GSK Clincal Study Register

Transcription

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 Clincal 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 The GlaxoSmithKline group group of companies of companies Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Pharmacology Study Report ZM2008/00081/00 Title: Phase: An open-label, randomized, repeat dose, 3 period crossover study to determine the bioequivalence of 3 different formulations of tamsulosin at steady state in healthy male volunteers I Compound Number: GI Effective Date: 13-OCT-2008 Description: A combination formulation of dutasteride 0.5 mg and tamsulosin hydrochloride (HCl) 0.4 mg is being developed for the treatment of males with symptomatic benign prostatic hyperplasia (BPH). This was an open-label, randomized, repeat dose, 3 period crossover study healthy adult males. The primary objectives were to assess the bioequivalence of tamsulosin when given in the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin 0.4 mg or the modified Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S. commercially available Flomax 0.4 mg capsules under fasting conditions and at steady state. The secondary objective was to assess the safety and tolerability of each formulation. The tamsulosin component of the combination capsule formulations of dutasteride 0.5 mg and either 10% or 15% enteric coated tamsulosin HCl 0.4 mg is bioequivalent to the concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg at steady-state. Administration of the combination capsule formulations of dutasteride 0.5 mg/tamsulosin HCl 0.4 mg to healthy adult male volunteers was generally well tolerated under the conditions of this study. Subject: AVODART, dutasteride, Flomax, tamsulosin hydrochloride, GI198745, healthy subject, steady state, bioequivalence, combination capsule Author(s): Initiation Date: 26 FEB 2008 Completion Date: 23 APR 2008 Date of Report: OCT

3 CONFIDENTIAL ZM2008/00081/00 The GlaxoSmithKline group group of companies of companies Sponsor Signatory: (and Medical Officer) MD VP, Discovery Medicine, Metabolic Pathways Center of Excellence for Drug Discovery 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 2008 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited 2 2

4 CONFIDENTIAL ZM2008/00081/00 TABLE OF CONTENTS Page LIST OF ABBREVIATIONS INVESTIGATOR INFORMATION AND STUDY ADMINISTRATION List of Investigators ETHICAL CONDUCT OF THE STUDY OBJECTIVES & ENDPOINTS Objectives Primary Secondary Endpoints Primary Secondary STUDY RATIONALE AND DESIGN Study Rationale Study Design DIAGNOSIS AND CRITERIA FOR INCLUSION Inclusion Criteria Exclusion Criteria Permitted Medications Prohibited Medications TREATMENT ADMINISTRATION Treatments Administered Identity of Investigational Product (s) STUDY ASSESSMENTS AND PROCEDURES Pharmacokinetic Assessments Collection and Preparation of Samples Assay Methodology Safety Assessments Adverse Events and Serious Adverse Events Clinical Laboratory Evaluations Other Safety Assessments METHODS Data Quality Assurance

5 CONFIDENTIAL ZM2008/00081/ Data Analysis Methods Sample size considerations Interim Analyses Final Analyses Changes in Conduct of the Study or Planned Analyses Pharmacokinetic Methods STUDY POPULATION RESULTS Subject Disposition and Demographics Protocol Deviations Populations of Interest Concomitant Medications SAFETY RESULTS Extent of Exposure Adverse Events Drug-Related Adverse Events Serious Adverse Events Fatal Events Non-Fatal Events Adverse Events Leading to Premature Discontinuation of Investigational Product and/or Study Pregnancies Clinical Laboratory Evaluations Vital Signs Orthostatic Vital Signs ECGs PHARMACOKINETIC RESULTS Drug Concentration Data Serum Pharmacokinetic Parameters Statistical Analyses of Pharmacokinetic Parameters Tamsulosin Steady State Bioequivalence Statistical Analysis Details DISCUSSION AND CONCLUSIONS Discussion Conclusions REFERENCES CASE NARRATIVES

6 CONFIDENTIAL ZM2008/00081/00 STUDY POPULATION DATA SOURCE TABLES PHARMACOKINETIC SOURCE FIGURES AND TABLES SAFETY DATA SOURCE FIGURES AND TABLES ATTACHMENTS Attachment 1 Study Administration Attachment 2 Time and Events Table

7 CONFIDENTIAL ZM2008/00081/00 LIST OF TABLES Page Table 1 Clinical Laboratory Assessments Table 2 Sample Size Considerations Table 3 Summary of Subject Disposition and Demographic Characteristics. 21 Table 4 Summary of Concomitant Medications by Treatment Regimen Table 5 Extent of Exposure Table 6 Summary of Adverse Events Reported in 2 or More Subjects within any Treatment Regimen Table 7 Summary of Drug-Related Adverse Events Table 8 Summary of Selected Serum Tamsulosin Pharmacokinetic Parameters Table 9 Summary of Serum Tamsulosin Trough Concentrations (Cτ ng/ml) 1 after Repeat Administration Table 10 Summary of Results of Statistical Analysis of Tamsulosin Bioequivalence at Steady-State Table 11 Tamsulosin at Steady-State Assessment

8 CONFIDENTIAL ZM2008/00081/00 LIST OF ABBREVIATIONS AE ALT (SGPT) AST (SGOT) AUC(0- ) AUC(0-72) BMI BPH BP bpm BUN Cmax CPDM CPKMS CRF CSSO CVU DB DDS DM ECG FDA FDC GCP GGT GI GSK GSO HBsAg HCl HR hrs HIV ICF IRB IND IP kg L M MCH MCHC MCV Adverse Event Alanine aminotransferase Aspartate aminotransferase Area under the serum drug concentration versus time curve extrapolated to infinity Area under the serum drug concentration versus time curve over 72 hours Body mass index Benign prostatic hyperplasia Blood pressure Beats per minute Blood urea nitrogen Maximum observed drug concentration Clinical Pharmacology and Discovery Medicine Clinical Pharmacokinetics Modelling & Simulation Case report form Clinical Science and Study Operations Cardiovascular and Urology Discovery Biometrics Drug Development Sciences Discovery Medicine Electrocardiogram Food and Drug Administration Fixed dose combination Good Clinical Practice Gamma glutamyl transferase Gastrointestinal GlaxoSmithKline Global Supply Operations Hepatitis B surface antigen Hydrochloride Heart rate Hours Human immunodeficiency virus Informed consent form Institutional Review Board Investigational New Drug application Investigational product Kilogram Liter Meters Mean corpuscular hemoglobin Mean corpuscular hemoglobin concentration Mean corpuscular volume 5 7

