. The investigator must assess the results of all clinical laboratory tests to determine each subject s eligibility to participate in the study. Any subject with all analytes within their respective reference range is eligible to continue. For any subject who has an analyte outside the reference range, the investigator has three options: 1. Exclude the subject from the study due to the deviant result and/or the uncertain clinical significance of the deviant result. 2. Repeat, at the earliest opportunity, the test for the analyte on a new specimen to assess the possibility of laboratory error. 3. Document the subject s eligibility for the study on the basis of one of the following explanations for the deviant result: Abnormality due to concurrent illness, disease process, or condition that would not render the subject in question at higher risk than a subject without a similar deviation in laboratory tests (e.g., eosinophilia in atopic subjects). Normal deviation for age (e.g., elevated alkaline phosphatase). Clinically insignificant deviation from normal values (i.e., in the judgement of the physician/investigator, the deviation does not indicate the presence of a disease state or compromised, predisposing state which renders the subject in question at higher risk than a subject without a similar deviation in laboratory tests). The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant. Section 14.4, Appendix 4 details the laboratory tests that are to be performed during this study. 28

246 ZM2004/00069/02 CONFIDENTIAL Pregnancy Only premenarchal females are eligible to participate in this study (Tanner Stage 1). Any female who begins to menstruate during the study will be discontinued and must have a serum pregnancy test at the Early Withdrawal visit. For the serum pregnancy test, 4 ml of blood will be collected to determine pregnancy status. Following analysis, the blood sample will be held for 2 weeks and then destroyed Time period for collecting pregnancy information The time period for collecting pregnancy information is from Visit 2 (Randomization) through study completion (Visit 5 or Early Withdrawal). Any subject who becomes pregnant during the study will be discontinued Action to be taken if pregnancy occurs The investigator, or his/her designee, will collect pregnancy information on any female subject who becomes pregnant while participating in this study. The investigator, or his/her designee, will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of a subject's pregnancy. The subject will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported. While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or a SAE, as described in Section 10.6, "Recording of AEs and SAEs" and will be followed as described in Section 10.8, "Follow-up of AEs and SAEs." A spontaneous abortion is always considered to be a SAE and will be reported as described in Section 10, Adverse Events (AE) and Serious Adverse Events (SAE). Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered reasonably related to the investigational product by the investigator, will be reported to GSK as described in Section 10.11, "Post-study AEs and SAEs." While the investigator is not obligated to actively seek this information in former study participants, he/she may learn of an SAE through spontaneous reporting Efficacy No efficacy measures will be collected in the study Compliance Assessment Subjects will be required to answer a compliance question ( Did you spray two sprays of your medication into each nostril today? ) each morning regarding use of their nasal spray on a diary card. 29

247 ZM2004/00069/02 CONFIDENTIAL In addition, study nasal spray devices will be weighed by site staff prior to dispensing and again when returned by the subjects at each visit to assess subject compliance. Weights of the nasal spray devices will be documented in the appropriate CRF. An appropriate balance for weighing the nasal spray devices will be provided to the study site by the sponsor. Detailed information will be provided to the site regarding the proper use and maintenance of the balances. The nasal spray devices will also be weighed at the beginning and end of each study period and the weights recorded in the CRF. The balance used to weigh the devices should be recalibrated according to the time table determined by the manufacturer. 7. INVESTIGATIONAL PRODUCT(S) 7.1. Description of Investigational Product GlaxoSmithKline will manufacture all double-blind, study medication. GW685698X Nasal Spray will be manufactured as a preserved, aqueous suspension containing 0.05% w/w of micronized GW685698X. The preservative system consists of benzalkonium chloride and disodium edetate. Each nasal spray bottle will contain a volume of suspension sufficient to deliver a minimum of 120 actuations. Each spray of the suspension will contain approximately 25mcg of GW685698X. The matching placebo nasal spray is comprised of the GW685698X vehicle. All spray devices must be primed according to the subject instruction leaflet for proper functioning prior to dispensing. Demonstration devices will be made available to allow site staff to demonstrate proper administration Dosage and Administration The investigator should discuss with the subject s parent(s)/guardian(s) whether the subject will be able to use the nasal spray device with supervision or whether the subject will require the parent/guardian to administer the daily dose. The Subject Instruction Leaflet should be reviewed with the subject/parent(s)/guardian(s) and a copy provided to take with them. If the subject is capable of administering the dose, both the subject and the parent(s)/guardian(s) will be educated in the use of the nasal spray using a placebo demonstration device. Otherwise, only the parent(s)/guardian(s) will be taught how to use the nasal spray device. All randomized subjects will receive a single-blind, placebo nasal spray treatment at Visit 1. The subject/parent/guardian will be instructed to administer two sprays per nostril each morning beginning the morning of the following day. Administration of the dose throughout the study period should be performed by alternately spraying one spray to each nostril followed by a second spray to each nostril. At the entry to the double-blind treatment period (Visit 2), eligible subjects will be assigned to a study treatment sequence in accordance with the randomization schedule. This first dose of double-blind study treatment will be administered beginning the morning of the first day following Visit 2 through and including the morning of Visit 3. 30

248 ZM2004/00069/02 CONFIDENTIAL Single-blind placebo nasal spray will be dispensed at Visit 3 and subjects will begin administering their dose from this spray device the morning after Visit 3 through and including the morning of Visit 4. Following this wash-out period, subjects will receive the alternate study treatment of their treatment sequence at Visit 4 to begin using the morning following Visit 4 through and including the morning of Visit 5. The daily dose should be administered each morning. Administration of the spray should be conducted according to the subject instruction leaflet that will be provided to the site by GSK Dose Rationale FFR20001 was the phase 2b dose-ranging study that examined doses of GW685698X 50 mcg, 100 mcg, 200 mcg and 400 mcg once daily. Based on results from this study, the 100-mcg dose of GW685698X aqueous nasal spray once daily has been selected as the adult dose to move forward in phase 3 clinical trials for the treatment of seasonal allergic rhinitis. All doses in the study were statistically superior to placebo for the primary and key secondary endpoints. When evaluating the lowest optimal dose to select to take forward into phase 3, 100 mcg exhibited numerically greater improvement in symptom scores for most endpoints compared to 50 mcg. Also, 100 mcg achieved an onset of 8 hours compared to 24 hours for 50 mcg. The 100-mcg dose exhibited a statistically significant difference over placebo of 21% in the primary endpoint (daily reflective total nasal symptom score) and was rated by more subjects than any other dose (28%) as providing significant improvement in an overall evaluation of treatment at study end. Overall adverse events rates were as follows by treatment group: 27% (placebo), 28% (50mcg), 29% (100mcg), 27% (200 mcg), and 24% (400mcg). The only adverse event that occurred at an incidence of 3% across all groups was epistaxis with incidence rates of 4% for placebo and 3% for 50 mcg, 8% for the 100 mcg, 9% for 200 mcg, and 7% for 400 mcg. All the events of epistaxis observed during treatment were mild in intensity. The incidence of drug-related adverse events was 11% for the 100-mcg dose and for the placebo group. The incidence of epistaxis that was deemed drug-related was 3% for placebo and 7% for the 100-mcg dose. No differences between the active and placebo treatments were noted in change from baseline in 24-hour, urinary free cortisol excretion. No other clinically relevant safety findings were noted for the 100-mcg dose or the other doses studied in relation to changes in ECGs, physical examinations, nasal examinations, or laboratory parameters. A pediatric dose for GW685698X has not been established. Thus, the primary objective of this study will be to evaluate the effect on growth of the highest likely dose that would be administered to pediatric subjects (GW685698X 100 mcg QD) to assure its safety in this regard in the treatment of rhinitis in children Blinding Only in the case of an emergency, when knowledge of the investigational product is essential for the clinical management or welfare of the subject, the investigator may unblind a subject s treatment assignment. If the blind is broken for any reason, the 31

249 ZM2004/00069/02 CONFIDENTIAL investigator must notify GSK immediately of the unblinding incident without revealing the subject s study treatment assignment. In addition, the investigator will record the date and reason for revealing the blinded treatment assignment for that subject in the appropriate CRF. If a serious adverse event (SAE; as defined in Section 10.2, "Definition of a SAE") is reported to GSK, Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment assignment for the individual subject. If an expedited regulatory report to one or more regulatory agencies is required, the report will identify the subject s treatment assignment. When applicable, a copy of the regulatory report may be sent to investigators in accordance with relevant regulations, GSK policy, or both Treatment Assignment Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product, in accordance with all applicable regulatory requirements. Only authorized site staff may supply or administer investigational product. Subjects will be assigned to study treatment, in accordance with a GSK computergenerated randomization schedule, via an Interactive Voice Response System (IVRS) called Registration and Medication Ordering System (RAMOS). Once a subject is determined eligible for randomization, a unique randomization number and medication pack will be assigned to the subject via RAMOS. A single-blind, placebo nasal spray pack will be dispensed at Visit 1 and Visit 3, while a double-blind nasal spray medication pack will be dispensed at Visit 2 and Visit 4. A container number on the medication pack will determine the numbering of these medication packs. The assignment of the double-blinded medication pack will be performed by the IVRS and accessed via personal identification numbers (PIN) assigned to authorised site personnel. The container number of the medication pack assigned to a subject will be linked to that subject s unique randomization number. Once assigned, container numbers and randomisation numbers cannot be reassigned to any other subject. The randomisation number will be documented in the subject s clinic notes and in the CRF. Detailed IVRS user instructions and worksheets will be provided at study start-up Packaging and Labeling The contents of the label will be in accordance with all applicable regulatory requirements. GSK will supply the investigator with sufficient quantities of blinded study drug for subjects to complete the study. Study drug will be dispatched to the site only after GSK has received the required documents, in accordance with all applicable regulatory requirements and GSK procedures. 32

250 ZM2004/00069/02 CONFIDENTIAL Treatment Pack At Visit 1 and Visit 3, a single-blinded, placebo nasal spray will be dispensed to each subject. Each treatment pack dispensed will contain a single-blinded nasal spray treatment labelled with a single-language label containing the protocol number, dosing instructions, contents, storage conditions, and sponsor name and address. At Visit 2 and Visit 4, a treatment pack containing a double-blinded nasal spray treatment will be assigned to randomized subjects via RAMOS. Each treatment pack dispensed will contain a double-blinded nasal spray treatment labelled with a single-language label containing the protocol number, pack number, dosing instructions, contents, storage conditions, and sponsor name and address. The contents of the label of all nasal sprays dispensed will be in accordance with all applicable regulatory requirements Allergy Rescue Medication At screening, all subjects will be dispensed loratadine tablets and/ or loratadine syrup, a non-prescription antihistamine, to use as allergy rescue medication on an as needed basis. The daily dose is not to exceed the maximum labelled dose for a given subjects age. The subject s parent/guardian or the subject, where deemed appropriate by the investigator, will record any use of rescue medication on the diary card. The investigator, or designee, will document the date rescue medication was dispensed and the amount dispensed on the Investigational Product Accountability log maintained at the study site Preparation No preparation of medication is required prior to administration of the study drug. Study drug is administered as is from the nasal spray device. However, a new nasal spray device must be primed before it is used for the first time. This ensures that a full dose will be delivered when the spray is used in the nose. Priming should be performed by site personnel in the clinic prior to dispensing. Please refer to the subject instruction leaflet for detailed directions for priming Handling and Storage Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product, in accordance with all applicable regulatory requirements. Only authorized site staff may supply or administer investigational product. All investigational products must be stored in a secure area with access limited to the investigator and authorized site staff and under physical conditions that are consistent with investigational product-specific requirements. 33

251 ZM2004/00069/02 CONFIDENTIAL 7.9. Product Accountability The investigator is responsible for investigational product accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or designated site staff must maintain investigational product accountability records throughout the course of the study. This person(s) will document the amount of investigational product received from GSK, the amount supplied and/or administered to and returned by subjects, if applicable Assessment of Compliance Subjects (and/or subject s parent/guardian) will also affirm the administration of their daily dose on the treatment diary card by answering the question Did you spray 2 sprays of your medication into each nostril today?. Study nasal spray devices will be weighed by site staff prior to dispensing and again when returned by the subjects at each visit to assess subject compliance. The subjects or their parent(s)/guardian(s) should not be made aware that the devices have been weighed. Weights of the nasal spray devices will be documented in the CRF. An appropriate balance for weighing the nasal spray devices will be provided to the study sites by the sponsor along with detailed information regarding the proper use and maintenance of the balance Treatment of Investigational Product Overdose An overdose is defined as a dose greater than the total doses described above which results in clinical signs or symptoms. In the event of an overdose of study medication, the investigator should use clinical judgement in treating the overdose and contact the study medical monitor. The investigator brochure for GW685698X should be referenced for any safety concerns Occupational Safety Investigational product is not expected to pose significant occupational safety risk to site staff under normal conditions of use and administration. However, precautions are to be taken to avoid direct skin contact, eye contact, and generating aerosols or mists. In the case of unintentional occupational exposure, treat as if the substance contains the active pharmaceutical even though it is absent from placebo formulations, and notify the monitor. A Material Safety Data Sheet (MSDS) describing occupational hazards and recommended handling precautions either will be provided to the investigator, where this is required by local laws, or is available upon request from GSK. 34

252 ZM2004/00069/02 CONFIDENTIAL 8. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES 8.1. Permitted Medications All concomitant medications taken during the study will be recorded in the CRF as well as any medications, such as asthma or allergy medication, taken in the previous 6 months that have the potential to affect growth. The minimum requirement is that drug name and the dates of administration are to be recorded. No other anti-allergy or anti-rhinitis medications, including oral, intranasal, ocular or throat treatments, will be permitted during the study except for the rescue medication loratadine provided by the sponsor and dispensed to the subject by the site. Immunotherapy patients may be enrolled in the study as long as the immunotherapy was not initiated within 30 days of Visit 1. All medications for other disorders may be continued throughout the study, provided the dose remains constant and their use would not be expected to affect the subject s growth. Inhaled or intranasal corticosteroids are not permitted within 2 weeks of study start to ensure at least 4 weeks washout before randomisation to study medication. Corticosteroids administered by other route (eg oral, intramuscular, intravenous, dermatological, ocular, otic) are not permitted within 4 weeks of study start. Subjects with mild, intermittent asthma may be treated with short-acting, inhaled beta 2 agonists on an as needed basis only Allergy rescue medication GSK will provide loratadine tablets and/or loratadine syrup, a non-prescription antihistamine, to all subjects to use as allergy rescue medication during the study on an as needed basis. The subject s parent/guardian or the subject, when deemed appropriate, will record their daily use of allergy rescue medication. The daily dose is not to exceed the maximum labelled dose for a given subject s age. No other anti-allergy/anti-rhinitis medications, including oral and intranasal products, are allowed during this study Prohibited Medications Concurrent use of any prescription or non-prescription medication containing a corticosteroid will not be allowed during this study. Concomitant use of any treatment that may potentially influence linear growth will not be allowed, including, but not limited to, the following medications: methylphenidate, thyroid hormone, growth hormone, androgens, calcitonin, estrogens, progestins, biphosphonates, anticonvulsants, or phosphate-binding antacids. Use of any medications that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazole, are prohibited. 35

253 ZM2004/00069/02 CONFIDENTIAL 8.3. Medical Devices No medical devices are involved in this study. 9. SUBJECT COMPLETION AND WITHDRAWAL 9.1. Subject Completion A subject that remains in the study throughout the screening and treatment periods (through Visit 5) is considered to have completed the study. Any subject who withdraws prior to Visit 5 will be considered an early withdrawal Subject Withdrawal Subject Withdrawal from Study A subject who takes double-blinded study drug but withdraws prior to Visit 5 has withdrawn early. Subjects who withdraw early will not be replaced. Subject withdrawal from the study is required and Early Withdrawal procedures must be performed, when: a subject is significantly non-compliant with the requirements of the protocol a subject has not completed the two 2-week treatment periods a subject becomes pregnant a subject has an adverse event that would, in the investigator s judgement, make continued participation in the study an unacceptable risk a subject demonstrates a decline in pulmonary function, as determined by the investigator, that warrants administration of inhaled or oral corticosteroids subject experiences major trauma to the legs, requires major surgery, or, in the opinion of the investigator, becomes severely dehydrated a subject has a change in Tanner stage the treatment blind is broken for a subject (by other than GSK GCSP personnel), or GlaxoSmithKline discontinues the study. A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, discontinue the subject from participating in this study at any time. If a subject is prematurely discontinued from participation in the study for any reason, the investigator must make every effort to perform the following evaluations at an Early Withdrawal visit: 36