9 CONFIDENTIAL Mg Milligram ml Milliliter mmhg Millimeters of mercury MSDS Material Safety Data Sheet MTOPS Medical Therapy of Prostatic Symptoms oz Ounce PCD Pre-clinical Development PGx Pharmacogenetics PK Pharmacokinetics RBC Red blood cells SAE Serious adverse event SPM Study procedures manual ss Steady state t1/2 Elimination half-life Tmax Time at which Cmax was observed tsp Teaspoon ULN Upper limit of normal U.S. United States WBC White blood cells ZM2008/00081/00 Trademark Information Trademarks of the GlaxoSmithKline group of companies AVODART Trademarks not owned by the GlaxoSmithKline group of companies Flomax 6 8

10 CONFIDENTIAL ZM2008/00081/00 1. INVESTIGATOR INFORMATION AND STUDY ADMINISTRATION 1.1. List of Investigators Investigator MD and PharmD Investigator/ Site/Center Number. Hospital/ Institution and Address USA 2. ETHICAL CONDUCT OF THE STUDY The study protocol, the informed consent, and other information that required preapproval were reviewed and approved by an institutional review board. This study was conducted in accordance with "good clinical practice" (GCP) and all applicable regulatory requirements, and, the guiding principles of the 2004 Declaration of Helsinki. Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. Case report forms (electronic) were provided for each subject s data to be recorded. 3. OBJECTIVES & ENDPOINTS 3.1. Objectives Primary 1. To investigate the bioequivalence of tamsulosin at steady state of a Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg under fasting conditions. 2. To investigate the bioequivalence of tamsulosin at steady state of a Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg under fasting conditions Secondary 1. To assess the safety and tolerability of dosing with the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg, the Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated 7 9

11 tamsulosin HCl 0.4 mg, and concomitant dosing of AVODART 0.5 mg and the U.S.- sourced Flomax 0.4 mg Endpoints Primary 1. AUC (0-24) and Cmax of tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg after a single dose and at steady state. 2. AUC (0-24) and Cmax of tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg after a single dose and at steady state. 3. AUC (0-24) and Cmax of tamsulosin in concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg Secondary 1. C(tau) (defined as the concentration at 24 hours after the Day 7 dose), t1/2, tmax, λ, Cmin and fluctuation [(Cmax Cmin)/(AUC(0-24)/24)] of tamsulosin, as data permit. 2. Safety and tolerability of all treatments as assessed by blood pressure and pulse rate measurements, adverse events and clinical laboratory safety tests. 4. STUDY RATIONALE AND DESIGN 4.1. Study Rationale Depending on the results of this study and other completed studies as well as the results of ongoing formulation development work, the decision will be made to move forward with either the 10% or the 15% enteric coated formulation of tamsulosin in the combination capsule. This current study will establish bioequivalence of the 10% enteric coated tamsulosin in the combination product and the 15% enteric coated tamsulosin in the modified combination product relative to concomitant dosing with separate capsules of dutasteride and tamsulosin commercial formulations at steady state, with respect to tamsulosin. There is concern that tamsulosin may accumulate after repeat dosing, therefore, this study will establish bioequivalence at steady state of tamsulosin only Study Design CONFIDENTIAL ZM2008/00081/00 This was an open-label, randomized, repeat dose, 3 period crossover study in healthy males. Each subject was to receive one of the three treatment regimens in each dosing session. There was an approximately 5-7 day washout between dosing of each session. Subjects were to participate in 3 dosing sessions. In order to minimize the potential 8 10

12 impact of genetic variability to the pharmacokinetics of tamsulosin, poor CYP2D6 metabolizers were excluded from this study. Eligible subjects were admitted to the research unit the evening prior to dosing (Day -1) and remained in the unit until approximately 48 hours after dosing on Day 7. The subjects returned to the research unit for an outpatient visit at approximately 72 hours post-dose Day 7 after each treatment session. On days when full PK sampling took place (Days 1 and 7) subjects were fasted for 10 hours prior to drug administration and for 4 hours after. There was a washout period of approximately 5-7 days after the last dose in each treatment session. Subjects returned to the research unit 10 days after the last dose for follow-up and were subsequently discharged from the study. The total duration of each subject's participation from screening to follow-up will be approximately 9 weeks. 5. DIAGNOSIS AND CRITERIA FOR INCLUSION 5.1. Inclusion Criteria A subject was eligible for inclusion in this study only if all of the following criteria apply: 1. Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Subjects with orthostasis at screening should be excluded from enrollment. 1. Males between 18 and 45 years of age (inclusive). 2. Male subjects agreed to use one of the contraception methods listed in the protocol. This criterion was followed from the time of the first dose of study medication until follow-up from the study. 3. Body weight 55 kg and BMI within the range kg/m2 (inclusive). 4. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. 5. QTcB or QTcF < 450 msec. 6. Subjects agreed not to donate blood and blood products for 6 months after the last dose of study medication Exclusion Criteria CONFIDENTIAL ZM2008/00081/00 A subject was not eligible for inclusion in this study if any of the following criteria apply: 1. The subject had a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines. 9 11

13 2. Slow metabolizer for CYP2D6 as determined by screening PGx analysis. 3. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. 4. A positive test for HIV antibody. 5. History of regular alcohol consumption within 6 months of the study defined as: 6. An average weekly intake of >14 drinks/week. One drink is equivalent to: 12 g alcohol = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits. 7. The subject participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). 8. Exposure to more than four new chemical entities within 12 months prior to the first dosing day. 9. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John s Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and until collection of the final PK sample from the study, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. 10. History of sensitivity to any of the study medications, or components thereof, including sulfonamides, or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. 11. History of postural hypotension, dizziness, poor hydration, vertigo, vaso-vagal reactions or any other signs and symptoms of orthostasis, which in the opinion of the investigator could be exacerbated by tamsulosin and result in putting the subject at risk of injury. 12. Orthostatic hypotension at screening, defined as a reduction in systolic blood pressure of 20 mmhg or more and/or a reduction in diastolic blood pressure of 10 mmhg or more for standing vs. supine measurements. 13. Where participation in the study would result in donation of blood or blood products in excess of 500 ml within a 56 day period. 14. Unwillingness or inability to follow the procedures outlined in the protocol. 15. History of sensitivity to heparin or heparin-induced thrombocytopenia. 16. Consumption of red wine, seville oranges, grapefruit, grapefruit juice or cruciferous vegetables (watercress, broccoli, cabbage, Brussels sprouts) from 7 days prior to the first dose of study medication and until collection of the final PK sample in the study 5.3. Permitted Medications CONFIDENTIAL ZM2008/00081/00 Acetaminophen, at doses of 2 grams/day was permitted. Other concomitant medication could be considered on a case by case basis by the GSK Medical Monitor