254 ZM2004/00069/02 CONFIDENTIAL Knemometry Review all information recorded on the diary cards Conduct adverse event assessment Physical examination Nasal examination Concomitant medication assessment Study drug collection (single-blind, double-blind, and rescue) These data should be recorded in the patient record and CRF, as appropriate, as they comprise an essential evaluation that should be done prior to discharging any subject from the study. Any clinically significant adverse event, nasal examination, or clinically significant unfavorable change observed during the Early Withdrawal Visit will necessitate that the subject be followed or treated until satisfactory resolution occurs. In the event that a subject is prematurely discontinued from the study at any time due to an AE (as defined in Section 10.1, Definition of an AE ) or SAE (as defined in Section 10.2, Definition of an SAE ), the procedures stated in Section 10, ( AEs and SAEs ) must be followed Subject Withdrawal from Investigational Product Subjects who discontinue administration of study drug prematurely will be withdrawn from the study. Premature discontinuation of the study drug will be defined as discontinuation of the double-blind study treatment for more than 2 consecutive days before the end of that study period Extension Study There is no extension study associated with this protocol Screen and Baseline Failures A subject who is assigned a subject number, but is not randomized has failed screening. The following information will be collected on subjects who fail screening: demographic information including race, age, and gender reason for screen failure (inclusion/exclusion criteria CRF page, screening failure CRF page, and randomization criteria CRF page) SAE information. 37

255 ZM2004/00069/02 CONFIDENTIAL 10. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE as provided in this protocol. During the study, when there is a safety evaluation, the investigator or site staff will be responsible for detecting AEs and SAEs, as detailed in this section of the protocol Definition of an AE Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. Examples of an AE includes: Significant or unexpected worsening or exacerbation of the condition/indication under study. See Section 10.3, Lack of Efficacy, for additional information. Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition. New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study. Signs, symptoms, or the clinical sequelae of a suspected interaction. Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concurrent medication (overdose per se should not be reported as an AE/SAE). Examples of an AE does not include a/an: Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE. Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital). Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen. The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject s condition. 38

256 ZM2004/00069/02 CONFIDENTIAL For GSK clinical studies, AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject s previous therapeutic regimen) Definition of a SAE A serious adverse event is any untoward medical occurrence that, at any dose: a. results in death. b. is life-threatening. NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe. c. requires hospitalization or prolongation of existing hospitalization. NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether hospitalization occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. d. results in disability/incapacity, or NOTE: The term disability means a substantial disruption of a person s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption. e. is a congenital anomaly/birth defect. Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse. 39

257 ZM2004/00069/02 CONFIDENTIAL Lack of Efficacy Lack of efficacy per se will not be reported as an AE. The signs and symptoms or clinical sequelae resulting from lack of efficacy will be reported if they fulfill the AE or SAE definition (including clarifications) Clinically Abnormal Assessments as AEs and SAEs Abnormal laboratory findings post-randomization (e.g., clinical chemistry, hematology) or other abnormal assessments (e.g., ECGs, vital signs, etc.]) that are judged by the investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section 10.1, ("Definition of an AE"), or SAE, as defined in Section 10.2, ("Definition of a SAE"). Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with the disease being studied, unless judged by the investigator as more severe than expected for the subject s condition, or that are present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs. The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant Time Period, Frequency, and Method of Detecting AEs and SAEs All AEs and SAEs will be collected from Visit 1 through the follow-up visit. At every visit, after the subject has had an opportunity to spontaneously mention any problems, the Investigator should inquire about AEs by asking the following standard questions: 1. Have you had any (other) medical problems or worsening of any medical problems since your last visit/assessment? 2. Have you taken any new medicines, other than those given to you in this study, since your last visit/assessment? Diary cards will be reviewed at each visit and if the subject does not mention an event that is recorded, he/she should be questioned for further information in order to determine if there was some occurrence of an adverse event. If an AE is unresolved at the time of the last visit, refer to Section 10.8 for follow-up requirements Recording of AEs and SAEs When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event. The investigator will then record all relevant information regarding an 40

258 ZM2004/00069/02 CONFIDENTIAL AE/SAE on the CRF. It is not acceptable for the investigator to send photocopies of the subject s medical records to GSK in lieu of completion of the appropriate AE/SAE CRF pages. However, there may be instances when copies of medical records for certain cases are requested by GSK. In this instance, all subject identifiers will be blinded on the copies of the medical records prior to submission to GSK. The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be documented as the AE/SAE and not the individual signs/symptoms Evaluating AEs and SAEs Assessment of Intensity The investigator will make an assessment of intensity for each AE and SAE reported during the study. The assessment will be based on the investigator s clinical judgement. The intensity of each AE and SAE recorded in the CRF should be assigned to one of the following categories: Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities. Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities. Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should not be confused with a SAE. Severity is a category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. An event is defined as serious when it meets one of the pre-defined outcomes as described in Section 10.2, Definition of a SAE Assessment of Causality The investigator is obligated to assess the relationship between investigational product and the occurrence of each AE/SAE. The investigator will use clinical judgement to determine the relationship. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the investigational product will be considered and investigated. The investigator will also consult the CIB/IB and/or Product Information, for marketed products, in the determination of his/her assessment. There may be situations when an SAE has occurred and the investigator has minimal information to include in the initial report to GSK. However, it is very important that the investigator always make an assessment of causality for every event prior to transmission of the SAE CRF to GSK. The investigator may change his/her opinion of causality in light of follow-up information, amending the SAE CRF accordingly. The causality 41

259 ZM2004/00069/02 CONFIDENTIAL assessment is one of the criteria used when determining regulatory reporting requirements. The investigator will provide the assessment of causality as per instructions on the SAE form in the CRF Follow-Up of AEs and SAEs After the initial AE/SAE report, the investigator is required to proactively follow each subject and provide further information to GSK on the subject s condition. All AEs and SAEs documented at a previous visit/contact and are designated as ongoing, will be reviewed at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up. Once resolved, the appropriate AE/SAE CRF page(s) will be updated. The investigator will ensure that follow-up includes any supplemental investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. This may include additional laboratory tests or investigations, histopathological examinations, or consultation with other health care professionals. GSK may request that the investigator perform or arrange for the conduct of supplemental measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of the AE or SAE. The investigator is obligated to assist. If a subject dies during participation in the study or during a recognized follow-up period, GSK will be provided with a copy of any post-mortem findings, including histopathology. New or updated information will be recorded on the originally completed SAE CRF, with all changes signed and dated by the investigator. The updated SAE CRF should be resent to GSK within the time frames outlined in Section Prompt Reporting of SAEs to GSK SAEs will be reported promptly to GSK as described in the following table once the investigator determines that the event meets the protocol definition of an SAE Timeframes for Submitting SAE Reports to GSK Initial SAE Reports Follow-up Information on a Previously Reported SAE Type of SAE Time Frame Documents Time Frame Documents All SAEs 24 hrs "SAE" CRF pages 24 hrs Updated "SAE" CRF pages 42

260 ZM2004/00069/02 CONFIDENTIAL Completion and Transmission of the SAE Reports Once an investigator becomes aware that an SAE has occurred in a study subject, she/he will report the information to GSK within 24 hours as outlined in Section 10.9, Prompt Reporting of SAEs to GSK. The SAE CRF will always be completed as thoroughly as possible with all available details of the event, signed by the investigator (or designee), and forwarded to GSK within the designated time frames. If the investigator does not have all information regarding an SAE, he/she will not wait to receive additional information before notifying GSK of the event and completing the form. The form will be updated when additional information is received. The investigator will always provide an assessment of causality at the time of the initial report as described in Section , Assessment of Causality. Facsimile transmission of the SAE CRF is the preferred method to transmit this information to the project contact for SAE receipt. In rare circumstances and in the absence of facsimile equipment, notification by telephone is acceptable, with a copy of the "SAE" CRF sent by overnight mail. Initial notification via the telephone does not replace the need for the investigator to complete and sign the SAE CRF within the time frames outlined in Section 10.9, Prompt Reporting of SAEs to GSK. GSK will provide a list of project contacts for SAE receipt, fax numbers, telephone numbers, and mailing addresses Regulatory Reporting Requirements For SAEs The investigator will promptly report all SAEs to GSK in accordance with the procedures detailed in Section 10.9, "Prompt Reporting of SAEs to GSK." GSK has a legal responsibility to notify, as appropriate, both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. Prompt notification of SAEs by the investigator to the appropriate project contact for SAE receipt is essential so that legal obligations and ethical responsibilities towards the safety of other subjects are met. The investigator, or responsible person according to local requirements, will comply with the applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). This protocol has been filed under an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). A given SAE may qualify as an IND Safety Report if the SAE is both attributable to the investigational product and unexpected. In this case, all investigators filed to the IND (and associated INDs for the same compound) will receive an Expedited Investigator Safety Report (EISR), identical in content to the IND Safety Report submitted to the FDA. EISRs are prepared according to GSK policy and are forwarded to investigators as necessary. An EISR is prepared for a SAE that is both attributable to investigational 43

261 ZM2004/00069/02 CONFIDENTIAL product and unexpected. The purpose of the EISR is to fulfill specific regulatory and Good Clinical Practice (GCP) requirements, regarding the product under investigation. When a site receives from GSK an Initial or Follow-up EISR or other safety information (e.g., revised Clinical Investigator s Brochure/Investigator s Brochure), the responsible person according to local requirements is required to promptly notify his or her IRB or IEC Post-study AEs and SAEs A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE detection period defined in Section 10.5, Time Period, Frequency, and Method of Detecting AEs and SAEs, of the protocol. Investigators are not obligated to actively seek AEs or SAEs in former study participants. However, if the investigator learns of any SAE, including a death, at any time after a subject has been discharged from the study, and he/she considers the event reasonably related to the investigational product, the investigator will promptly notify GSK SAEs Related to Study Participation An SAE considered related to study participation (e.g., procedures, invasive tests, a change in existing therapy), even if it occurs during the pre- or post-treatment period, will be reported promptly to GSK (see Section 10.9, "Prompt Reporting of SAEs to GSK"). 11. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS Hypotheses The purpose of this study is to assess the effect of GW685698X 100mcg QD aqueous nasal spray on short term lower leg growth. The primary objective is to demonstrate that GW685698X 100mcg is non-inferior compared to placebo on lower leg growth rate, measured by knemometry. The null and alternative hypotheses for the primary analysis are: H 0 : µ µ PBO δ H A : µ µ PBO > δ where µ 100 and µ PBO represent the mean growth rate (mm/week) over a 2-week treatment period for GW685698X 100mcg QD aqueous nasal spray and placebo treatment groups, respectively, and the pre-specified, non-inferiority margin δ is mm/week. Noninferiority will be demonstrated if the lower limit of the confidence interval (0.025, 1 sided-significance level) for mean difference in lower leg growth rate of GW685698X versus placebo is greater than 0.20 mm/week. 44

262 ZM2004/00069/02 CONFIDENTIAL Primary Comparison of Interest The primary comparison will be made on the mean lower leg growth rate as measured by knemometry over the 2-week treatment period for GW685698X and placebo Interim Analysis No interim analyses are planned Sample Size Considerations Sample Size Assumptions The estimated mean growth velocity for the placebo-treated group ranged from 0.40 to 0.50 mm/week in the previous GSK studies as well as in the literature for other knemometry studies. GW685698X 100mcg QD is considered to be non-inferior to placebo with respect to lower leg growth velocity if the lower limit of the two-sided 95% (or one-sided 97.5%) confidence interval for the treatment difference (GW685698X minus placebo) is greater than or equal to 0.20 mm/week (roughly 40%-50% of placebo growth rate). With 50 completed subjects (25 subjects per sequence), the study should provide 90% power, assuming a standard deviation of 0.30 mm/week based on GSK previous studies as well as the literature for knemometry and a true treatment difference (GW685698X minus placebo) in lower leg growth rate of 0.0 mm/week. In anticipation of a drop-out rate of 10%, approximately 56 subjects will be randomized to achieve completion of at least 50 subjects Sample Size Sensitivity To demonstrate the sensitivity of the sample size calculation for this study, the following table presents the power of the study under different circumstances in terms of the standard deviation and the true treatment difference in lower leg growth rate in mm/week for a fixed sample size of 50 subjects (25 subjects per sequence). The assumption used is shaded. Standard Deviation True Mean Difference between GW and Placebo % 99% >99% % 93% 97% % 82% 90% % 69% 80% 45

263 ZM2004/00069/02 CONFIDENTIAL Sample Size Re-estimation Sample size re-estimation is not planned Analysis Populations The analyses of all safety data will be performed on the Intention-To-Treat (ITT) population, defined as all randomized subjects who receive at least one dose of study drug. The analysis of the primary safety endpoint data, i.e., the lower leg growth rate, will also be performed on the growth population (of primary interest), in addition to the ITT population (as supportive). The growth population is defined to exclude from the ITT population subjects who did not have sufficient or reliable lower leg growth data in order to provide an estimate for both 2-week treatment periods (GW685698X and placebo) or subjects who have received any protocol-prohibited medications that may affect short term growth (e.g. systemic or inhaled corticosteroid medications that have confounding effects on the interpretation of the growth velocity). The growth population is defined as the ITT population excluding subjects who have any one of the following: 4. Did not fulfil the inclusion, exclusion and randomization criteria that are growth specific. 5. Did not have growth assessment(s) by knemometry at any protocol planned assessment time point (e.g. growth rate cannot be estimated for at least one treatment period). 6. Withdrawal from the study due to adverse events related to major trauma to the legs, major surgery, or severe dehydration. 7. Received protocol prohibited medications (other than the study medication) prior to randomization and during the study. 8. A change in Tanner stage during the study. The analysis of the primary endpoint (mean lower leg growth rate) will be performed for both the growth population (of primary interest) and the ITT population (supportive). Membership of the analysis populations will be determined prior to the database freeze based on a blind review of the study database General Considerations for Data Analysis Withdrawal For any subject who withdraws from the study early, all available data up to the time of discontinuation will be included for the safety report on the parameters other than knemometry. 46

264 ZM2004/00069/02 CONFIDENTIAL Missing Data Missing data will not be imputed for the safety measures Derived and Transformed Data For a given subject, the lower leg growth rate is estimated as change in lower leg length from beginning to end of a 2-week treatment period divided by the time interval between the two measurements as follows: Growth rate = Change in lower leg length 7 / (end date start date of the period). For each visit, the lower leg length is defined as the average of 3 repeated knemometry assessments. The unit for growth rate is mm/week Assessment Windows Assessment windows for the scheduled study visits are: Visit 2 (Randomization, 14± 3 days after Visit 1), Visit 3 (Week 2, 14 ± 3 days after randomization), Visit 4 (Week 4, 14 ± 3 days after Visit 3), and Visit 5 (Week 6, 14 ± 3 days after Visit 4). Individual assessments collected outside of the assessment window for scheduled visits will be included in the ITT analysis without adjustment. If multiple assessments are collected within the same assessment window, the last valid value prior to randomisation will be used as the baseline value and the first valid value will be used for all post-randomisation visits Treatment Compliance Treatment compliance will be assessed based on the compliance with the dose regimen recorded by subjects on the diary card and the weight of the dispensed nasal spray devices recorded on the CRF page at clinic visits when dispensing occur. Compliance data will be summarized. The compliance rate, based on the weight of the nasal spray, will also be summarised Efficacy Analyses No efficacy analyses will be performed Safety Analyses Primary Safety Analysis The primary safety endpoint is the mean lower leg growth rate (mm/week) measured by knemometry. All summary and analysis tables, as well as the graphs, will be provided 47