14 5.4. Prohibited Medications Subjects were to abstain from taking any vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until the collection of the final PK sample from the study, unless in the opinion of the Investigator and sponsor the medication would not interfere with the study. 6. TREATMENT ADMINISTRATION 6.1. Treatments Administered CONFIDENTIAL Subjects were be assigned to ABC, ACB, BAC, BCA, CAB, or CBA in accordance with the randomization schedule generated by Discovery Biometrics, prior to the start of the study, using validated internal software (RandAll) Identity of Investigational Product (s) ZM2008/00081/00 Treatment Drug Dose/Form/Route Frequency /Duration A B C Dutasteride and Tamsulosin Hydrochloride (10%) Combination Capsule Dutasteride and Tamsulosin Hydrochloride (15%) Combination Capsule Flomax AVODART (GI198745) 0.5 mg dutasteride, 0.4 mg tamsulosin HCl / capsules / oral 0.5 mg dutasteride, 0.4 mg tamsulosin HCl / capsules / oral 0.4 mg tamsulosin/ sustained release capsule / oral 0.5 mg dutasteride/ capsule / oral Once daily / 7 days Once daily / 7 days Once daily / 7 days with AVODART Once daily / 7 days with Flomax Lot or Batch Number Batch # Batch # Lot # Batch # AVODART was supplied by GlaxoSmithKline as oblong, dull yellow, soft gelatin capsules containing 0.5 mg dutasteride (GI198745). These capsules were identical in formulation to the commercially available AVODART except they were plain. They were not branded with the red ink commercial print. AVODART capsules were supplied as 100 capsules in a white 120cc HDPE bottle with a child resistant closure and a single clinical label. Flomax was supplied by GlaxoSmithKline as the commercially available product. Flomax capsules were elongated hard gelatin capsules with an olive green cap and orange body, each containing 0.4 mg tamsulosin hydrochloride. The capsules were imprinted on 11 13

15 one side with Flomax 0.4 mg and on the other side with BI 58 in black ink. Flomax capsules were supplied as 100 capsules in their white commercial bottle with commercial label. Dutasteride and Tamsulosin HCl Combination Capsules (10% and 15%) were supplied by GlaxoSmithKline as hard gelatin capsules with an orange cap and brown body, each containing 0.5 mg dutasteride (GI198745) and 0.4 mg tamsulosin HCl. The capsules were imprinted with GS 7CZ in black ink on the cap. Each formulation looked identical. Dutasteride and Tamsulosin HCl Combination Capsules (10% and 15%) were supplied as 30 capsules in a white 100cc HDPE bottle with a child resistant closure and a single clinical label. 7. STUDY ASSESSMENTS AND PROCEDURES 7.1. Pharmacokinetic Assessments Collection and Preparation of Samples In each session, blood samples (approximately 2 ml each) for analysis of tamsulosin concentrations were collected on Day 1 at pre-dose and at the following timepoints: 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 16 hours post-dose. Pre-dose samples were collected on Days 2 6. On Day 7, samples were collected at pre-dose and the following timepoints: 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, and 72 hours post-dose. Samples were collected into empty red top tubes without anticoagulant and allowed to clot at room temperature for no longer than 30 minutes. Samples were centrifuged at approximately 1500g for 15 minutes. The harvested serum was placed into a 1.4 ml Matrix screwtop tube. The tubes were labelled with the subject number, study number (), treatment regimen, date and time of sample collection. The samples were stored frozen at or below -20ºC until shipped on dry ice to the Department of Worldwide Bioanalysis, DMPK, GlaxoSmithKline, US for analysis Assay Methodology CONFIDENTIAL ZM2008/00081/00 Serum tamsulosin (GI138525) concentrations were determined by Worldwide Bioanalysis, Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC, USA. Human serum samples were analysed for tamsulosin concentrations using a validated method. Tamsulosin was extracted from human serum by protein precipitation. Extracts were analysed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS). The assay was validated over the tamsulosin concentration range 0.05 to 50 ng/ml in human serum [GSK Document Number RD2007/01642/00]. Quality controls were prepared and analyzed with each batch of samples against separately prepared calibration standards to assess the day-to-day performance of the assay. For the analysis to be acceptable, no more than one third of the quality control results were to deviate from the nominal concentration by more than 15%, with at least 12 14

16 one quality control result acceptable at each concentration. Quality control results from this study met these acceptance criteria [GSK Document Number RD2008/00913/00]. All data are stored in the GSK Archive Safety Assessments CONFIDENTIAL Adverse Events and Serious Adverse Events Adverse event (AE) and serious adverse event (SAE) data were collected and recorded on the CRF starting on Day 1 and continuing until the end of the study. The Investigator or site staff were responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE as provided in the study protocol. In the event that an AE or SAE occurred, it was the responsibility of the investigator to review all documentation (eg, hospital progress notes, laboratory, and diagnostics reports) relative to the event and attempt to establish a diagnosis of the event based on signs, symptoms, and other clinical information. The diagnosis was to be documented as the AE/SAE and not the individual signs/symptoms. Once an investigator became aware that an SAE had occurred in a study subject, they were to report the information to GSK within 24 hours and provide an assessment of causality Clinical Laboratory Evaluations ZM2008/00081/00 Table 1 represents the clinical laboratory assessments performed during the study. See Attachment 2 Time and Events Table for information on timing of the assessments. Table 1 Clinical Laboratory Assessments Test Clinical Chemistry Haematology Urinalysis Other Tests Assessment albumin (screening), ALT, alkaline phosphatase, AST, BUN, calcium, chloride, creatinine, GGT, glucose (fasting), potassium, sodium, total and direct bilirubin, total CO2, total protein (screening) CBC with RBC indices and WBC differential, platelet count. specific gravity, ph, glucose, protein, blood, ketones, microscopic examination. HIV antibody, Hepatitis B, Hepatitis C, urine drug screen, alcohol screen. Abnormal laboratory findings that were judged by the investigator as clinicallysignificant were recorded as AEs or SAEs if they met the definition of an AE or SAE as provided in the study protocol

17 Other Safety Assessments CONFIDENTIAL ZM2008/00081/ Physical Examinations Physical examinations were performed at the time points indicated in Attachment 2, Time and Events Table. A physical examination included height and body weight (screening only) and evaluation of the subject s medical conditions. Any new or worsening of medical conditions from the baseline condition was recorded as an AE or SAE Vital Signs Blood pressure and heart rate readings were performed at the time points indicated in Attachment 2, Time and Events Table. Subjects remained in the supine position for at least 5 minutes prior to each measurement Orthostatic Vital Signs Orthostatic vital signs were taken at the time points outlined in Attachment 2, Time and Events Table. In order to obtain orthostatic vital signs, subjects had the following procedures in sequential order: The staff reviewed the procedure with the subject. Subjects assumed a supine position and then remained in a supine position for 15 minutes. Conversation and noise were to be minimized for the duration of the assessment period. After remaining supine for 15 minutes, three measurements of blood pressure and heart rate were taken at one-minute intervals (one-minute between the completion of one measurement and the beginning of the next). All 3 blood pressure and heart rate measurements taken in the supine position were recorded in the CRF. The subject was then be asked to sit on the edge of the bed/table with feet on the floor (or with feet dangling from the bed/tableside depending on the height of the bed/table) for 30 seconds. The person performing the assessment asked the question, Are you ready to stand? If the subject responded in the affirmative, the subject proceeded to stand and then asked to remain standing for three (3) minutes. After standing for three minutes, one measurement was taken for blood pressure and heart rate. If the subject stated that he is not ready to stand, the subject was allowed to sit as positioned for one additional minute and then asked again if they were ready to stand. The subject would then proceed to stand. After standing for three minutes, one measurement was taken for blood pressure and heart rate. If the individual was still unable to stand, vital signs were measured while the subject was seated

18 CONFIDENTIAL ZM2008/00081/00 The person performing the assessment asked the subject a non-leading question about any associated symptoms after the measurement of vital signs either while standing or while seated if unable to stand. The question was, How do you feel? Electrocardiograms Supine 12-lead ECGs were taken at screening only. Subjects were required to rest for at least 5 minutes before the ECG was recorded. Extreme changes in room temperature were avoided before and during the ECG (subjects remained comfortable) and hot/cold drinks/food were avoided 30 minutes prior to the reading. 8. METHODS 8.1. Data Quality Assurance To ensure compliance with GCP and all applicable regulatory requirements, GSK can conduct a quality assurance audit. Regulatory agencies can also conduct a regulatory inspection of the study. Such audits/inspections can occur at any time during the study or after completion of the study. The bioanalytical phase of the study was audited and found to be in compliance by an independent quality assurance unit (QAU) within GSK. A regulatory audit or inspection did not occur as of the date of this report. The PK data generated were subject to QC procedures by Covance. This study was conducted using PACE InForm, a completely validated electronic data capture system. Paper case report forms were not utilized Data Analysis Methods Sample size considerations Table 2 below summarizes the observed estimates of within subject CV and observed ratio of geometric means for the primary end points AUC(0-t) and Cmax from the first pilot study of Synthon: Table 2 Sample Size Considerations Parameter Within subject CV Point Estimate (PE) of Ratio Cmax 16.13% 1.04 AUC(0-t) 11.65% 0.98 The within subject CV estimate, 11.65% for AUC(0-t), translated to a standard deviation (SD) of 0.12 on the natural log scale. Based on this SD, a sample size of 16 statistically evaluable subjects would have at least 90% power to demonstrate bioequivalence. This calculation assumed: 15 17

19 a true ratio of 1 the within-subject variability from the current study would not be larger that that used in the sample size calculations data is log-normally distributed, and each t-test is made at the 5% level A sensitivity analysis was conducted in the event that the variability was greater than expected and the point estimate of ratio was not 1. Based on the upper bound of 90% CVw(%) for AUC(0-t) of tamsulosin is 15.6%. With a sample size of 16 subjects, the power to conclude bioequivalence of AUC(0-t) was still over 90% assuming the point estimate of the ratio was Interim Analyses No interim analysis was planned or performed for this study Final Analyses CONFIDENTIAL ZM2008/00081/00 Statistical analyses were the responsibility of Discovery Biometrics, GlaxoSmithKline Pharmaceuticals, Philadelphia, PA. All displays were generated in the HARP (Harmonisation of Analysis and Reporting Program) environment which used SAS version 8 on a UNIX platform. Descriptive Statistics (n, arithmetic mean and corresponding 95% confidence interval, standard deviation, minimum median, maximum, CV%) were calculated for all pharmacokinetic endpoints by regimen. In addition, the geometric means and corresponding 95% confidence intervals were calculated for AUC(0-24)-ss, Cmax-ss, Cmin-ss, Cτ, t1/2 and fluctuation) by regimen. Plasma concentration - time data on day 1 and day 7 was listed, summarised and graphically presented. Safety data was listed and summarised only. Per GSK SOP-CPK-0007 v01, a linear regression analysis was performed for the log e - transformed Cτ s in Days 4, 5 and 6 (i.e. pre-dose concentration data in Days 5, 6 and 7) versus day, fitting day as covariate and subject as random effect, to check the achievement of the steady state for each regimen. The pharmacokinetic parameters AUC(0-24)-ss, Cmax-ss, Cmin-ss, Cτ, tmax and fluctuation were derived from the plasma concentration data and were listed and summarised. The log e -transformed values of AUC(0-24)-ss, Cmax-ss, Cmin-ss, Cτ, t1/2 and fluctuation were analyzed by analysis of variance (ANOVA) using a mixed effects model, fitting fixed effect terms for treatment sequence, period and regimen, and fitting subject within sequence as a random effect. Point estimates and associated 90% confidence intervals for the differences of A-C and B-C was separately constructed using the residual variance. These point estimates and confidence intervals were exponentially back-transformed to obtain point estimates and 90% confidence intervals for the ratios of geometric least square means (A:C and B:C). Bioequivalence of tamsulosin at steady state would be demonstrated if the 90% CIs for the ratios of AUC(0-24)-ss and Cmax-ss were completely contained within the range of and