265 ZM2004/00069/02 CONFIDENTIAL for both the growth population (of primary interest) and the ITT population (as supportive). The reasons for exclusion from the growth population will be listed by subject. The primary analysis method will be the comparison of the treatment groups (GW vs. placebo) using analysis of covariance (ANCOVA) adjusting for baseline lower leg growth rate measured by knemometry, age, and gender. Treatment will be included as fixed effect in the model, and subject as random effect. Period effect will be considered as a fixed effect. Individual patient, 2-week lower leg growth rates during each of the two treatment periods (GW685698X 100mcg and placebo) will be plotted against each other. The distribution of the lower leg growth rates will also be illustrated by treatment group via histogram for both the growth population and the ITT population. Summary statistics will be provided for the lower leg growth rate as measured by knemometry during each of the two treatment periods (GW685698X and placebo) as well as the following wash-out period. The least squares mean lower leg growth rate for each treatment period will be summarized and compared. The 95% confidence interval (CI) for the treatment mean difference (active and placebo) will also be reported Extent of Exposure Extent of exposure to study treatment (i.e., number of days on treatment) will be summarized by treatment group for both the ITT population and the Growth population, using the mean, standard deviation, median, minimum, and maximum Adverse Events Adverse events during the screening period, each of the two double-blind treatment periods, the wash-out period between the two double-blind treatment periods,and the post treatment period will be summarized and displayed. The onset date of the adverse events relative to the clinic visit dates will be used to determine in which period an adverse event occurs. Adverse events during the screening period include those with a date of onset prior to study treatment initiation (randomisation date). Adverse events during each of the two double-blind treatment periods include those with a date of onset within the period including both the beginning and the end date of the period. Adverse events during the wash-out periods include those with a date of onset within the wash-out period excluding the beginning and the end dates of the period. Adverse events with a date of onset after treatment termination will be reported for the post-treatment period. The CRF texts for adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and will be reported using the primary System Organ Class (SOC) and Preferred Term. Preferred Terms will be summarized within the primary SOC. The relationship of primary SOC, preferred terms, and verbatim text will be listed. 48

266 ZM2004/00069/02 CONFIDENTIAL The number of subjects with one or more events of any type will be calculated. Results will be displayed in the order of decreasing frequency, both across primary SOC and within primary SOC. Adverse events will also be listed. Demographic details (e.g., age, sex, and race), as well as details of the individual adverse events, will be included in these listings. Listings will be sorted within subject by the adverse event date of onset. Similar summaries and listings will be provided for drug-related adverse events. A listing will be provided for adverse events leading to withdrawal from study Deaths and Serious Adverse Events All serious adverse events will be listed. Any pregnancies and deaths reported during this study will also be summarized in case narratives written by Global Clinical Safety and Pharmacovigilance personnel Nasal Examination Nasal examinations will be performed at each visit, and will include assessments of patency, septum deviation, mucosa, secretions, ulcers, and polyposis. Nasal examination results will be summarized by visit for each of the 6 examination parameters listed above. At all visits, frequencies of classifications (yes/no, absent/present) will be calculated. Shift from baseline to end of the treatment, as well as from beginning to end of each period will also be summarized for each individual nasal examination parameter. All nasal examination results will be listed for those subjects with at least one abnormal nasal examination result post baseline Vital Signs Number of subjects, mean, standard deviation, median, minimum, and maximum will be used to summarise vital signs (heart rate, systolic blood pressure, and diastolic blood pressure) by visit. 12. STUDY ADMINISTRATION Regulatory and Ethical Considerations Regulatory Authority Approval GSK will obtain approval to conduct the study from the appropriate regulatory agency in accordance with any applicable country-specific regulatory requirements prior to a site initiating the study in that country. 49

267 ZM2004/00069/02 CONFIDENTIAL Ethical Conduct of the Study and Ethics Approval This study will be conducted in accordance with "good clinical practice" (GCP) and all applicable regulatory requirements, including, where applicable, the 1996 version of the Declaration of Helsinki. The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the site s informed consent form, and any other information that will be presented to potential subjects (e.g., advertisements or information that supports or supplements the informed consent) are reviewed and approved by the appropriate IEC. The investigator agrees to allow the IEC direct access to all relevant documents. The IEC must be constituted in accordance with all applicable regulatory requirements. GSK will provide the investigator with relevant document(s)/data that are needed for IEC review and approval of the study. Before investigational product(s) and CRFs can be shipped to the site, GSK must receive copies of the IEC approval, the approved informed consent form, and any other information that the IEC has approved for presentation to potential subjects. If the protocol, the informed consent form, or any other information that the IEC has approved for presentation to potential subjects is amended during the study, the investigator is responsible for ensuring the IEC reviews and approves, where applicable, these amended documents. The investigator must follow all applicable regulatory requirements pertaining to the use of an amended informed consent form including obtaining IEC approval of the amended form before new subjects consent to take part in the study using this version of the form. Copies of the IEC approval of the amended informed consent form/other information and the approved amended informed consent form/other information must be forwarded to GSK promptly Informed Consent Informed consent will be obtained before the subject can participate in the study. The contents and process of obtaining informed consent will be in accordance with all applicable regulatory requirements Investigator Reporting Requirements As indicated in Section 10.10, the investigator (or sponsor, where applicable) is responsible for reporting SAEs to the IEC, in accordance with all applicable regulations. Furthermore, the investigator may be required to provide periodic safety updates on the conduct of the study at his or her site and notification of study closure to the IEC/IRB. Such periodic safety updates and notifications are the responsibility of the investigator and not of GSK Study Monitoring In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the subject enrollment to review the protocol and data collection procedures with site staff. In addition, the monitor will periodically contact the 50

268 ZM2004/00069/02 CONFIDENTIAL site, including conducting on-site visits. The extent, nature and frequency of on-site visits will be based on such considerations as the study objective and/or endpoints, the purpose of the study, study design complexity, and enrollment rate. During these contacts, the monitor will: Check the progress of the study. Review study data collected. Conduct source document verification. Identify any issues and address their resolution. This will be done in order to verify that the: Data are authentic, accurate, and complete. Safety and rights of subjects are being protected. Study is conducted in accordance with the currently approved protocol (and any amendments), GCP, and all applicable regulatory requirements. The investigator agrees to allow the monitor direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the monitor to discuss findings and any relevant issues. At study closure, monitors will also conduct all activities described in Section 12.4, "Study and Site Closure." The monitor will also review subject-completed health outcomes questionnaire(s) for extraneous written comments that could indicate possible AEs. Information collected in the CRF and in the subject-completed health outcomes questionnaire(s) are independent components of this study. Except for header section information (e.g., subject number, treatment number, visit date) and other information as defined in the standard clarification agreement (SCA), neither the monitor nor the investigator will attempt to reconcile responses to individual questions/items recorded on the subject-completed health outcomes questionnaire(s) or health outcomes portions of diary cards (if applicable) with other data recorded in the CRFs. Subject-completed health outcome questionnaires generally serve as the source document; therefore, unless otherwise specified elsewhere, no other source document is available for data validation Quality Assurance To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any time during or after completion of the study. If an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues. 51

269 ZM2004/00069/02 CONFIDENTIAL Study and Site Closure Upon completion of the study, the monitor will conduct the following activities in conjunction with the investigator or site staff, as appropriate: Return of all study data to GSK. Data queries. Accountability, reconciliation, and arrangements for unused investigational product(s) and rescue medications. Review of site study records for completeness. Return of treatment codes to GSK. Shipment of samples to assay laboratory In addition, GSK reserves the right to temporarily suspend or prematurely discontinue this study either at a single site or at all sites at any time for reasons including, but are not limited to, safety or ethical issues or severe non-compliance. If GSK determines such action is needed, GSK will discuss this with the Investigator (including the reasons for taking such action) at that time. When feasible, GSK will provide advance notification to the investigator of the impending action prior to it taking effect. GSK will promptly inform all other investigators and/or institutions conducting the study if the study is suspended or terminated for safety reasons, and will also inform the regulatory authorities of the suspension or termination of the study and the reason(s) for the action. If required by applicable regulations, the investigator must inform the IEC/IRB promptly and provide the reason for the suspension or termination. If the study is prematurely discontinued, all study data must be returned to GSK. In addition, arrangements will be made for all unused investigational product(s) in accordance with the applicable GSK procedures for the study. Financial compensation to investigators and/or institutions will be in accordance with the agreement established between the investigator and GSK Records Retention Following closure of the study, the investigator must maintain all site study records in a safe and secure location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The investigator must assure that all reproductions are legible and are a true and accurate copy of the original, and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must 52

270 ZM2004/00069/02 CONFIDENTIAL ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions. GSK will inform the investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any institutional requirements or local laws or regulations, or GSK standards/procedures; otherwise, the retention period will default to 15 years. The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, the following: archival at an off-site facility, transfer of ownership of the records in the event the investigator leaves the site Provision of Study Results and Information to Investigators When a clinical study report is completed, GSK will provide the findings of the study to the investigator. In addition, details of the study treatment assignment will be provided to the investigator to enable him/her to review the data to determine the outcome of the study for his/her subjects Information Disclosure and Inventions Ownership: All information provided by GSK and all data and information generated by the site as part of the study (other than a subject s medical records) are the sole property of GSK. All rights, title, and interests in any inventions, know-how or other intellectual or industrial property rights which are conceived or reduced to practice by site staff during the course of or as a result of the study are the sole property of GSK, and are hereby assigned to GSK. If a written contract for the conduct of the study which includes ownership provisions inconsistent with this statement is executed between GSK and the study site, that contract s ownership provisions shall apply rather than this statement. Confidentiality: All information provided by GSK and all data and information generated by the site as part of the study (other than a subject s medical records) will be kept confidential by the investigator and other site staff. This information and data will not be used by the investigator or other site personnel for any purpose other than conducting the study. These restrictions do not apply to: (1) information which becomes publicly available through no fault of the investigator or site staff; (2) information which it is necessary to disclose in confidence to an IEC or IRB solely for the evaluation of the study; 53

271 ZM2004/00069/02 CONFIDENTIAL (3)information which it is necessary to disclose in order to provide appropriate medical care to a study subject; or (4) study results which may be published as described in the next paragraph. If a written contract for the conduct of the study which includes confidentiality provisions inconsistent with this statement is executed, that contract s confidentiality provisions shall apply rather than this statement. Publication: The first publication or disclosure of study results shall be a complete, joint publication or disclosure coordinated by GSK. Thereafter, any secondary publications will reference the original publication(s). Prior to submitting for publication, presentation, use for instructional purposes, or otherwise disclosing the study results generated by the site (collectively, a Publication ), the investigator shall provide GSK with a copy of the proposed Publication and allow GSK a period of at least thirty (30) days [or, for abstracts, at least five (5) working days] to review the proposed Publication. Proposed Publications shall not include either GSK confidential information other than the study results or personal data on any subject, such as name or initials. At GSK s request, the submission or other disclosure of a proposed Publication will be delayed a sufficient time to allow GSK to seek patent or similar protection of any inventions, know-how or other intellectual or industrial property rights disclosed in the proposed Publication. If a written contract for the conduct of the study, which includes publication provisions inconsistent with this statement is executed, that contract s publication provisions shall apply rather than this statement Data Management Subject data are collected by the investigator or designee using the Case Report Form (CRF) defined by GSK. Subject data necessary for analysis and reporting will be entered/transmitted into a validated database or data system. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures. Database freeze will occur when data management quality control procedures are completed. Original CRFs will be retained by GSK, while the investigator will retain a copy. 54

272 ZM2004/00069/02 CONFIDENTIAL 13. REFERENCES Agertoft L, Pedersen, S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000;343: Agertoft L, Pedersen S. Short-term lower leg growth rate in children with rhinitis treated with intranasal mometasone furoate and budesonide. J Allergy Clin Immunol 1999;104: Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med 2000;343: Global Initiative for Asthma (GINA) Guidelines, Available at Accessed September 28, Hermanussen M, Geiger-Benoit K, Burmeister J, et al. Knemometry in childhood: accuracy and standardization of a new technique of lower leg length measurement. Ann Hum Biol 1988;15:1-16. Pedersen S. Do inhaled corticosteroids inhibit growth in children? Am J Respir Crit Care Med 2001;164: Scadding GK. Corticosteroids in the treatment of pediatric allergic rhinitis. J Allergy Clin Immunol 2001; 108;S Skoner DP, Gentile D, Angelini B, et al. The effects of triamcinolone acetonide and intranasal fluticasone propionate on short-term bone growth and HPA axis in children with allergic rhinitis. Ann Allergy Asthma Immunol 2003;90: Task Force on Allergic Disorders. American Academy of Allergy, Asthma, and Immunology. The Allergy Report. Available at Accessed July 23, Wales JKH, Milner RDG. Knemometry is assessment of linear growth. Arch Dis Child 1987;62: Wit JM, Kalsbeek EJ, Wijk-Hoek, et al. Assessment of the usefulness of weekly knemometric measurements in growth studies. Acta Paediatr Scand 1987;76: Weiner JM, Abramson MJ, Puy RM. Intranasal corticosteroids versus oral H1 receptor antagonists in allergic rhinitis: systematic review of randomized controlled trials. BMJ 1998;317: Wolthers OD, Pedersen S. Controlled study of linear growth in asthmatic children during treatment with inhaled glucocorticosteroids. Pediatrics 1992; Wolthers OD, Pedersen S. Short-term linear growth in asthmatic children during treatment with prednisolone. BMJ 1990; 301(6744):

273 ZM2004/00069/02 CONFIDENTIAL 14. APPENDICES Appendix 1: Time and Events Table Visits F/U b Study Day or 46 EW a Activity ±3 ±3 ±3 ±3 ± Informed consent X Subject number assignment X Demography X Medical history X Rhinitis history X Evaluate Inclusion/Exclusion criteria X Height/Weight X Vital Signs X X X X X Physical examination X X Tanner staging X X Nasal examination X X X X X Nasal spray technique demonstration X Concomitant medication assessment X X X X Knemometric assessment X X X X X Blood sample for laboratory tests X Randomization number assignment X Weigh and dispense single-blind, X X placebo nasal spray Dispense rescue medication X Issue diary card X X X X Collect and weigh single-blind, X X placebo nasal spray Weigh and dispense double-blind, X X treatment nasal spray Collect and weigh double-blind, X X treatment nasal spray Adverse event assessment X X X X X Diary card assessment X X X X Follow up b phone call a. EW = Early Withdrawal; b. Follow-Up X 56

274 ZM2004/00069/02 CONFIDENTIAL Appendix 2: Study Schematic Diagram 57

275 ZM2004/00069/02 CONFIDENTIAL Appendix 3: Country Specific Requirements No country-specific requirements exist. 58

276 ZM2004/00069/02 CONFIDENTIAL Appendix 4: Laboratory Assessments An 8 ml blood sample will be drawn during the study at Visit 1 to assess the health of potential subjects. Following analysis, the blood sample will be held for 2 weeks and then destroyed. An additional 5 ml sample may also be needed to assess specific IgE antibody (as determined by the investigator). Both blood samples will be collected at the same time such that only one venipuncture will be required at this visit. A separate venipuncture will be required to obtain 4 mls of blood at an Early Withdrawal visit for any female who begins to menstruate during the study. Chemistry Hematology Electrolytes Total Bilirubin Hemoglobin Sodium Alkaline Phosphatase Hematocrit Potassium Alanine Amino-transferase (ALT or RBC SGPT) Aspartate Amino-transferase (AST WBC or SGOT) Glucose Neutrophils Creatinine Lymphocytes Urea nitrogen Monocytes Calcium Eosinophils Total Protein Basophils Albumin Platelets 59

277 ZM2004/00069/02 CONFIDENTIAL Appendix 5: History of Change Amendments 1 and 2 for this protocol led to the following changes in the protocol: 1. Section 3.2 Secondary Safety Endpoints was revised to remove the physical examination as a safety endpoint, as any new clinically significant abnormality found during physical examination will be reported as a clinical adverse event. 2. Section Inclusion Criteria, Section Randomization Criteria and Section Exclusion Criteria were changed to numbered instead of bulleted lists. 3. Section was also revised to clarify that the clinical laboratory blood sample could be drawn in conjunction with any sample taken for in vitro allergy testing. 4. Section was also revised to change the exclusionary period for intranasal and inhaled corticosteroid use from a minimum of six weeks to a minimum of four weeks prior to randomisation (at least two weeks prior to Visit 1 plus 2 weeks between Visit 1 and randomisation). 5. Section includes further details on the collection and storage procedures for a pregnancy testing. 6. Section 7.6.2, Section 8.1, and Section have been revised to allow for the use of sponsor provided loratadine syrup as well as loratadine tablets as rescue medication for the as needed relief of allergy symptoms. 7. Section 8.1 was also revised to change the permitted period for use of intranasal and inhaled corticosteroid prior to Visit Section was revised to allow the clinical laboratory blood sample to be drawn in conjunction with any sample taken for in vitro allergy testing. 9. Section and Appendix 4 (Laboratory assessments) were revised to allow for additional blood to be drawn for allergy testing and also to remove the assay for C reactive protein. Given below are the detailed changes as result of Amendments 1 and 2. Original Text: Section 3.2 Secondary Safety Endpoints Secondary safety assessments will be: the frequency and type of clinical adverse events experienced during treatment physical examination, including gross nasal examination vital signs (systolic and diastolic blood pressure, heart rate [pulse]) Revised Text: Section 3.2 Secondary Safety Endpoints Secondary safety assessments will be: the frequency and type of clinical adverse events experienced during treatment 60

278 ZM2004/00069/02 CONFIDENTIAL nasal examination vital signs (systolic and diastolic blood pressure, heart rate [pulse]) Original Text: Inclusion Criteria A subject will be eligible for inclusion in this study only if all of the following criteria apply: Pre-menarcheal female subjects who are 6 years to less than 11 years of age at the time of randomization Male subjects who are 6 years to less than 12 years of age at the time of randomization Tanner Stage 1 Documented clinical history of SAR or PAR of at least one year prior to study entry with (in the opinion of the investigator): a current level of allergic rhinitis symptoms that warrant treatment with an intranasal corticosteroid and/or expected symptoms during a majority of the study period Diagnosis must be confirmed by a positive skin test (by skin prick method) to an appropriate seasonal or perennial allergen within 12 months prior to Visit 1 or at Visit 1. A positive skin test is defined as a wheal 3 mm larger than the diluent control for prick testing. In vitro tests for specific IgE (such as RAST, PRIST) will also be permitted as confirmation for a diagnosis of SAR or PAR if performed within the last 12 months or at Visit 1. Normal current growth as reflected by baseline height within the 5 th and 95 th percentiles of normal for their age and gender as determined by stadiometry and Danish longitudinal standard charts Subjects must be willing and able to comply with study procedures Written informed consent must be provided by the parent or guardian Revised Text: Inclusion Criteria A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. Pre-menarcheal female subjects who are 6 years to less than 11 years of age at the time of randomization 2. Male subjects who are 6 years to less than 12 years of age at the time of randomization 3. Tanner Stage 1 61

279 ZM2004/00069/02 CONFIDENTIAL 4. Documented clinical history of SAR or PAR of at least one year prior to study entry with (in the opinion of the investigator): a a current level of allergic rhinitis symptoms that warrant treatment with an intranasal corticosteroid and/or b expected symptoms during a majority of the study period Diagnosis must be confirmed by a positive skin test (by skin prick method) to an appropriate seasonal or perennial allergen within 12 months prior to Visit 1 or at Visit 1. A positive skin test is defined as a wheal 3 mm larger than the diluent control for prick testing. In vitro tests for specific IgE (such as RAST, PRIST) will also be permitted as confirmation for a diagnosis of SAR or PAR if performed within the last 12 months or at Visit 1. For these tests, 5mls of blood will be collected to determine allergenicity. Following analysis, the blood sample will be held for 2 weeks and then destroyed. (This sample will be drawn in conjunction with the blood required for the clinical laboratory tests such that only one venepuncture will be required at this visit.) 5. Normal current growth as reflected by baseline height within the 5 th and 95 th percentiles of normal for their age and gender as determined by stadiometry and Danish longitudinal standard charts 6. Subjects must be willing and able to comply with study procedures 7. Written informed consent must be provided by the parent or guardian Original Text Randomization Criteria Subject has completed at least 80% of responses to the diary compliance questions during the 2 week, single-blind, placebo run-in period. Revised Text Randomization Criteria 1. Subject has completed at least 80% of responses to the diary compliance questions during the 2 week, single-blind, placebo run-in period. Original Text:Section Exclusion Criteria A subject will not be eligible for inclusion in this study if any of the following criteria apply: History of abnormal growth or gross malnutrition Findings of a clinically significant laboratory abnormality (Section 6.4.4) History of any condition that may have substantially affected growth Subjects with historical or current evidence of clinically significant, uncontrolled disease of any body system (in addition to allergic rhinitis), such as uncontrolled, epilepsy, active tuberculosis, attention deficit hyperactive disorder, psychological disorders or eczema, will not be eligible. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through 62

280 ZM2004/00069/02 CONFIDENTIAL study participation or which would confound the interpretation of the study results if the disease/condition exacerbated during the study Any asthma other than mild, intermittent asthma controlled by short-acting, β- agonists [GINA, 2003] Recent major surgery and/or trauma to the legs Current or history of glaucoma and/or cataracts or ocular herpes simplex History of adrenal insufficiency Current or prior treatment with any medication that may have a potential for an ongoing effect on linear growth Use of corticosteroids, defined as: Any corticosteroid use by any route within 4 weeks prior to Visit 1 Any nasal condition or deformity that would impair nasal breathing or deposition of medication (i.e., nasal polyps, marked septal deviation) Physical impairment that would affect the subject s ability to participate in the study Documented evidence of acute or significant chronic sinusitis Upper or lower respiratory or sinus infection during the 7 days before screening Clinical evidence of a nasal or oropharyngeal Candida infection Rhinitis medicamentosa Severe dehydration Use of any medications that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazole Subjects with known hypersensitivity to any excipients in the study medications Previous clinical trial experience with GW685698X aqueous nasal spray Exposure to clinical trial/experimental medication within 30 days of Visit 1 Affiliation with investigational site such that the subject is an immediate family member of any site personnel Chickenpox or measles infections A subject is not eligible if he/she currently has chickenpox or measles, or has been exposed to chickenpox or measles during the last 3 weeks and is non-immune. If a subject develops chickenpox or measles during the study, he/she will be withdrawn from the study. If a non-immune subject is exposed to chickenpox or measles during the study, his/her continuation in the study will be at the discretion of the investigator, taking into consideration the likelihood of developing active disease. Revised Text:5.2.3 Exclusion Criteria A subject will not be eligible for inclusion in this study if any of the following criteria apply: 63

281 ZM2004/00069/02 CONFIDENTIAL 1. History of abnormal growth or gross malnutrition 2. Findings of a clinically significant laboratory abnormality (Section 6.4.4) 3. History of any condition that may have substantially affected growth 4. Subjects with historical or current evidence of clinically significant, uncontrolled disease of any body system (in addition to allergic rhinitis), such as uncontrolled, epilepsy, active tuberculosis, attention deficit hyperactive disorder, psychological disorders or eczema, will not be eligible. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or which would confound the interpretation of the study results if the disease/condition exacerbated during the study 5. Any asthma other than mild, intermittent asthma controlled by short-acting, β- agonists [GINA, 2003] 6. Recent major surgery and/or trauma to the legs 7. Current or history of glaucoma and/or cataracts or ocular herpes simplex 8. History of adrenal insufficiency 9. Current or prior treatment with any medication that may have a potential for an ongoing effect on linear growth 10. Use of corticosteroids, defined as: Inhaled and intranasal corticosteroids within 2 weeks prior to Visit 1 Corticosteroids by all other routes (eg oral, intramuscular, intravenous, dermatological, ocular, otic) within 4 weeks prior to Visit Any nasal condition or deformity that would impair nasal breathing or deposition of medication (i.e., nasal polyps, marked septal deviation) 12. Physical impairment that would affect the subject s ability to participate in the study 13. Documented evidence of acute or significant chronic sinusitis 14. Upper or lower respiratory or sinus infection during the 7 days before screening 15. Clinical evidence of a nasal or oropharyngeal Candida infection 16. Rhinitis medicamentosa 17. Severe dehydration 18. Use of any medications that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including ritonavir and ketoconazole 19. Subjects with known hypersensitivity to any excipients in the study medications 20. Previous clinical trial experience with GW685698X aqueous nasal spray 21. Exposure to clinical trial/experimental medication within 30 days of Visit Affiliation with investigational site such that the subject is an immediate family member of any site personnel 23. Chickenpox or measles infections 64

282 ZM2004/00069/02 CONFIDENTIAL A subject is not eligible if he/she currently has chickenpox or measles, or has been exposed to chickenpox or measles during the last 3 weeks and is non-immune. If a subject develops chickenpox or measles during the study, he/she will be withdrawn from the study. If a non-immune subject is exposed to chickenpox or measles during the study, his/her continuation in the study will be at the discretion of the investigator, taking into consideration the likelihood of developing active disease. Original Text: Screening Visit (Visit 1) Obtain blood sample for clinical laboratory tests. Revised Text: Screening Visit (Visit 1) Obtain an 8 ml blood sample for clinical laboratory tests. (This sample will be drawn in conjunction with the 5mls of blood needed for the in vitro test for specific IgE, if required to determine allergy, such that only one venipuncture will be required at this visit.) Original Text (Paragraph 1) Clinical Laboratory Tests Routine laboratory tests (Appendix 4: Laboratory Assessments) will be performed at Visit 1. Subjects will not be required to fast prior to collection of the laboratory specimens. Quest Diagnostics, a central laboratory, will provide a manual to each site containing detailed instructions for collecting all specimens. Results of the laboratory tests will be transmitted electronically to GSK. A printout from the central laboratory of the results will be maintained at the site and will be signed and dated by the investigator confirming review. Revised Text (Paragraph 1) Section Clinical Laboratory Tests Routine laboratory tests (Appendix 4: Laboratory Assessments) will be performed at Visit 1. An 8 ml blood sample will be drawn at this visit to help assess the health of potential subjects. Following analysis, the blood sample will be held for 2 weeks and then destroyed. Subjects will not be required to fast prior to collection of the laboratory specimens. Quest Diagnostics, a central laboratory, will provide a manual to each site containing detailed instructions for collecting all specimens. Results of the laboratory tests will be transmitted electronically to GSK. A printout from the central laboratory of the results will be maintained at the site and will be signed and dated by the investigator confirming review. Original Text: Section Pregnancy Only premenarchal females are eligible to participate in this study (Tanner Stage 1). Any female who begins to menstruate during the study will be discontinued and must have a serum pregnancy test at the Early Withdrawal visit. Revised Text: Section Pregnancy Only premenarchal females are eligible to participate in this study (Tanner Stage 1). Any female who begins to menstruate during the study will be discontinued and must have a serum pregnancy test at the Early Withdrawal visit. For the serum pregnancy test, 4 ml 65

283 ZM2004/00069/02 CONFIDENTIAL of blood will be collected to determine pregnancy status. Following analysis, the blood sample will be held for 2 weeks and then destroyed. Original Text: Section Allergy Rescue Medication At screening, all subjects will be dispensed 10 mg loratadine tablets, a non-prescription antihistamine, to use as allergy rescue medication on an as needed basis. The daily dose is not to exceed one tablet (10 mg/day). The subject s parent/guardian or the subject, where deemed appropriate by the investigator, will record any use of rescue medication on the diary card. The investigator, or designee, will document the date rescue medication was dispensed and the amount dispensed on the Investigational Product Accountability log maintained at the study site. Revised Text: Section Allergy Rescue Medication At screening, all subjects will be dispensed loratadine tablets and/ or loratadine syrup, a non-prescription antihistamine, to use as allergy rescue medication on an as needed basis. The daily dose is not to exceed the maximum labelled dose for a given subjects age. The subject s parent/guardian or the subject, where deemed appropriate by the investigator, will record any use of rescue medication on the diary card. The investigator, or designee, will document the date rescue medication was dispensed and the amount dispensed on the Investigational Product Accountability log maintained at the study site. Original Text: Section 8.1 Permitted Medications All concomitant medications taken during the study will be recorded in the CRF as well as any medications, such as asthma or allergy medication, taken in the previous 6 months that have the potential to affect growth. The minimum requirement is that drug name and the dates of administration are to be recorded. No other anti-allergy or anti-rhinitis medications, including oral, intranasal, ocular or throat treatments, will be permitted during the study except for the rescue medication, loratadine tablets, provided by the sponsor. Immunotherapy patients may be enrolled in the study as long as the immunotherapy was not initiated within 30 days of Visit 1. All medications for other disorders may be continued throughout the study, provided the dose remains constant and their use would not be expected to affect the subject s growth. No corticosteroids administered by any route are permitted within 4 weeks of study start. Subjects with mild, intermittent asthma may be treated with short-acting, inhaled beta 2 agonists on an as needed basis only Revised Text: 8.1 Permitted Medications All concomitant medications taken during the study will be recorded in the CRF as well as any medications, such as asthma or allergy medication, taken in the previous 6 months that have the potential to affect growth. The minimum requirement is that drug name and the dates of administration are to be recorded. No other anti-allergy or anti-rhinitis 66

284 ZM2004/00069/02 CONFIDENTIAL medications, including oral, intranasal, ocular or throat treatments, will be permitted during the study except for the rescue medication loratadine provided by the sponsor and dispensed to the subject by the site. Immunotherapy patients may be enrolled in the study as long as the immunotherapy was not initiated within 30 days of Visit 1. All medications for other disorders may be continued throughout the study, provided the dose remains constant and their use would not be expected to affect the subject s growth. Inhaled or intranasal corticosteroids are not permitted within 2 weeks of study start to ensure at least 4 weeks washout before randomisation to study medication. Corticosteroids administered by other route (eg oral, intramuscular, intravenous, dermatological, ocular, otic) are not permitted within 4 weeks of study start. Subjects with mild, intermittent asthma may be treated with short-acting, inhaled beta 2 agonists on an as needed basis only. Original Text: Allergy Rescue Medication GSK will provide loratadine tablets, a non-prescription antihistamine, to all subjects to use as allergy rescue medication during the study on an as needed basis. The subject s parent/guardian or the subject, when deemed appropriate, will record their daily use of allergy rescue medication. The daily dose for loratadine is not to exceed 10 mg/day. No other anti-allergy/anti-rhinitis medications, including oral and intranasal products, are allowed during this study. Revised Text: Allergy rescue medication GSK will provide loratadine tablets and/ or loratadine syrup, a non-prescription antihistamine, to all subjects to use as allergy rescue medication during the study on an as needed basis. The subject s parent/guardian or the subject, when deemed appropriate, will record their daily use of allergy rescue medication. The daily dose is not to exceed the maximum labelled dose for a given subjects age. No other anti-allergy/anti-rhinitis medications, including oral and intranasal products, are allowed during this study. 67

285 ZM2004/00069/02 CONFIDENTIAL Original Text: 14.4 Appendix 4: Laboratory Assessments Chemistry Hematology Electrolytes Total Bilirubin Hemoglobin Sodium Alkaline Phosphatase Hematocrit Potassium Alanine Amino-transferase (ALT or RBC SGPT) Aspartate Amino-transferase (AST WBC or SGOT) Glucose Neutrophils Creatinine Lymphocytes Urea nitrogen Monocytes Calcium Eosinophils Total Protein Basophils Albumin Platelets C Reactive Protein Revised Text: 14.4 Appendix 4: Laboratory Assessments An 8 ml blood sample will be drawn during the study at Visit 1 to assess the health of potential subjects. Following analysis, the blood sample will be held for 2 weeks and then destroyed. An additional 5 ml sample may also be needed to assess specific IgE antibody (as determined by the investigator). Both blood samples will be collected at the same time such that only one venipuncture will be required at this visit. A separate venipuncture will be required to obtain 4 mls of blood at an Early Withdrawal visit for any female who begins to menstruate during the study. Chemistry Hematology Electrolytes Total Bilirubin Hemoglobin Sodium Alkaline Phosphatase Hematocrit Potassium Alanine Amino-transferase (ALT or RBC SGPT) Aspartate Amino-transferase (AST WBC or SGOT) Glucose Neutrophils Creatinine Lymphocytes Urea nitrogen Monocytes Calcium Eosinophils Total Protein Basophils Albumin Platelets 68

286 Annotated Trial Design Page 1 of 3 Annotated Design For Trial 'ffr101747_szs' Protocol: Generated By InForm Architect November 7, :19AM CONFIDENTIAL 1