20 Within subject and between-subject CVs were calculated for AUC(0-24)-ss, Cmax-ss, Cmin-ss, Cτ, t1/2 and fluctuation using the following equations: CVw = 100*sqrt(exp(MSE)-1) CVb = 100*sqrt(exp(Var(subject(sequence))+MSE)-1) where MSE is the mean squared residual error and Var(subject(sequence)) is the subject variance component from the model. Tmax was analyzed nonparametrically using the Wilcoxon Matched Pairs Method to obtain the point estimate and 90% confidence interval for the median difference for each comparison of interest Changes in Conduct of the Study or Planned Analyses The data analyses plan in the RAP was following the guidance document from Health Canada: GUIDANCE FOR INDUSTRY - Conduct and Analysis of Bioavailability And Bioequivalence Studies - Part B: Oral Modified Release Formulations (1996). The statistical analyses in this report were adjusted following the guidance documents from FDA: GUIDANCE FOR INDUSTRY - Statistical Approaches to Establishing Bioequivalence (2001), per GlaxoSmithKline Standard Operating Procedure, SOP-CPK- 0003: Standard Methods for the Non-Compartmental analysis of Bioequivalence Studies Pharmacokinetic Methods CONFIDENTIAL ZM2008/00081/ Drug Concentration Data Serum tamsulosin concentrations, along with the actual blood sampling dates and times were listed by subject and planned sampling time. Serum tamsulosin concentrations were summarised by planned sampling time. Figures of individual and mean/median serum tamsulosin concentration-time profiles were produced on both semi-log and linear scales. For the calculation of individual PK profiles, if an NQ (not quantifiable) value occurred in a profile before the first measurable concentration, it was assigned a value of zero concentration. Additionally, if an NQ value occurred after a measurable concentration in a profile and was followed by a value above the LLQ (lower limit of quantification), then NQ was generally omitted. If two NQ values occurred in succession (after Cmax), the profile was deemed to have terminated at the first NQ value and any subsequent concentrations were omitted from PK calculations. For the calculation of mean and median profiles, when estimating the mean and median values for the concentration at a given time point, NQ values were handled in a manner consistent with calculation of individual PK profiles (i.e., all NQ values were set to zero except when an individual NQ fell between two quantifiable values, in which case it was omitted). The mean/median value at a time with one or more NQ values was reported (in tabular or graphical fashion) unless the resulting mean/median value was below the LLQ of the assay, in which case the value was assigned NQ

21 Pharmacokinetic Analyses CONFIDENTIAL PK analyses were conducted by Covance Laboratories Inc, Madison, WI, USA, under the direction of Clinical Pharmacokinetics/Modeling and Simulation, CPDM, GlaxoSmithKline. The statistical analyses of pharmacokinetic data were the responsibility of Discovery Biometrics (DB), GlaxoSmithKline. PK analyses of serum tamsulosin concentration-time data were conducted using non-compartmental Model 200 (for extravascular administration) of WinNonlin Professional Edition version 5.2 (Pharsight Corporation, Mountain View, CA) according to the guidance described in Non-Compartmental Analysis of Pharmacokinetic Data (GUI-CPK-3001 v01, 28-Sep-07). Actual elapsed time from dosing was used to estimate all individual serum PK parameters for evaluable subjects. Values for the following PK parameters were estimated following administration of single and multiple doses of tamsulosin, as appropriate. The maximum observed serum concentration (Cmax), the first time to reach Cmax (tmax), and the trough concentrations (Cτ) were the actual observed values. Where possible, the terminal serum elimination rate-constant (λz) was estimated from log-linear regression analysis of the terminal phase of the serum concentration-time profile. The number of points included in the terminal phase was determined by visual inspection of the semi-log plots of the serum concentration-time profiles. The associated apparent terminal elimination half-life (t1/2) was calculated as ln2/λz. Fluctuation (FL) of tamsulosin was calculated [(Cmax Cmin)/(AUC(0-24)/24)]. The area under the serum concentration-time curve from time zero to 24 hours post-dose [AUC(0-24)] were calculated by a combination of linear and logarithmic trapezoidal methods. The linear trapezoidal method was used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. Serum tamsulosin PK parameter estimates were listed by subject and treatment and study day. Individual serum tamsulosin parameter estimates were plotted by treatment on linear scales. Serum tamsulosin PK parameter values were summarized by treatment and study day. In accordance with GlaxoSmithKline SOP-NPD-0003 v01, Management of the Sponsor's Clinical Study Documents (Sponsor Study Records), all PK analyses were stored in the Archive, GlaxoSmithKline, Research and Development under protocol. 9. STUDY POPULATION RESULTS 9.1. Subject Disposition and Demographics ZM2008/00081/00 Twenty-four subjects enrolled in the study and 23 completed the study. One subject was withdrawn from the study due to an SAE of epididymitis, which was deemed by the Investigator to be not related to study medication

22 CONFIDENTIAL ZM2008/00081/00 Table 3 Summary of Subject Disposition and Demographic Characteristics Number of Subjects Number of subjects planned, N: 24 Number of subjects randomized, N: 24 Number of subjects included in All subjects (safety) population, n (%): 24 (100) Number of subjects included in PK population, n (%): 24 (100) Number of subjects completed as planned, n (%): 23 (96) Number of subjects withdrawn (any reason), n (%): 1 (4) Reasons for subject withdrawal, n (%) Serious Adverse Event 1 (4) Demographics Age in Years, Mean (Range) 24 (19-45) Sex, n (%) Female: 0 Male: 24 (100) BMI, Mean (Range) 26.0 ( ) Height, Mean (Range) 177 ( ) Weight, Mean (Range) 81.4 ( ) Ethnicity, n (%) Hispanic or Latino: 2 (8) Not Hispanic or Latino: 22 (92) Race, n (%) African American/African Heritage 11 (46) Asian South East Asian Heritage 2 (8) White White/Caucasian/European Heritage 10 (42) Mixed Race 1 (4) Source Data: Study Population Table 9.01, Study Population Table 9.02, Study Population Table Protocol Deviations There were no reported protocol deviations Populations of Interest The PK concentration population included all subjects for whom at least one PK sample was obtained and analyzed. All 24 subjects were included in the PK concentration population. For each PK parameter, the PK parameter population included all subjects who provided PK parameter data. The safety population consisted of all subjects enrolled into the study and received at least one dose of study medication. All 24 subjects were included in the safety population

23 9.4. Concomitant Medications CONFIDENTIAL ZM2008/00081/00 A similar proportion of subjects by regimen took a concomitant medication during the treatment phase of the study. Based on what is known about the metabolism of the study medications and the concomitant medications taken, there is no expectation that these concomitant medications would have had a significant impact on the PK of dutasteride or tamsulosin. Therefore, the use of the concomitant medications described in Table 4 was not thought to affect subject safety or the interpretation of study results. Table 4 Summary of Concomitant Medications by Treatment Regimen Number (%) of subjects who took any concomitant medication Regimen A Regimen B Regimen C (n=23) (n=24) (n=23) 4 (17) 4 (17) 3 (13) Generic Term, N (%) Acetylsalicylic Acid 1 (4) Paracetamol 3 (13) 4 (17) 3 (13) Source: Study Population Table 9.04 Regimen A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride Regimen B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride Regimen C: Flomax 0.4 mg and AVODART 0.5 mg 10. SAFETY RESULTS Extent of Exposure This was a 3-session cross-over study in 24 subjects. Twenty-three subjects completed the study as planned. Extent of exposure to each treatment regimen is summarized in Table 5. Table 5 Extent of Exposure Number of Subjects Exposed Regimen A Regimen B Regimen C Source: Safety Table Regimen A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride Regimen B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride Regimen C: Flomax 0.4 mg and AVODART 0.5 mg Adverse Events There was one SAE which led to withdrawal from the study. Details for this subject are found in Section

24 CONFIDENTIAL ZM2008/00081/00 The most commonly reported AEs in any regimen (>10%) were headache, dizziness and nasal congestion. A slightly higher proportion of AEs were seen with Regimen A (Dutasteride and Tamsulosin Hydrochloride (10%) Combination Capsule) than with either Regimens B or C. All adverse events were considered by the investigator to be mild or moderate in intensity. The investigator was unable to reach the subject after the end of the study for follow-up. Table 6 Summary of Adverse Events Reported in 2 or More Subjects within any Treatment Regimen Number of Subjects with AE (%) Regimen A (n=23) Regimen B (n=24) Regimen C (n=23) Total (n=24) Subjects with any AE 15 (65) 10 (42) 9 (39) 20 (83) System Organ Class Preferred Term Headache 4 (17) 5 (21) 4 (17) 8 (33) Dizziness 1 (4) 2 (8) 3 (13) 5 (21) Dizziness postural 2 (9) 1 (4) 0 3 (13) Nasal congestion 1 (4) 3 (13) 0 4 (17) Cough 0 2 (8) 1 (4) 3 (13) Pain in extremity 2 (9) (8) Abnormal dreams 0 1 (4) 2 (9) 3 (13) Source Data: Safety Table Regimen A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride Regimen B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride Regimen C: Flomax 0.4 mg and AVODART 0.5 mg Drug-Related Adverse Events A slightly higher proportion of drug-related AEs were seen with Regimen A (Dutasteride and Tamsulosin Hydrochloride (10%) Combination Capsule) than with either Regimens B or C. The most common drug-related adverse events were dizziness and headache. These AEs are consistent with the expected side effects of tamsulosin [Flomax, 2008]

25 CONFIDENTIAL ZM2008/00081/00 Table 7 Summary of Drug-Related Adverse Events Number of Subjects with Drug-Related AEs (%) Regimen A (n=23) Regimen B (n=24) Regimen C (n=23) Total (n=24) Subjects with any AE 7 (30) 4 (17) 5 (22) 12 (50) System Organ Class Preferred Term Dizziness 1 (4) 1 (4) 3 (13) 5 (21) Headache 3 (13) 2 (8) 0 4 (17) Dizziness postural 2 (9) 1 (4) 0 3 (13) Abnormal dreams 0 1 (4) 2 (9) 3 (13) Abdominal pain upper 1 (4) (4) Nasal congestion 1 (4) (4) Source Data: Safety Table Regimen A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride Regimen B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride Regimen C: Flomax 0.4 mg and AVODART 0.5 mg Serious Adverse Events Fatal Events There were no fatal SAEs reported in this study Non-Fatal Events One subject experienced a non-fatal SAE which led to withdrawal Adverse Events Leading to Premature Discontinuation of Investigational Product and/or Study One subject was withdrawn from the study due to an SAE that was not considered drug related: 22 24

26 CONFIDENTIAL ZM2008/00081/ Pregnancies There were no partner pregnancies reported during this study Clinical Laboratory Evaluations Four subjects had clinical laboratory values of potential clinical importance (PCI). None of these were considered to be clinically relevant and none were recorded as AEs Vital Signs There were 62 vitals signs of potential clinical importance reported in 17 subjects in this study. Four of these led to adverse events of dizziness or dizziness postural in 4 subjects. The adverse events were all mild in intensity and resolved within approximately 30 minutes. Each of these also met the protocol definition of orthostatic hypotension. All of these adverse events occurred on Day 1 or Day 7 of the session, when subjects were fasted. A complete listing of vital signs of potential clinical importance can be found in Table and the listing for all vital signs for subjects with values potential clinical importance can be found in Table Orthostatic Vital Signs There were 25 vitals signs in 13 subjects which met the protocol definition of orthostatic hypotension, based on the average of the 3 supine readings compared to the standing reading. Seven of these led to adverse events of dizziness or dizziness postural in 6 subjects. The adverse events were all mild in intensity and resolved within approximately 33 minutes ECGs Two subjects had ECGs of potential clinical importance. These were not considered by the investigator to be clinically relevant. 11. PHARMACOKINETIC RESULTS Drug Concentration Data Individual serum tamsulosin concentration listings and associated summary statistics were prepared. Individual serum tamsulosin concentration-time profiles are displayed with actual time on both semi-logarithmic and linear scales by subject and treatment. Descriptive statistics for serum tamsulosin concentration data at each planned relative time are presented by treatment. Mean and median steady-state serum tamsulosin concentration-time profiles for all treatments are displayed with scheduled time and are presented on both semi-logarithmic and linear scales