287 Annotated Trial Design Page 2 of 3 2 Time and Events Schedule For Trial 'ffr101747_szs' Assessment CRF Screening Randomization Interim Visit Interim Visit Final Visit Logs EARLY WITHDRAWAL UNSCHEDULED VISIT 1 Conflict UNSCHEDULED VISIT 2 UNSCHEDULED VISIT 3 UNSCHEDULED VISIT 4 VISIT 1 VISIT 2 VISIT 3 VISIT 4 VISIT 5 (LOGS) (WDW) (UNSCHED1) (Conflict) (UNSCHED2) (UNSCHED3) (UNSCHED4) (VISIT1) (VISIT2) (VISIT3) (VISIT4) (VISIT5) [S] [U/O] [U/O] [U/R/D] [U/O/D] [U/O/D] [ U/O/D ] [S] [S] [S] [S] [S] 1 DATE AND TIME OF VISIT/ASSESSMENT DOV SUBJECT IDENTIFICATION SUB ID 2 3 ELIGIBILITY QUESTION ELIG 3 4 DEMOGRAPHY DEMOG 4 5 MEDICAL CONDITIONS MEDHX 5 6 ALLERGEN TEST ALGTST 6-DF 7 DIAGNOSIS OF RHINITIS DIAG 7 8 DISEASE DURATION DISDUR 8 9 NASAL EXAMINATION NASAL VITAL SIGNS VS KNEMOMETRY KNEE LAB DATA LAB INVESTIGATIONAL PRODUCT IP ELIGIBILITY QUESTION ELIG_ VITAL SIGNS VS RANDOMISATION NUMBER RAND 6 17 Subject's Rhinitis Diary Card DRC 8-DF 6-DF 6-DF 6-DF 6-DF 18 Subject's Rhinitis Diary Card DRC TANNER TAN ADVERSE EVENTS AE 2-RF 21 CONCOMITANT MEDICATIONS CONMEDS 3-RF 22 INVPCOMP INVPCOMP 4 23 STATUS OF TREATMENT BLIND BLIND 5 24 STUDY CONCLUSION CONC 6 Key: [S] = Scheduled Visit [O] = Optional Visit [D] = Dynamic Visit [U] = Unscheduled Visit [R] = Repeating Visit C = Common Form DF = Dynamic Form RF = Repeating Form CONFIDENTIAL

288 CONFIDENTIAL Annotated Trial Design Page 1 of 36 Annotated Design For Trial 'ffr101747_szs' Protocol: Generated By InForm Architect 3

289 CONFIDENTIAL Annotated Trial Design Page 2 of 36 FORM: INFORM SCREENING (SCREEN) TRIAL: ffr101747_szs INFORM SCREENING 1. Subject initials [hidden] * (MAPPINGS7:t_SCREEN.txtScrSINIT) 2. Date of birth // ( ) (MAPPINGS7:t_SCREEN.BIRTHDT) * Item is not required Form Design Note: Trial designers must use this form as specified here. Allowed changes are mentioned in the particular item level notes. Item Design Notes: Item No. Design Note 1. This item is hidden to all users and will be autopopulated by the system as "---" 2. Will be automatically mapped to demography form CDD: MAPPINGS7 Table: t_screen Key Type: PATIENTVISIT Column Name Column Data Type Design Note txtscrsinit BIRTHDT STRING(3) - A3 DATE - DDMONYYYY 4

290 CONFIDENTIAL Annotated Trial Design Page 3 of 36 FORM: INFORM ENROLMENT (ENROL) TRIAL: ffr101747_szs SUBJECT NUMBER 1. Subject number (MAPPINGS7:t_ENROL.mtxtSubjectNumber) CDD: MAPPINGS7 Table: t_enrol Key Type: PATIENTVISIT Column Name Column Data Type Design Note mtxtsubjectnumber STRING(6) - A6 5

291 CONFIDENTIAL Annotated Trial Design Page 4 of 36 FORM: DATE AND TIME OF VISIT/ASSESSMENT (DOV) TRIAL: ffr101747_szs DATE AND TIME OF VISIT/ASSESSMENT 1. Date and time of visit/assessment Hr:Min (00:00-23:59) / / ( ) (MAPPINGS7:t_DOV.DOV) : 2. * SDV Performed at this Visit [GSK usage only] [hidden] (MAPPINGS7:t_DOV.chkSDVYes) [Y] Yes * Item is not required CDD: MAPPINGS7 Table: t_dov Key Type: PATIENTVISIT Column Name Column Data Type Design Note DOV chksdvyes DATE - DDMONYYYY HHMM STRING(255) 6

292 CONFIDENTIAL Annotated Trial Design Page 5 of 36 FORM: SUBJECT IDENTIFICATION (SUB ID) TRIAL: ffr101747_szs SUBJECT IDENTIFICATION If Subject number was entered incorrectly, please correct and submit; otherwise disregard 1. Subject number (MAPPINGS7:t_SUBID.mtxtSubjectNumber) Form Design Note: IDSL Version 01.00A - 01 DEC 04 Item Design Notes: Item No. Design Note 1. This item will be mapped from the InForm enrollment form so that the number can be changed if needed CDD: MAPPINGS7 Table: t_subid Key Type: PATIENTVISIT Column Name Column Data Type Design Note mtxtsubjectnumber STRING(6) - A6 7

293 CONFIDENTIAL Annotated Trial Design Page 6 of 36 FORM: ELIGIBILITY QUESTION (ELIG) TRIAL: ffr101747_szs ELIGIBILITY QUESTION 1. Did the subject meet all the entry criteria? (MAPPINGS7:t_ELIG.IEELIG) [Y] Yes [N] (MAPPINGS7:t_ELIG.IECRTNUMI01) [I01] Inclusion Criteria 1 (MAPPINGS7:t_ELIG.IECRTNUMI02) [I02] Inclusion Criteria 2 (MAPPINGS7:t_ELIG.IECRTNUMI03) [I03] Inclusion Criteria 3 (MAPPINGS7:t_ELIG.IECRTNUMI04) [I04] Inclusion Criteria 4 (MAPPINGS7:t_ELIG.IECRTNUMI05) [I05] Inclusion Criteria 5 (MAPPINGS7:t_ELIG.IECRTNUMI06) [I06] Inclusion Criteria 6 (MAPPINGS7:t_ELIG.IECRTNUMI07) [I07] Inclusion Criteria 7 (MAPPINGS7:t_ELIG.IECRTNUME01) [E01] Exclusion Criteria 1 (MAPPINGS7:t_ELIG.IECRTNUME02) [E02] Exclusion Criteria 2 (MAPPINGS7:t_ELIG.IECRTNUME03) [E03] Exclusion Criteria 3 (MAPPINGS7:t_ELIG.IECRTNUME04) [E04] Exclusion Criteria 4 (MAPPINGS7:t_ELIG.IECRTNUME05) [E05] Exclusion Criteria 5 (MAPPINGS7:t_ELIG.IECRTNUME06) [E06] Exclusion Criteria 6 (MAPPINGS7:t_ELIG.IECRTNUME07) [E07] Exclusion Criteria 7 (MAPPINGS7:t_ELIG.IECRTNUME08) [E08] Exclusion Criteria 8 (MAPPINGS7:t_ELIG.IECRTNUME09) [E09] Exclusion Criteria 9 (MAPPINGS7:t_ELIG.IECRTNUME10) [E10] Exclusion Criteria 10 (MAPPINGS7:t_ELIG.IECRTNUME11) [E11] Exclusion Criteria 11 (MAPPINGS7:t_ELIG.IECRTNUME12) [E12] Exclusion Criteria 12 (MAPPINGS7:t_ELIG.IECRTNUME13) [E13] Exclusion Criteria 13 (MAPPINGS7:t_ELIG.IECRTNUME14) [E14] Exclusion Criteria 14 (MAPPINGS7:t_ELIG.IECRTNUME15) [E15] Exclusion Criteria 15 (MAPPINGS7:t_ELIG.IECRTNUME16) [E16] Exclusion Criteria 16 (MAPPINGS7:t_ELIG.IECRTNUME17) [E17] Exclusion Criteria 17 (MAPPINGS7:t_ELIG.IECRTNUME18) [E18] Exclusion Criteria 18 (MAPPINGS7:t_ELIG.IECRTNUME19) [E19] Exclusion Criteria 19 (MAPPINGS7:t_ELIG.IECRTNUME20) [E20] Exclusion Criteria 20 (MAPPINGS7:t_ELIG.IECRTNUME21) [E21] Exclusion Criteria 21 (MAPPINGS7:t_ELIG.IECRTNUME22) [E22] Exclusion Criteria 22 (MAPPINGS7:t_ELIG.IECRTNUME23) [E23] Exclusion Criteria 23 (MAPPINGS7:t_ELIG.txtEligExempt) CDD: MAPPINGS7 Table: t_elig Key Type: PATIENTVISIT Column Name Column Data Type Design Note IEELIG IECRTNUMI01 IECRTNUMI02 IECRTNUMI03 IECRTNUMI04 IECRTNUMI05 IECRTNUMI06 IECRTNUMI07 IECRTNUME01 IECRTNUME02 IECRTNUME03 IECRTNUME04 IECRTNUME05 IECRTNUME06 IECRTNUME07 IECRTNUME08 IECRTNUME09 IECRTNUME10 IECRTNUME11 IECRTNUME12 IECRTNUME13 IECRTNUME14 IECRTNUME15 IECRTNUME16 IECRTNUME17 IECRTNUME18 IECRTNUME19 IECRTNUME20 IECRTNUME21 IECRTNUME22 IECRTNUME23 txteligexempt STRING(1) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(200) - A200 8

294 CONFIDENTIAL Annotated Trial Design Page 7 of 36 FORM: DEMOGRAPHY (DEMOG) TRIAL: ffr101747_szs DEMOGRAPHY 1. Date of birth // ( ) (MAPPINGS7:t_DEMO.BIRTHDT) 2. Sex (MAPPINGS7:t_DEMO.SEX1) [M] Male [F] 3.Ethnicity (MAPPINGS7:t_DEMO.ETHNICCD) [1] Hispanic or Latino [2] Not Hispanic or Latino4.Race (MAPPINGS7:t_DEMO.RACECCD1) [1] American Hispanic (MAPPINGS7:t_DEMO.RACECCD2) [2] Arabic/North African (MAPPINGS7:t_DEMO.RACECCD3) [3] Black (MAPPINGS7:t_DEMO.RACECCD4) [4] East & South East Asian (MAPPINGS7:t_DEMO.RACECCD5) [5] Japanese (MAPPINGS7:t_DEMO.RACECCD6) [6] South Asian (MAPPINGS7:t_DEMO.RACECCD7) [7] White/Caucasian (MAPPINGS7:t_DEMO.RACECCDZ) [Z] Other Female Item Design Notes: Item No. Design Note 1. Will be automatically mapped to demography form 2. This item is conditional; Use it if you DO NOT need to collect childbearing potential information; Remove the other Sex item CDD: MAPPINGS7 Table: t_demo Key Type: PATIENTVISIT Column Name Column Data Type Design Note BIRTHDT SEX1 ETHNICCD RACECCD1 RACECCD2 RACECCD3 RACECCD4 RACECCD5 RACECCD6 RACECCD7 RACECCDZ DATE - DDMONYYYY STRING(1) STRING(1) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) STRING(255) 9

295 CONFIDENTIAL Annotated Trial Design Page 8 of 36 FORM: MEDICAL CONDITIONS (MEDHX) TRIAL: ffr101747_szs MEDICAL CONDITIONS Check only one response for each MedDRA System Organ Class 1. Blood (MAPPINGS7:t_MEDHIST_C.MHSTATCD) and [1] Current lymphatic system disorders [2] Past [3] No Medical History [4] Not Assessed2.Cardiac disorders (MAPPINGS7:t_MEDHIST_C.MHSTATC1) [1] Current [2] Past[3] No Medical History[4] Not Assessed3.Ear and labyrinth disorders (MAPPINGS7:t_MEDHIST_C.MHSTATC2) [1] Current [2] Past[3] No Medical History[4] Not Assessed4.Endocrine disorders (MAPPINGS7:t_MEDHIST_C.MHSTATC3) [1] Current [2] Past[3] No Medical History[4] Not Assessed5.Eye disorders (MAPPINGS7:t_MEDHIST_C.MHSTATC4) [1] Current [2] Past[3] No Medical History[4] Not Assessed6.Gastrointestinal disorders (MAPPINGS7:t_MEDHIST_C.MHSTATC5) [1] Current [2] Past[3] No Medical History[4] Not Assessed7.Hepatobiliary disorders (MAPPINGS7:t_MEDHIST_C.MHSTATC6) [1] Current [2] Past[3] No Medical History[4] Not Assessed8.Immune system disorders (MAPPINGS7:t_MEDHIST_C.MHSTATC7) [1] Current [2] Past[3] No Medical History[4] Not Assessed9.Metabolism and nutrition disorders (MAPPINGS7:t_MEDHIST_C.MHSTATC8) [1] Current [2] Past[3] No Medical History[4] Not Assessed10.Musculoskeletal and connective tissue disorders (MAPPINGS7:t_MEDHIST_C.MHSTATC9) [1] Current [2] Past[3] No Medical History[4] Not Assessed11.Neoplasms benign, malignant and unspecified (including cysts and polyps) (MAPPINGS7:t_MEDHIST_C.MHSTAT10) [1] Current [2] Past[3] No Medical History[4] Not Assessed12.Nervous system disorders (MAPPINGS7:t_MEDHIST_C.MHSTAT11) [1] Current [2] Past[3] No Medical History[4] Not Assessed13.Psychiatric disorders (MAPPINGS7:t_MEDHIST_C.MHSTAT12) [1] Current [2] Past[3] No Medical History[4] Not Assessed14.Renal and urinary disorders (MAPPINGS7:t_MEDHIST_C.MHSTAT13) [1] Current [2] Past[3] No Medical History[4] Not Assessed15.Reproductive system and breast disorders (MAPPINGS7:t_MEDHIST_C.MHSTAT14) [1] Current [2] Past[3] No Medical History[4] Not Assessed16.Respiratory, thoracic and mediastinal disorders (MAPPINGS7:t_MEDHIST_C.MHSTAT15) [1] Current [2] Past[3] No Medical History[4] Not Assessed17.Skin and subcutaneous tissue disorders (MAPPINGS7:t_MEDHIST_C.MHSTAT16) [1] Current [2] Past[3] No Medical History[4] Not Assessed18.Vascular disorders (MAPPINGS7:t_MEDHIST_C.MHSTAT17) [1] Current [2] Past[3] No Medical History[4] Not Assessed19.Infections and infestations (MAPPINGS7:t_MEDHIST_C.MHSTAT18) [1] Current [2] Past[3] No Medical History[4] Not Assessed20.Congenital, familial and genetic disorders (MAPPINGS7:t_MEDHIST_C.MHSTAT19) [1] Current [2] Past[3] No Medical History[4] Not Assessed21.General disorders and administration site conditions (MAPPINGS7:t_MEDHIST_C.MHSTAT20) [1] Current [2] Past[3] No Medical History[4] Not Assessed22.Injury, poisoning and procedural complications (MAPPINGS7:t_MEDHIST_C.MHSTAT21) [1] Current [2] Past[3] No Medical History[4] Not Assessed23.Investigations (MAPPINGS7:t_MEDHIST_C.MHSTAT22) [1] Current [2] Past[3] No Medical History[4] Not Assessed Form Design Note: This form is optional Section Design Notes: Title MEDICAL CONDITIONS Design Note The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History. Not Assessed is optional for all combinations. Combinations must be consistent for all terms specified CDD: MAPPINGS7 Table: t_medhist_c Key Type: PATIENTVISIT Column Name Column Data Type Design Note MHSTATCD MHSTATC1 MHSTATC2 MHSTATC3 MHSTATC4 MHSTATC5 MHSTATC6 MHSTATC7 MHSTATC8 MHSTATC9 MHSTAT10 MHSTAT11 MHSTAT12 MHSTAT13 MHSTAT14 MHSTAT15 MHSTAT16 MHSTAT17 MHSTAT18 STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) 10

296 CONFIDENTIAL Annotated Trial Design Page 9 of 36 MHSTAT19 MHSTAT20 MHSTAT21 MHSTAT22 STRING(1) STRING(1) STRING(1) STRING(1) 11

297 CONFIDENTIAL Annotated Trial Design Page 10of36 FORM: ALLERGEN TEST (ALGTST) TRIAL: ffr101747_szs ALLERGEN TEST 1. Diluent Control Wheal (mm in diameter) (MAPPINGS7:t_ALGTST.DCWHLSZ) TESTED ALLERGEN Entry 2.a Tested Allergen (MAPPINGS7:t_ALGTST.TSTALGCD) 2.b Wheal (mm in diameter) (MAPPINGS7:t_ALGTST.WHLSZ) TESTED RAST ALLERGEN Entry 3.a Tested RAST Allergen (MAPPINGS7:t_ALGTST.RASALGCD) 3.b Specific IGE Class (MAPPINGS7:t_ALGTST.IGESPECD) Pulldown List 1: RefName Display Text Value Design Note estrzallrgn8 Other Grass 8 estrzallrgn9 Alder tree 9 estrzallrgn10 Ash tree 10 estrzallrgn11 Birch tree 11 estrzallrgn20 Other tree 20 estrzallrgn34 Alternaria mould 34 estrzallrgn35 Cladosporium mould 35 estrzallrgn37 Cat dander 37 estrzallrgn39 Dog dander 39 estrzallrgn40 Dust mites 40 estrzallrgn41 Other (not in list) 41 Pulldown List 2: RefName Display Text Value Design Note estrzallrgn8 Other Grass 8 estrzallrgn9 Alder tree 9 estrzallrgn10 Ash tree 10 estrzallrgn11 Birch tree 11 estrzallrgn20 Other tree 20 estrzallrgn34 Alternaria mould 34 estrzallrgn35 Cladosporium mould 35 estrzallrgn37 Cat dander 37 estrzallrgn39 Dog dander 39 estrzallrgn40 Dust mites 40 estrzallrgn41 Other (not in list) 41 Pulldown List 3: RefName Display Text Value Design Note estrigespecd0 <=70 0 estrigespecd estrigespecd estrigespecd estrigespecd estrigespecd estrigespecd6 > CDD: MAPPINGS7 Table: t_algtst Key Type: PATIENTVISIT Column Name Column Data Type Design Note DCWHLSZ NUMERIC - N3 TSTALGCD STRING(255) - 8, 9, 10, 11, 20, 34, 35, 37, 39, 40, 41 WHLSZ NUMERIC - N3 RASALGCD STRING(255) - 8, 9, 10, 11, 20, 34, 35, 37, 39, 40, 41 IGESPECD STRING(255) - 0, 1, 2, 3, 4, 5, 6 12

298 CONFIDENTIAL Annotated Trial Design Page 11of36 FORM: DIAGNOSIS OF RHINITIS (DIAG) TRIAL: ffr101747_szs DIAGNOSIS OF RHINITIS 1. History of seasonal allergic rhinitis? (MAPPINGS7:t_NSDHIS.SARYN) Yes No [Y] [N] (MAPPINGS7:t_NSDHIS.PARHSYN) 2. History of perennial allergic rhinitis? [Y] Yes [N] No CDD: MAPPINGS7 Table: t_nsdhis Key Type: PATIENTVISIT Column Name Column Data Type Design Note SARYN PARHSYN STRING(1) STRING(1) 13

299 CONFIDENTIAL Annotated Trial Design Page 12of36 FORM: DISEASE DURATION (DISDUR) TRIAL: ffr101747_szs DISEASE DURATION 1. Duration of Rhinitis (MAPPINGS7:t_DISDUR.DURCATCD) Pulldown List 1: RefName Display Text Value Design Note eintdurcat26 < 1 year 26 eintdurcat4 >= 1 year 4 to < 3 years eintdurcat7 >= 3 years 7 CDD: MAPPINGS7 Table: t_disdur Key Type: PATIENTVISIT Column Name Column Data Type Design Note DURCATCD STRING(255) - 26, 4, 7 14

300 CONFIDENTIAL Annotated Trial Design Page 13of36 FORM: NASAL EXAMINATION (NASAL) TRIAL: ffr101747_szs NOSTRIL PATENT 1. Left nostril patent? (MAPPINGS7:t_NSLEXM.LNPTN) Yes No [Y] [N] (MAPPINGS7:t_NSLEXM.RNPTN) 2. Right nostril patent? [Y] Yes [N] No SEPTUM 3. Septum normal? (MAPPINGS7:t_NSLEXM.SEPNRM) [Y] Yes [N] (MAPPINGS7:t_NSLEXM.SEPDEVCD) [1] Left [2] Right MUCOSA Specify if the following are absent or present for both the left and right nostril: 4. Left nostril oedema? (MAPPINGS7:t_NSLEXM.LNMCOCD) [0] Absent [1] Present (MAPPINGS7:t_NSLEXM.LNMCCRCD) 5. Left nostril crusting? [0] Absent [1] Present (MAPPINGS7:t_NSLEXM.LNMCBLCD) 6. Left nostril bleeding? [0] Absent [1] Present (MAPPINGS7:t_NSLEXM.RNMCOCD) 7. Right nostril oedema? [0] Absent [1] Present (MAPPINGS7:t_NSLEXM.RNMCCRCD1) 8. Right nostril crusting? [0] Absent [1] Present (MAPPINGS7:t_NSLEXM.RNMCBLCD) 9. Right nostril bleeding? [0] Absent [1] Present SECRETIONS 10. Left nostril secretions? (MAPPINGS7:t_NSLEXM.LNSECCD) [0] Absent [1] (MAPPINGS7:t_NSLEXM.LNSECCCD) [1] Clear [2] Yellow [3] Green 11.Right nostril secretions? (MAPPINGS7:t_NSLEXM.RNSECCD) [0] Absent [1] (MAPPINGS7:t_NSLEXM.RNSECCCD) [1] Clear [2] Yellow [3] Green ULCERS Specify if ulcers are absent or size of largest ulcer if present: 12. Left nostril turbinates? (MAPPINGS7:t_NSLEXM.LNULCTCD) [1] None [2] Small (<2mm) [3] Large (>=2mm)13.Left nostril septum? (MAPPINGS7:t_NSLEXM.LNULCSCD) [1] None [2] Small (<2mm)[3] Large (>=2mm)14.Right nostril turbinates? (MAPPINGS7:t_NSLEXM.RNULCTCD) [1] None [2] Small (<2mm)[3] Large (>=2mm)15.Right nostril septum? (MAPPINGS7:t_NSLEXM.RNULCSCD) [1] None [2] Small (<2mm)[3] Large (>=2mm) POLYPOSIS Specify if polyps are absent or size of largest polyp if present: 16. Left nostril turbinates? (MAPPINGS7:t_NSLEXM.LNPLPTCD) [1] None [2] Small (<2mm) [3] Large (>=2mm)17.Left nostril septum? (MAPPINGS7:t_NSLEXM.LNPLPSCD) [1] None [2] Small (<2mm)[3] Large (>=2mm)18.Right nostril turbinates? (MAPPINGS7:t_NSLEXM.RNPLPTCD) [1] None [2] Small (<2mm)[3] Large (>=2mm)19.Right nostril septum? (MAPPINGS7:t_NSLEXM.RNPLPSCD) [1] None [2] Small (<2mm)[3] Large (>=2mm) CDD: MAPPINGS7 Table: t_nslexm Key Type: PATIENTVISIT Column Name Column Data Type Design Note LNPTN RNPTN SEPNRM SEPDEVCD LNMCOCD LNMCCRCD LNMCBLCD RNMCOCD RNMCCRCD1 RNMCBLCD LNSECCD LNSECCCD RNSECCD RNSECCCD LNULCTCD LNULCSCD RNULCTCD RNULCSCD LNPLPTCD LNPLPSCD RNPLPTCD RNPLPSCD STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) STRING(1) 15

301 CONFIDENTIAL Annotated Trial Design Page 14of36 FORM: VITAL SIGNS (VS) TRIAL: ffr101747_szs VITAL SIGNS 1. Height (MAPPINGS7:t_VITALS.HEIGHT) 2. Weight (MAPPINGS7:t_VITALS.WEIGHT) 3. Blood pressure (MAPPINGS7:t_VITALS.SYSBP) (MAPPINGS7:t_VITALS.DIABP) 4. Heart rate (MAPPINGS7:t_VITALS.HEART) Form Design Note: This form is optional. This form is to be used when one Vitals is taken at a visit. Section Design Notes: Title VITAL SIGNS Design Note All items are optional CDD: MAPPINGS7 Table: t_vitals Key Type: PATIENTVISIT Column Name Column Data Type Design Note HEIGHT NUMERIC - N3 WEIGHT FLOAT - F5.1 SYSBP DIABP HEART NUMERIC - N3 NUMERIC - N3 NUMERIC - N3 16

302 CONFIDENTIAL Annotated Trial Design Page 15of36 FORM: KNEMOMETRY (KNEE) TRIAL: ffr101747_szs KNEMOMETRY 1. Measurement 1: (MAPPINGS7:t_KNEE.MSR1) 2. Measurement 2: (MAPPINGS7:t_KNEE.MSR2) 3. Measurement 3: (MAPPINGS7:t_KNEE.MSR3) 4. Knemometry Average: (MAPPINGS7:t_KNEE.KNMAV) CDD: MAPPINGS7 Table: t_knee Key Type: PATIENTVISIT Column Name Column Data Type Design Note MSR1 FLOAT - F5.1 MSR2 FLOAT - F5.1 MSR3 FLOAT - F5.1 KNMAV STRING(255) 17

303 CONFIDENTIAL Annotated Trial Design Page 16of36 FORM: LAB DATA (LAB) TRIAL: ffr101747_szs LAB DATA 1. Date Blood Sample taken (MAPPINGS7:t_LABLINK_A.rdcLABDTTM) [-99] Date / / ( ) (MAPPINGS7:t_LABLINK_A.LABDTTM1) [ND] Haem Lab type code [hidden] Not Done (MAPPINGS7:t_LABLINK_A.LBTYPCD1) Form Design Note: This form is optional. Add an item for each labtype to be collected. Section Design Notes: Title LAB DATA sctlbtypcd Design Note If only one sample date and time is needed for all lab tests performed remove the last two items and modify the text of the first item This section is required and should be the last section on this form. Add or remove items as required by the trial Item Design Notes: Item No. Design Note 1. Time is optional. Use this item as the first item on this form. For additional tests, use the second item. itmlbtypcd1 This item will be calculated by InForm CDD: MAPPINGS7 Table: t_lablink_a Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdclabdttm LABDTTM1 LBTYPCD1 STRING(3) DATE - DDMONYYYY STRING(255) 18

304 CONFIDENTIAL Annotated Trial Design Page 17of36 FORM: INVESTIGATIONAL PRODUCT (IP) TRIAL: ffr101747_szs INVESTIGATIONAL PRODUCT 1. Start Date / / ( ) (MAPPINGS7:t_EXPOSURE_IP.EXSTDTTM) 2. Stop Date / / ( ) (MAPPINGS7:t_EXPOSURE_IP.EXENDTTM) INVESTIGATIONAL PRODUCT CONTAINER NUMBER Record the identifying number from the investigational product container dispensed at this visit 3. Investigational product container number (MAPPINGS7:t_EXPOSURE_IP.EXINVNUM) Form Design Note: This form is required when IP is administered. If Planned Timepoint is not used, but repeats are needed, make this form repeating. Use this form for: Multiple assessments (per visit) running log (per study)) Item Design Notes: Item No. Design Note 1. Time is optional 2. Time is optional CDD: MAPPINGS7 Table: t_exposure_ip Key Type: PATIENTVISIT Column Name Column Data Type Design Note EXSTDTTM EXENDTTM EXINVNUM DATE - DDMONYYYY DATE - DDMONYYYY NUMERIC - N6 19

305 CONFIDENTIAL Annotated Trial Design Page 18of36 FORM: ELIGIBILITY QUESTION (ELIG_2) TRIAL: ffr101747_szs ELIGIBILITY QUESTION 1. Did the subject meet all the entry criteria? (MAPPINGS7:t_ELIG_2.IEELIG) [Y] Yes [N] (MAPPINGS7:t_ELIG_2.IECRTNUMI01) [I01] Inclusion Criteria 1 CDD: MAPPINGS7 Table: t_elig_2 Key Type: PATIENTVISIT Column Name Column Data Type Design Note IEELIG IECRTNUMI01 STRING(1) STRING(255) 20

306 CONFIDENTIAL Annotated Trial Design Page 19of36 FORM: VITAL SIGNS (VS) TRIAL: ffr101747_szs VITAL SIGNS 1. Blood pressure (MAPPINGS7:t_VITALS_2.SYSBP) (MAPPINGS7:t_VITALS_2.DIABP) 2. Heart rate (MAPPINGS7:t_VITALS_2.HEART) Form Design Note: This form is optional. This form is to be used when one Vitals is taken at a visit. Section Design Notes: Title VITAL SIGNS Design Note All items are optional CDD: MAPPINGS7 Table: t_vitals_2 Key Type: PATIENTVISIT Column Name Column Data Type Design Note SYSBP DIABP HEART NUMERIC - N3 NUMERIC - N3 NUMERIC - N3 21

307 CONFIDENTIAL Annotated Trial Design Page 20of36 FORM: RANDOMISATION NUMBER (RAND) TRIAL: ffr101747_szs RANDOMISATION NUMBER 1. Was the subject able to be randomised? (MAPPINGS7:t_RAND.rdcRandYN) [N] No [Y] (MAPPINGS7:t_RAND.RANDNUM) CDD: MAPPINGS7 Table: t_rand Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdcrandyn RANDNUM STRING(1) NUMERIC - N6 22

308 CONFIDENTIAL Annotated Trial Design Page 21of36 FORM: Subject's Rhinitis Diary Card (DRC) TRIAL: ffr101747_szs Day 1 1. * Date Of Assessment [read-only] / / ( ) (MAPPINGS7:t_RHDIARY.ACTDT) 2. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM) [Y] Yes [N] 3. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM) Day 2 No 4. * Date Of Assessment / / ( ) (MAPPINGS7:t_RHDIARY.ACTDT2) 5. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY.TRTADM2) [Y] Yes [N] 6. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? (MAPPINGS7:t_RHDIARY.RESCNUM2) Day 3 No 7. * Date Of Assessment [read-only] / / ( ) (MAPPINGS7:t_RHDIARY.ACTDT3) 8. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM3) [Y] Yes [N] 9. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM3) Day 4 No 10. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT4) 11. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM4) [Y] Yes [N] 12. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM4) Day 5 No 13. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT5) 14. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM5) [Y] Yes [N] 15. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM5) Day 6 No 16. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT6) 17. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM6) [Y] Yes [N] 18. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.Copy_of_RESCNUM5) Day 7 No 19. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT7) 20. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM7) [Y] Yes [N] 21. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM7) Day 8 No 22. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT8) 23. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM8) [Y] Yes [N] 24. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM8) Day 9 No 25. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT9) 26. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM9) [Y] Yes [N] 27. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM9) Day 10 No 28. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT10) 29. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM10) [Y] Yes [N] 30. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM10) Day 11 No 31. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT11) 32. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM11) [Y] Yes [N] 33. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM11) Day 12 No 34. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT12) 35. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM12) [Y] Yes [N] 36. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM12) Day 13 No 37. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT13) 38. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM13) [Y] Yes [N] 39. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM13) Day 14 No 40. * Date Of Assessment [read-only] // ( ) (MAPPINGS7:t_RHDIARY.ACTDT14) 41. * Did the subject spray 2 sprays of the study medication in each nostril today? [read-only] (MAPPINGS7:t_RHDIARY.TRTADM14) [Y] Yes 23