27 CONFIDENTIAL ZM2008/00081/ Serum Pharmacokinetic Parameters Selected tamsulosin PK parameters are summarized in Table 8 and Table 9 below. Table 8 Summary of Selected Serum Tamsulosin Pharmacokinetic Parameters 1 AUC(0-24) Cmax Cmin FL t1/2 tmax Regimen Day N (ng hr/ml) (ng/ml) (ng/ml) (%) (hr) (hr) NC NC NC (25.4) (22.8) ( ) A (30.8) (26.3) (49.6) (25.3) (19.4) ( ) NC NC NC (46.8) (42.1) ( ) B (37.3) (30.4) (58.9) (26.8) (22.1) ( ) NC NC NC (28.5) (19.0) ( ) C (25.0) (20.7) (50.9) (23.6) (17.9) ( ) Source Data: Pharmacokinetic Table 10.2 and Table Geometric mean (CVb%) 2. Median (range) NC = Not calculated Regimen: A 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C Flomax 0.4 mg and AVODART 0.5 mg Table 9 Summary of Serum Tamsulosin Trough Concentrations (Cτ ng/ml) 1 after Repeat Administration 1 Regimen N Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 A (50.6) 2.79 (47.9) 3.25 (45.4) 3.13 (51.1) 3.16 (58.4) 3.14 (45.9) 3.09 (52.8) B (58.0) 2.92 (54.8) 3.28 (55.5) 3.34 (53.0) 3.15 (56.5) 3.10 (53.8) 3.05 (60.1) C (56.4) 2.85 (50.0) 3.17 (54.2) 3.28 (51.9) 3.15 (54.1) 3.18 (45.1) 2.89 (50.8) Source Data: Pharmacokinetic Table Geometric mean (CVb%) Regimen: A 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C Flomax 0.4 mg and AVODART 0.5 mg 24 26

28 CONFIDENTIAL Following once daily oral administration of regimens A, B and C, tamsulosin was absorbed readily with a median tmax value of 5.00 hours on Day 1 and Day 7. Tamsulosin was eliminated slowly with mean t1/2 values ranging from 13.7 to 14.1 hours on Day 7. Following once daily oral administrations of regimens A, B and C for 7 days, the Cτ ranged from 2.22 to 3.34 ng/ml Statistical Analyses of Pharmacokinetic Parameters Tamsulosin Steady State Bioequivalence ZM2008/00081/00 Table 10 Summary of Results of Statistical Analysis of Tamsulosin Bioequivalence at Steady-State Parameter Comparison Least Square Geometric Mean Test Reference Point Estimate of Ratio 90% CI AUC(0-24)-ss 1 A : C (0.93,1.11) (ng*hr/ml) B : C (0.85,1.02) Cmax-ss 1 A : C (0.91,1.06) (ng/ml) B : C (0.85,0.98) Cmin-ss 1 A : C (0.90,1.19) (ng/ml) B : C (0.91,1.20) Cτ 1 (ng/ml) A : C (0.95,1.23) B : C (0.91,1.18) 1/2 1 (hr) A : C (0.94,1.04) B : C (0.97,1.08) Fluctuation 1 (%) A : C (0.90,1.01) B : C (0.89,1.00) tmax 2 (hr) A - C (-0.50,0.50) B - C (0.00,0.50) Source data: Pharmacokinetic Table 10.7 and Table Point estimate is the ratio of adjusted geometric means between regimens 2. Point estimate represents the estimated median difference between regimens 3. CVw% represents a pooled estimate of within-subject variability across regimens 4. CVb% represents a pooled estimate of between-subject variability across regimens CVw 3 (%) CVb 4 (%) Regimens: A 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C Flomax 0.4 mg and AVODART 0.5 mg Comparing regimen A with regimen C, the point estimates of AUC(0-24), Cmax, Cmin, Cτ, t1/2 and FL were contained within the 0.80 to 1.25 interval, indicating no significant differences between regimen A and regimen C. Similarly, the point estimates of AUC(0-24), Cmax, Cmin, Cτ and t1/2 were contained within the 0.80 to 1.25 interval, indicating no significant difference between regimen B and regimen C. The 90% CIs for the tmax point estimates include zero, indicating no significant differences were observed between regimens A and B versus regimen C. Low to moderate within-subject variability was observed in these PK parameters

29 CONFIDENTIAL ZM2008/00081/00 Table 11 Tamsulosin at Steady-State Assessment Point Estimate of Parameter Regimen Slope 90% CI CVw% A 1.00 (0.96, 1.04) 12.7 Cτ B 0.96 (0.92, 1.00) 16.8 (ng/ml) C 0.98 (0.93, 1.04) 22.0 Source Data: Pharmacokinetic Table 10.5 Regimen: A 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C Flomax 0.4 mg and AVODART 0.5 mg The point estimates of slope (versus day) and corresponding 90% CIs for tamsulosin Cτ values in regimens A, B and C were 1.00 (0.96, 1.04), 0.96 (0.92, 1.00), and 0.98 (0.93, 1.04) respectively. The 90% CIs were all within (0.91, 1.10), indicating that the steadystate was achieved for all regimens Statistical Analysis Details Statistical analyses of pharmacokinetic data were performed under the direct auspices of Discovery Biometrics (DB), GlaxoSmithKline, Philadelphia. Data was released to DB by CPK via HARP. Main results of the summary statistics are presented to the accuracy of the raw data. All summary statistics were carried out using SAS 8.02 for UNIX running under the HARP environment

30 CONFIDENTIAL ZM2008/00081/ DISCUSSION AND CONCLUSIONS Discussion Clinical data exist to support that tamsulosin (an alpha-1-adrenoceptor antagonist), when used in combination with dutasteride (a 5-alpha reductase inhibitor), offers a more effective treatment for the symptoms of benign prostatic hyperplasia than either drug used alone. To support the product label for the Dutasteride and Tamsulosin HCl Combination Capsule, this study was to establish bioequivalence at steady state of tamsulosin only. The primary objectives were to assess the bioequivalence of tamsulosin when given in the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin 0.4 mg or the modified Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S. commercially available Flomax 0.4 mg capsules under fasting conditions and at steady state. This study demonstrated bioequivalence of tamsulosin at steady state in each of the Combination Capsule formulations of dutasteride 0.5 mg/enteric coated tamsulosin 0.4 mg (10% and 15%) compared to concomitant dosing of AVODART 0.5 mg and the U.S. commercially available Flomax 0.4 mg. The most commonly reported AEs in any regimen (>10%) were headache, dizziness and nasal congestion. All adverse events were considered by the investigator to be mild or moderate in intensity and all but 1 resolved. There was one SAE which was not considered to be related to study drug and lead to withdrawal from the study Conclusions The tamsulosin component of the combination capsule formulations of dutasteride 0.5 mg and either 10% or 15% enteric coated tamsulosin HCl 0.4 mg are bioequivalent to the concomitant dosing of AVODART 0.5 mg and the U.S.- sourced Flomax 0.4 mg at steady-state. Administration of the combination capsule formulations of dutasteride 0.5 mg/tamsulosin HCl 0.4 mg to healthy adult male volunteers was generally well tolerated under the conditions of this study