309 CONFIDENTIAL Annotated Trial Design Page 22of36 [N] 42. * How many tablets of allergy rescue medication did the subject take in the last 24 hours? [read-only] (MAPPINGS7:t_RHDIARY.RESCNUM14) [read-only] No Day 15 Plus 43.a * Date of assessment / / ( ) (MAPPINGS7:t_RHDIARY.ACTDT15) 43.b * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY.TRTADM15) Yes No [Y] [N] 43.c * How many tablets of allergy rescue medication did the subject take in the last 24 hours? (MAPPINGS7:t_RHDIARY.RESCNUM15) * Item is not required CDD: MAPPINGS7 Table: t_rhdiary Key Type: PATIENTVISIT Column Name Column Data Type Design Note ACTDT TRTADM DATE - DDMONYYYY STRING(1) RESCNUM FLOAT - F5.2 ACTDT2 TRTADM2 DATE - DDMONYYYY STRING(1) RESCNUM2 FLOAT - F5.2 ACTDT3 TRTADM3 DATE - DDMONYYYY STRING(1) RESCNUM3 FLOAT - F5.2 ACTDT4 TRTADM4 DATE - DDMONYYYY STRING(1) RESCNUM4 FLOAT - F5.2 ACTDT5 TRTADM5 DATE - DDMONYYYY STRING(1) RESCNUM5 FLOAT - F5.2 ACTDT6 TRTADM6 DATE - DDMONYYYY STRING(1) Copy_of_RESCNUM5 FLOAT - F5.2 ACTDT7 TRTADM7 DATE - DDMONYYYY STRING(1) RESCNUM7 FLOAT - F5.2 ACTDT8 TRTADM8 DATE - DDMONYYYY STRING(1) RESCNUM8 FLOAT - F5.2 ACTDT9 TRTADM9 DATE - DDMONYYYY STRING(1) RESCNUM9 FLOAT - F5.2 ACTDT10 TRTADM10 DATE - DDMONYYYY STRING(1) RESCNUM10 FLOAT - F5.2 ACTDT11 TRTADM11 DATE - DDMONYYYY STRING(1) RESCNUM11 FLOAT - F5.2 ACTDT12 TRTADM12 DATE - DDMONYYYY STRING(1) RESCNUM12 FLOAT - F5.2 ACTDT13 TRTADM13 DATE - DDMONYYYY STRING(1) RESCNUM13 FLOAT - F5.2 ACTDT14 TRTADM14 DATE - DDMONYYYY STRING(1) RESCNUM14 FLOAT - F5.2 ACTDT15 TRTADM15 DATE - DDMONYYYY STRING(1) RESCNUM15 FLOAT - F5.2 24

310 CONFIDENTIAL Annotated Trial Design Page 23of36 FORM: Subject's Rhinitis Diary Card (DRC) TRIAL: ffr101747_szs Day 1 1. * Date Of Assessment / / ( ) (MAPPINGS7:t_RHDIARY_1.ACTDTa) 2. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADMa) [Y] Yes [N] 3. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM1a) [Y] Yes [N] No Day 2 No 4. * Date Of Assessment / / ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT2a) 5. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM2a) [Y] Yes [N] 6. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM2a) [Y] Yes [N] No Day 3 No 7. * Date Of Assessment / / ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT3a) 8. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM3) [Y] Yes [N] 9. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM3a) [Y] Yes [N] No Day 4 No 10. * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT4a) 11. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM4a) [Y] Yes [N] 12. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM4a) [Y] Yes [N] No Day 5 No 13. * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT5a) 14. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM5a) [Y] Yes [N] 15. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM5a) [Y] Yes [N] No Day 6 No 16. * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT6a) 17. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM6a) [Y] Yes [N] 18. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM6a) [Y] Yes [N] No Day 7 No 19. * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT7a) 20. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM7a) [Y] Yes [N] 21. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM7a) [Y] Yes [N] No Day 8 No 22. * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT8a) 23. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM8a) [Y] Yes [N] 24. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM8a) [Y] Yes [N] No Day 9 No 25. * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT9a) 26. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM9a) [Y] Yes [N] 27. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM9a) [Y] Yes [N] No Day 10 No 28. * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT10a) 29. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM10a) [Y] Yes [N] 30. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM10a) [Y] Yes [N] No Day 11 No 31. * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT11a) 32. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM11a) [Y] Yes [N] 33. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM11a) [Y] Yes [N] No No 25

311 CONFIDENTIAL Annotated Trial Design Page 24of36 Day * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT12a) 35. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM12a) [Y] Yes [N] 36. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM12a) [Y] Yes [N] No Day 13 No 37. * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT13a) 38. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM13a) [Y] Yes [N] 39. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM13a) [Y] Yes [N] No Day 14 No 40. * Date Of Assessment // ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT14a) 41. * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM14a) [Y] Yes [N] 42. * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM14a) [Y] Yes [N] No No Day 15 Plus 43.a * Date of assessment / / ( ) (MAPPINGS7:t_RHDIARY_1.ACTDT15a) 43.b * Did the subject spray 2 sprays of the study medication in each nostril today? (MAPPINGS7:t_RHDIARY_1.TRTADM15a) Yes No [Y] [N] 43.c * Did the subject take Loratadine allergy rescue medication in the last 24 hours? (MAPPINGS7:t_RHDIARY_1.rdcRESCNUM15a) [Y] Yes [N] * Item is not required No CDD: MAPPINGS7 Table: t_rhdiary_1 Key Type: PATIENTVISIT Column Name Column Data Type Design Note ACTDTa TRTADMa rdcrescnum1a ACTDT2a TRTADM2a rdcrescnum2a ACTDT3a TRTADM3 rdcrescnum3a ACTDT4a TRTADM4a rdcrescnum4a ACTDT5a TRTADM5a rdcrescnum5a ACTDT6a TRTADM6a rdcrescnum6a ACTDT7a TRTADM7a rdcrescnum7a ACTDT8a TRTADM8a rdcrescnum8a ACTDT9a TRTADM9a rdcrescnum9a ACTDT10a TRTADM10a rdcrescnum10a ACTDT11a TRTADM11a rdcrescnum11a ACTDT12a TRTADM12a rdcrescnum12a ACTDT13a TRTADM13a rdcrescnum13a ACTDT14a TRTADM14a rdcrescnum14a ACTDT15a TRTADM15a rdcrescnum15a DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) DATE - DDMONYYYY STRING(1) STRING(1) 26

312 CONFIDENTIAL Annotated Trial Design Page 25of36 FORM: TANNER (TAN) TRIAL: ffr101747_szs TANNER 1. Has the subject's Tanner Stage changed since visit 1? If yes, withdraw patient and go to study completion form [Y] (MAPPINGS7:t_STATUS_TAN.TANSTG) [N] No Yes CDD: MAPPINGS7 Table: t_status_tan Key Type: PATIENTVISIT Column Name Column Data Type Design Note TANSTG STRING(1) 27

313 CONFIDENTIAL Annotated Trial Design Page 26of36 FORM: ADVERSE EVENTS (AE) TRIAL: ffr101747_szs # Sequence Number Event Start Date Outcome Maximum Intensity Frequency Action Taken Subject Withdrawn? Relationship Serious? 1 ADVERSE EVENTS Sequence Number 1. Event Diagnosis Only (if known) Otherwise Sign/Symptom (MAPPINGS7:t_AE.AESEQ) (MAPPINGS7:t_AE.AETERM) 2. * Modified term [hidden] (AE_CODE:0.LOGS.AE.sctAE.0.itmAELLTCD.AELLTCD) (AE_SYNONYM:0.LOGS.AE.sctAE.0.itmAEMEDSYN.AEMEDSYN) (AE_FAILED:0.LOGS.AE.sctAE.0.itmAE_FAILED.calAE_FAILED) (MAPPINGS7:t_AE.AEMODIFY) MedDRA synonym [hidden] MedDRA lower level term code [hidden] Failed coding [hidden] (MAPPINGS7:t_AE.AEMEDSYN) (MAPPINGS7:t_AE.AELLTCD) (MAPPINGS7:t_AE.calAE_FAILED) 3. Start Date // ( ) (MAPPINGS7:t_AE.AESTDT) 4. Outcome / End Date and Time Hr:Min (00:00-23:59) (MAPPINGS7:t_AE.AEOUTCD) [1] Recovered/Resolved, provide End Date / / ( ) (MAPPINGS7:t_AE.AEENDTTM1) [2] Recovering/Resolving [3] Not recovered/not resolved [4] Recovered/Resolved with sequelae, provide End Date // ( ) (MAPPINGS7:t_AE.AEENDTTM2) [5] Fatal, record Date and of Death // ( ) (MAPPINGS7:t_AE.AEENDTTM3) 5.Maximum Intensity (MAPPINGS7:t_AE.AESEVCD) [1] Mild [2] Moderate[3] Severe6.Frequency (MAPPINGS7:t_AE.AEFREQCD) [1] Single Episode [2] Intermittent7.Action Taken with Investigational Product(s) as a Result of the AE (MAPPINGS7:t_AE.AEACTRCD) [1] Investigational product(s) withdrawn [2] Dose reduced[3] Dose increased[4] Dose not changed[5] Dose interrupted[x] Not applicable8.did the subject withdraw from study as a result of this AE? (MAPPINGS7:t_AE.AEWD) [Y] Yes [N] No9.Is there a reasonable possibility that the AE may have been caused by the investigational product? (MAPPINGS7:t_AE.AEREL) [Y] Yes [N] No10.Does this Adverse Event meet the definition of serious? If Yes, complete paper SAE form and fax to GSK Safety within 24 hr (MAPPINGS7:t_AE.AESER) [N] No [Y] (MAPPINGS7:t_AE.AESERDTH) [A] Results in death (MAPPINGS7:t_AE.AESERLIF) [B] Is life-threatening (MAPPINGS7:t_AE.AESERHOS) [C] Requires hospitalisation or prolongation of existing hospitalisation (MAPPINGS7:t_AE.AESERDIS) [D] Results in disability/incapacity (MAPPINGS7:t_AE.AESERCON) [E] Congenital anomaly/birth defect (MAPPINGS7:t_AE.AESEROTH) [F] (MAPPINGS7:t_AE.AESERSPE) (MAPPINGS7:t_AE.rdcAESERCause) [N] No [Y] Yes 11.Serious Flag [hidden] (MAPPINGS7:t_AE.calSeriousFlag) * Item is not required Section Design Notes: Title ADVERSE EVENTS Design Note One of the following items must be used: Maximum Intensity, Maximum Toxicity, or Maximum Toxicity or Intensity. The CRF designer must remove the other two items from the form Item Design Notes: Item No. Design Note 3. Start Time is optional 4. End Time is optional 5. Grade 5 is optional 10. G is an optional criterion and may be removed CDD: MAPPINGS7 Table: t_ae Key Type: PATIENTVISIT Column Name Column Data Type Design Note AESEQ AETERM AEMODIFY AEMEDSYN AELLTCD calae_failed AESTDT AEOUTCD AEENDTTM1 AEENDTTM2 AEENDTTM3 AESEVCD AEFREQCD AEACTRCD AEWD AEREL AESER AESERDTH AESERLIF AESERHOS STRING(255) STRING(100) - A100 STRING(100) - A100 STRING(255) STRING(255) STRING(255) DATE - DDMONYYYY STRING(1) DATE - DDMONYYYY DATE - DDMONYYYY DATE - DDMONYYYY STRING(1) NUMERIC STRING(1) STRING(1) STRING(1) STRING(1) STRING(255) STRING(255) STRING(255) 28

314 CONFIDENTIAL Annotated Trial Design Page 27of36 AESERDIS AESERCON AESEROTH AESERSPE rdcaesercause calseriousflag STRING(255) STRING(255) STRING(255) STRING(100) - A100 STRING(1) STRING(255) 29

315 CONFIDENTIAL Annotated Trial Design Page 28of36 FORM: CONCOMITANT MEDICATIONS (CONMEDS) TRIAL: ffr101747_szs # Sequence Number 1 Drug Name (Trade Name preferred) Unit Dose Units Frequency Route Reason for Medication Start Date Taken Prior to Study? Ongoing? CONCOMITANT MEDICATIONS Sequence Number 1. Drug Name (Trade Name preferred) (MAPPINGS7:t_CONMEDS.CMSEQ) (MAPPINGS7:t_CONMEDS.CMTERM) 2. * Modified reported term [hidden] (CM_CODE:0.LOGS.CONMEDS.sctCM.0.itmCMDRGCOL.CMDRGCOL) (CM_FAILED:0.LOGS.CONMEDS.sctCM.0.itmCM_FAILED.calCM_FAILED) (CM_SYNONYM:0.LOGS.CONMEDS.sctCM.0.itmCMDRGSYN.CMDRGSYN) (MAPPINGS7:t_CONMEDS.CMMODIFY) GSK Drug synonym [hidden] GSK Drug Collection code [hidden] Failed coding [hidden] (MAPPINGS7:t_CONMEDS.CMDRGSYN) (MAPPINGS7:t_CONMEDS.CMDRGCOL) (MAPPINGS7:t_CONMEDS.calCM_FAILED) 3. Unit Dose (MAPPINGS7:t_CONMEDS.CMUDOS) 4. Units (MAPPINGS7:t_CONMEDS.CMUNIT) 5. Frequency (MAPPINGS7:t_CONMEDS.CMFREQ) 6. Route (MAPPINGS7:t_CONMEDS.CMROUTCD) 7. Reason for Medication (MAPPINGS7:t_CONMEDS.CMREAS) 8. Start Date / / ( ) (MAPPINGS7:t_CONMEDS.CMSTDT) 9. Taken Prior to Study? (MAPPINGS7:t_CONMEDS.CMPRIOR) [Y] Yes [N] 10.Ongoing? (MAPPINGS7:t_CONMEDS.CMONGO) [Y] Yes [?] No, specify End Date // ( ) (MAPPINGS7:t_CONMEDS.CMENDT) * Item is not required No Form Design Note: This form can be used for disease specific conmeds or as a generic conmed form. If both are required in the trial, copy this form and adjust the form title and section titles Item Design Notes: Item No. Design Note 3. This item is conditional 4. This item is conditional 5. This item is conditional 6. This item is optional 7. This item is optional 8. Time is optional 9. This item is optional 10. Time is optional Pulldown List 1: RefName Display Text Value Design Note mestrunitactu Actuation ACTU mestrunitamp Ampoule AMP mestrunitapp Application APP mestrunitbot Bottle BOT mestrunitcap Capsule CAP mestrunitcc Cubic centimeter CC mestrunitgtt Drops GTT mestrunitgm Gram G mestrunitiu International units IU mestrunitiukg International units per kilogram IU/KG mestrunitiuml International units per millilitre IU/ML mestrunitl Litre L mestrunitlpm Litre per minute L/MIN mestrunitloz Lozenge LOZ mestrunitmu Megaunits (million units) MU mestrunitmcg Microgram (MCG) MCG mestrunitug Microgram (UG) UG mestrunitmcgkg Microgram/kilogram MCG/KG mestrunitmcgkgmin Microgram/kilogram/minute MCG/KG/MIN mestrunitmcgmin Micrograms/minute MCG/MIN mestrunitmcl Microlitre MCL mestrunitmeq Milliequivalent MEQ mestrunitmeq24hr Milliequivalent/24 hours MEQ/24HR mestrunitmg Milligram MG mestrunitmgper Milligrams percent MG% mestrunitmghr Milligram/hour MG/HR mestrunitmgkg Milligram/kilogram MG/KG mestrunitmgkghr Milligram/kilogram/hour MG/KG/HR mestrunitmgkgmin Milligram/kilogram/minute MG/KG/MIN mestrunitmgm2 Milligram/metre squared MG/M2 mestrunitmgml Milligram/millilitre MG/ML mestrunitml Millilitre ML mestrunitmlhr Millilitre/hour ML/HR mestrunitmlmin Millilitre/minute ML/MIN mestrunitmmol Millimole MMOL 30

316 CONFIDENTIAL Annotated Trial Design Page 29of36 mestrunitmiu Million international units MIU mestrunitmac Minimum alveolar concentration MAC mestrunitneb Nebule NEB mestrunitpatch Patch PATCH mestrunitper Percent % mestrunitpuff Puff PUFF mestrunitsach Sachet SACH mestrunitsp Spray SPR mestrunitsupp Suppository SUPP mestrunittbsp Tablespoon TBLSP mestrunittab Tablet TAB mestrunittsp Teaspoon TSP mestrunitunit Units U mestrunitunk Unknown UNK mestrunitvial Vial VIAL mestrunit100iuml 100 International units/ml 100IU/ML mestrunitcup Cup CUP mestrunitinh Inhalation INH mestrunitmcgml Microgram per mililitre MCG/ML mestrunitoz Ounce OZ mestrunituhr Units per hour U/HR Pulldown List 2: RefName Display Text Value Design Note mestrfreq2xwk 2 times per week 2XWK mestrfreq3xwk 3 times per week 3XWK mestrfreq4xwk 4 times per week 4XWK mestrfreq5xd 5 times per day 5XD mestrfreq5xwk 5 times per week 5XWK mestrfreqac AC AC mestrfreqbid BID BID mestrfreqcinf Continuous CINF infusion mestrfreqq2wk Every 2 weeks Q2WK mestrfreqq3wk Every 3 weeks Q3WK mestrfreqq3m Every 3 months Q3M mestrfreqqod Every other day QOD mestrfreqhs HS HS mestrfreqqm Once a month QM mestrfreqqwk Once a week QWK mestrfreqqd Once daily QD mestrfreqone Once only ONE mestrfreqpc PC PC mestrfreqprn PRN PRN mestrfreqq2h Q2H Q2H mestrfreqq3d Q3D Q3D mestrfreqq4d Q4D Q4D mestrfreqq4h Q4H Q4H mestrfreqq6h Q6H Q6H mestrfreqq8h Q8H Q8H mestrfreqq12h Q12H Q12H mestrfreqqam QAM QAM mestrfreqqh QH QH mestrfreqqid QID QID mestrfreqqpm QPM QPM mestrfreqtid TID TID mestrfrequnk Unknown UNK Pulldown List 3: RefName Display Text Value Design Note mestrrouteou Both eyes OU mestrrouteep Epidural EP mestrroutegtt Gastrostomy tube GTT mestrrouteih Inhalation IH mestrrouteinj Injection INJ mestrrouteia Intra-arterial IA mestrrouteib Intra-bursa IB mestrrouteim Intramuscular IM mestrroutein Intranasal IN mestrrouteio Intraocular IO mestrrouteios Intraosteal IOS mestrrouteit Intrathecal IT mestrrouteiu Intrauterine IU mestrrouteiv Intravenous IV mestrroutens Nasal NS mestrroutepo Oral PO mestrroutepr Rectal PR mestrroutesc Subcutaneous SC mestrroutesl Sublingual SL mestrroutetp Topical TP mestrroutetd Transdermal TD mestrrouteunk Unknown UNK mestrroutevg Vaginal VG mestrrouteil Intralesion IL mestrrouteip Intraperitoneal IP 31

317 CONFIDENTIAL Annotated Trial Design Page 30of36 mestrrouteiart Intra-articular IART mestrrouteoth Other OTH CDD: MAPPINGS7 Table: t_conmeds Key Type: PATIENTVISIT Column Name Column Data Type Design Note CMSEQ CMTERM CMMODIFY CMDRGSYN CMDRGCOL STRING(255) STRING(100) - A100 STRING(100) - A100 STRING(255) STRING(255) calcm_failed STRING(255) CMUDOS CMUNIT CMFREQ CMROUTCD CMREAS CMSTDT CMPRIOR CMONGO CMENDT STRING(10) - A10 STRING(255) - ACTU, AMP, APP, BOT, CAP, CC, GTT, G, IU, IU/KG, IU/ML, L, L/MIN, LOZ, MU, MCG, UG, MCG/KG, MCG/KG/MIN, MCG/MIN, MCL, MEQ, MEQ/24HR, MG, MG%, MG/HR, MG/KG, MG/KG/HR, MG/KG/MIN, MG/M2, MG/ML, ML, ML/HR, ML/MIN, MMOL, MIU, MAC, NEB, PATCH, %, PUFF, SACH, SPR, SUPP, TBLSP, TAB, TSP, U, UNK, VIAL, 100IU/ML, CUP, INH, MCG/ML, OZ, U/HR STRING(255) - 2XWK, 3XWK, 4XWK, 5XD, 5XWK, AC, BID, CINF, Q2WK, Q3WK, Q3M, QOD, HS, QM, QWK, QD, ONE, PC, PRN, Q2H, Q3D, Q4D, Q4H, Q6H, Q8H, Q12H, QAM, QH, QID,QPM,TID,UNK STRING(255) - OU, EP, GTT, IH, INJ, IA, IB, IM, IN, IO, IOS, IT, IU, IV, NS, PO, PR, SC, SL, TP, TD, UNK, VG, IL, IP, IART, OTH STRING(70) - A70 DATE - DDMONYYYY STRING(1) STRING(42) DATE - DDMONYYYY 32

318 CONFIDENTIAL Annotated Trial Design Page 31of36 FORM: INVPCOMP (INVPCOMP) TRIAL: ffr101747_szs INVESTIGATIONAL PRODUCT COMPLIANCE (Dispensed at VISIT 1) 1. Weight of Investigational Product When Dispensed (MAPPINGS7:t_INVPCOMP.DISPWT) 2. Weight of Investigational Product When Returned (MAPPINGS7:t_INVPCOMP.RETRNWT) 3. Investigational product container number [read-only] (MAPPINGS7:t_INVPCOMP.EXINVNUM) INVESTIGATIONAL PRODUCT COMPLIANCE (Dispensed at VISIT 2) 4. Weight of Investigational Product When Dispensed (MAPPINGS7:t_INVPCOMP.DISPW1) 5. Weight of Investigational Product When Returned (MAPPINGS7:t_INVPCOMP.RETRNW1) 6. Investigational product container number [read-only] (MAPPINGS7:t_INVPCOMP.EXINVNU1) INVESTIGATIONAL PRODUCT COMPLIANCE (Dispensed at VISIT 3) 7. Weight of Investigational Product When Dispensed (MAPPINGS7:t_INVPCOMP.DISPW2) 8. Weight of Investigational Product When Returned (MAPPINGS7:t_INVPCOMP.RETRNW2) 9. Investigational product container number [read-only] (MAPPINGS7:t_INVPCOMP.EXINVNU2) INVESTIGATIONAL PRODUCT COMPLIANCE (Dispensed at VISIT 4) 10. Weight of Investigational Product When Dispensed (MAPPINGS7:t_INVPCOMP.DISPW3) 11. Weight of Investigational Product When Returned (MAPPINGS7:t_INVPCOMP.RETRNW3) 12. Investigational product container number [read-only] (MAPPINGS7:t_INVPCOMP.EXINVNU3) INVESTIGATIONAL PRODUCT COMPLIANCE (First Replacement, if used) 13. Weight of Investigational Product When Dispensed (MAPPINGS7:t_INVPCOMP.DISPW4) 14. Weight of Investigational Product When Returned (MAPPINGS7:t_INVPCOMP.RETRNW4) 15. Investigational product container number [read-only] (MAPPINGS7:t_INVPCOMP.EXINVNU4) INVESTIGATIONAL PRODUCT COMPLIANCE (Second Replacement, if used) 16. Weight of Investigational Product When Dispensed (MAPPINGS7:t_INVPCOMP.DISPW5) 17. Weight of Investigational Product When Returned (MAPPINGS7:t_INVPCOMP.RETRNW5) 18. Investigational product container number [read-only] (MAPPINGS7:t_INVPCOMP.EXINVNU5) INVESTIGATIONAL PRODUCT COMPLIANCE (Third Replacement, if used) 19. Weight of Investigational Product When Dispensed (MAPPINGS7:t_INVPCOMP.DISPW6) 20. Weight of Investigational Product When Returned (MAPPINGS7:t_INVPCOMP.RETRNW6) 21. Investigational product container number [read-only] (MAPPINGS7:t_INVPCOMP.EXINVNU6) INVESTIGATIONAL PRODUCT COMPLIANCE (Fourth Replacement, if used) 22. Weight of Investigational Product When Dispensed (MAPPINGS7:t_INVPCOMP.DISPW7) 23. Weight of Investigational Product When Returned (MAPPINGS7:t_INVPCOMP.RETRNW7) 24. Investigational product container number [read-only] (MAPPINGS7:t_INVPCOMP.EXINVNU7) CDD: MAPPINGS7 Table: t_invpcomp Key Type: PATIENTVISIT Column Name Column Data Type Design Note DISPWT FLOAT - F5.2 RETRNWT FLOAT - F5.2 EXINVNUM NUMERIC - N6 DISPW1 FLOAT - F5.2 RETRNW1 FLOAT - F5.2 EXINVNU1 NUMERIC - N6 DISPW2 FLOAT - F5.2 RETRNW2 FLOAT - F5.2 EXINVNU2 NUMERIC - N6 DISPW3 FLOAT - F5.2 RETRNW3 FLOAT - F5.2 EXINVNU3 NUMERIC - N6 DISPW4 FLOAT - F5.2 RETRNW4 FLOAT - F5.2 EXINVNU4 NUMERIC - N6 DISPW5 FLOAT - F5.2 RETRNW5 FLOAT - F5.2 EXINVNU5 NUMERIC - N6 DISPW6 FLOAT - F5.2 RETRNW6 FLOAT - F5.2 EXINVNU6 NUMERIC - N6 DISPW7 FLOAT - F5.2 RETRNW7 FLOAT - F5.2 EXINVNU7 NUMERIC - N6 33

319 CONFIDENTIAL Annotated Trial Design Page 32of36 FORM: STATUS OF TREATMENT BLIND (BLIND) TRIAL: ffr101747_szs STATUS OF TREATMENT BLIND 1. Was the treatment blind broken during the study? If yes, complete the Adverse Event form and/or Investigational Product forms as appropriate [Y] (MAPPINGS7:t_BLIND.BLBRK) [N] No Date blind broken / / ( ) (MAPPINGS7:t_BLIND.BLDTTM) (MAPPINGS7:t_BLIND.BLREASCD) [1] Medical emergency requiring identification of investigational product for further treatment [Z] (MAPPINGS7:t_BLIND.BLRSOTH) Item Design Notes: Item No. Design Note 1. Time blind broken is optional CDD: MAPPINGS7 Table: t_blind Key Type: PATIENTVISIT Column Name Column Data Type Design Note BLBRK BLDTTM BLREASCD BLRSOTH STRING(1) DATE - DDMONYYYY STRING(1) STRING(200) - A200 34

320 CONFIDENTIAL Annotated Trial Design Page 33of36 FORM: STUDY CONCLUSION (CONC) TRIAL: ffr101747_szs STUDY CONCLUSION Perform follow-up phonecall prior to completing study conclusion details. 1. Date of subject completion / / ( ) (MAPPINGS7:t_DISPOSIT_SCRNFAIL.DSDTTM) 2. Was this subject a run-in / screen failure or did the (MAPPINGS7:t_DISPOSIT_SCRNFAIL.SFFAILDSWD) subject withdraw from the study? No [N] (MAPPINGS7:t_DISPOSIT_SCRNFAIL.rdcSFFailReas) [Y] [-99] (MAPPINGS7:t_DISPOSIT_SCRNFAIL.DSREASCD) [1] Adverse event [2] Lost to followup [3] Protocol violation [4] Subject decided to withdraw from the study [5] Lack of efficacy [6] Sponsor terminated study [17] Non-compliance[24] Did not meet treatment eligibility criteria[26] Investigator decision[z] (MAPPINGS7:t_DISPOSIT_SCRNFAIL.DSRSOTH) [-98] (MAPPINGS7:t_DISPOSIT_SCRNFAIL.SFREASCD) [1] Adverse event [2] Lost to follow-up [3] Protocol violation[4] Subject decided to withdraw from the study[5] Prohibited medication use[6] Did not fulfill eligibility criteria[ot] (MAPPINGS7:t_DISPOSIT_SCRNFAIL.SFRSOTH) LOG STATUS 3. Did the subject experience any adverse events during the study? (MAPPINGS7:t_DISPOSIT_SCRNFAIL.rdcConcAEAny) [N] No [Y] Yes 4.Were any concomitant medications taken by the subject prior to screening and/or during the study? (MAPPINGS7:t_DISPOSIT_SCRNFAIL.rdcConcCMAny) [N] No [Y] Yes5.Did the subject experience an SAE during the study? (MAPPINGS7:t_DISPOSIT_SCRNFAIL.SAEANY) [N] No [Y] Yes6.Did the subject become pregnant during the study? (MAPPINGS7:t_DISPOSIT_SCRNFAIL.PGYN) [N] No [Y] Yes[NAElement] Not Applicable7.Did any nasal spray device(s) supplied to the subject malfunction during the course of the study? (MAPPINGS7:t_DISPOSIT_SCRNFAIL.rdcConcIPFnnas) [N] No [Y] Yes 8. * Q1 [hidden] (MAPPINGS7:t_DISPOSIT_SCRNFAIL.AXCOMPLETERADIO) [Y] Yes [N] 9. * Q2 [hidden] (MAPPINGS7:t_DISPOSIT_SCRNFAIL.REASONRADIO) [?] PF_SC_LOST [?] PF_SC_DEATH [?] PF_SC_SPONSORDECISION [?] PF_SC_PHYSICIANDECISION [?] PF_SC_PATIENTDECISION [?] PF_SC_AE [?] PF_SC_ALE [?] PF_SC_CRITERIA [?] PF_SC_OTHER * Item is not required No Form Design Note: This form is optional and is to be used when screen failures or run-in failures are to be captured in the trial. Item Design Notes: Item No. Design Note 1. Time is optional 2. Choices after Subject decided to withdraw from the study (including other) are optional choices. Other is required for primary reason for withdrawal but not for the run-in/screen failures radio 3. This item is not part of the SI datasets 4. This item is not part of the SI datasets CDD: MAPPINGS7 Table: t_disposit_scrnfail Key Type: PATIENTVISIT Column Name Column Data Type Design Note DSDTTM SFFAILDSWD rdcsffailreas DSREASCD DSRSOTH SFREASCD SFRSOTH rdcconcaeany rdcconccmany SAEANY PGYN rdcconcipfnnas AXCOMPLETERADIO REASONRADIO DATE - DDMONYYYY STRING(1) NUMERIC STRING(2) STRING(200) - A200 STRING(2) STRING(200) - A200 STRING(1) STRING(1) STRING(1) STRING(9) STRING(1) STRING(1) STRING(42) 35

321 CONFIDENTIAL Annotated Trial Design Page 34of36 FORM: VISIT REPORTS (VRP) TRIAL: ffr101747_szs VISIT REPORTS 1. * This section is not implemented for your study (MAPPINGS7:t_VISITREPORT.NOTAVAIL_CC) * Item is not required Form Design Note: IDSL Version 01.00A - 01 DEC 04 CDD: MAPPINGS7 Table: t_visitreport Key Type: PATIENTVISIT Column Name Column Data Type Design Note NOTAVAIL_CC STRING(255) 36

322 CONFIDENTIAL Annotated Trial Design Page 35of36 FORM: REGULATORY DOCUMENTS (REGDOCS) TRIAL: ffr101747_szs REGULATORY DOCUMENTS 1. * This section is not implemented for your study (MAPPINGS7:t_REGDOCS.NOTAVAIL_CC) * Item is not required Form Design Note: IDSL Version 01.00A - 01 DEC 04 CDD: MAPPINGS7 Table: t_regdocs Key Type: PATIENTVISIT Column Name Column Data Type Design Note NOTAVAIL_CC STRING(255) 37

323 CONFIDENTIAL Annotated Trial Design Page 36of36 CRB Electronic Signature Affidavit By my dated signature below, I, [First Name] [Last Name], verify that all case report form pages accurately display the results of the examinations, tests, evaluations and treatments performed on this patient. Pursuant to Section of Title 21 of the Code of Federal Regulations, this is to certify that I intend that this electronic signature is to be the legally binding equivalent of my handwritten signature. To this I do attest by supplying my password and clicking the button marked Submit below. CRF Electronic Signature Affidavit By my dated signature below, I, [First Name] [Last Name], verify that this case report form accurately displays the results of the examinations, tests, evaluations and treatments noted within. Pursuant to Section of Title 21 of the Code of Federal Regulations, this is to certify that I intend that this electronic signature is to be the legally binding equivalent of my handwritten signature. To this I do attest by supplying my password and clicking the button marked Submit below. 38

324 LIST OF INVESTIGATORS AND IECS/IRBS FOR Investigator Investigator/ Site no. Hospital/ Institution and Address Dr IEC/IRB Committee Chair and Name of Committee Denmark CONFIDENTIAL 1

325 This section contained Principal Investigator s Curriculum Vitae and has been excluded to protect Principal Investigator privacy.

326 CONFIDENTIAL 1

327 CONFIDENTIAL 2

328 CONFIDENTIAL 3

329 CONFIDENTIAL 4