31 CONFIDENTIAL ZM2008/00081/ REFERENCES Flomax (Tamsulosin hydrochloride) Product Information. March, GlaxoSmithKline Document Number RD2007/01642/00 Study ID. The Validation of a Bioanalytical Method for the Determination of GI and GI in Human Serum (range 0.1 to 50 ng/ml and 0.05 to 50 ng/ml, respectively) using UPLC-MS/MS. Report Date 08-Apr GlaxoSmithKline Document Number RD2008/00913/00 Study ID. Within- Study Analytical Performance Data for the Determination of Tamsulosin (GI138525) in Human Serum. Report Date 09-Oct

32 This section contained patient narratives which are textual descriptions of medical history, treatment and outcome for individual patients who experienced a clinically important adverse event including serious adverse events during the trial. They have been excluded to protect patient privacy. This data may be made available subject to an approved research proposal and a determination of the ability to provide information from the specific narratives whilst protecting the patient s privacy. For further information please see the Patient Level Data section of the GSK Clincal Study Register.

33 CONFIDENTIAL ZM2008/00081/00 Study Population Data Source Tables Page Table 9.01 Summary of Demographic Characteristics (Safety Population).. 34 Table 9.02 Summary of Race and Racial Characteristics (Safety Population) Table 9.03 Summary of Subject Disposition (Safety Population) Table 9.04 Summary of Concomitant Medications by Generic Term (Safety Population)

34 34 Protocol: Page 1 of 2 Population: Safety Table 9.01 Summary of Demographic Characteristics Total (N=24) Age (y) n 24 Mean 30.6 SD 8.56 Median 28.0 Min. 19 Max. 45 Sex n 24 Male 24 (100%) Ethnicity n 24 Hispanic/Latino 2 (8%) Not Hispanic/Latino 22 (92%) Height (cm) n 24 Mean SD 5.02 Median Min. 165 Max. 185 Weight (kg) n 24 Mean SD Median Min Max. 93.0

35 Protocol: Page 2 of 2 Population: Safety Table 9.01 Summary of Demographic Characteristics Total (N=24) Body Mass Index n 24 (kg/m^2) Mean SD Median Min Max

36 36 Protocol: Page 1 of 1 Population: Safety Table 9.02 Summary of Race and Racial Characteristics Total Race (N=24) n 24 African American/African Heritage 11 (46%) American Indian or Alaska Native 0 Asian - Central/South Asian Heritage 0 Asian - East Asian Heritage 0 Asian - Japanese Heritage 0 Asian - South East Asian Heritage 2 (8%) Asian - Mixed Race 0 Native Hawaiian or other Pacific Islander 0 White - Arabic/North African Heritage 0 White - White/Caucasian/European Heritage 10 (42%) White - Mixed Race 0 Mixed Race 1 (4%)

37 Protocol: Page 1 of 1 Population: Safety Table 9.03 Summary of Subject Disposition A B C Total (N=23) (N=24) (N=23) (N=24) Completion Status Completed 23 (100%) 23 (96%) 23 (100%) 23 (96%) Prematurely Withdrawn 0 1 (4%) 0 1 (4%) Primary reason for withdrawal Adverse event 0 1 (4%) 0 1 (4%) 37 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

38 Protocol: Page 1 of 1 Population: Safety Table 9.04 Summary of Concomitant Medications by Generic Term A B C Total Generic Term (N=23) (N=24) (N=23) (N=24) Any medication 4 (17%) 4 (17%) 3 (13%) 9 (38%) ACETYLSALICYLIC ACID 1 (4%) (4%) PARACETAMOL 3 (13%) 4 (17%) 3 (13%) 8 (33%) 38 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

39 CONFIDENTIAL ZM2008/00081/00 Pharmacokinetic Data Source Figures and Tables Page Figure 10.1 Individual Serum Tamsulosin Concentration-Time Plots at Day 1 (Linear and Semi-Log) Figure 10.2 Mean Serum Tamsulosin Concentration-Time Plots at Day 1 (Linear and Semi-Log) Figure 10.3 Median Serum Tamsulosin Concentration-Time Plots at Day 1 (Linear and Semi-Log) Figure 10.4 Individual Serum Tamsulosin Concentration-Time Plots at Day 7 (Linear and Semi-Log) Figure 10.5 Mean Serum Tamsulosin Concentration-Time Plots at Day 7 (Linear and Semi-Log) Figure 10.6 Median Serum Tamsulosin Concentration-Time Plots at Day 7 (Linear and Semi-Log) Figure 10.7 Comparative Plot of Tamsulosin PK Parameter AUC(0-24) at Day 1 (A vs C) Figure 10.8 Comparative Plot of Tamsulosin PK Parameter AUC(0-24) at Day 1 (B vs C) Figure 10.9 Comparative Plot of Tamsulosin PK Parameter AUC(0-24) at Day 7 (A vs C) Figure Comparative Plot of Tamsulosin PK Parameter AUC(0-24) at Day 7 (B vs C) Figure Comparative Plot of Tamsulosin PK Parameter Cmax at Day 1 (A vs C) Figure Comparative Plot of Tamsulosin PK Parameter Cmax at Day 1 (B vs C) Figure Comparative Plot of Tamsulosin PK Parameter Cmax at Day 7 (A vs C) Figure Comparative Plot of Tamsulosin PK Parameter Cmax at Day 7 (B vs C) Figure Comparative Plot of Tamsulosin PK Parameter Tmax at Day 1 (A vs C)

40 CONFIDENTIAL ZM2008/00081/00 Figure Comparative Plot of Tamsulosin PK Parameter Tmax at Day 1 (B vs C) Figure Comparative Plot of Tamsulosin PK Parameter Tmax at Day 7 (A vs C) Figure Comparative Plot of Tamsulosin PK Parameter Tmax at Day 7 (B vs C) Figure Mean (+/- SE) Plot of Tamsulosin Plasma Predose Concentration (Day 5 - Day 7) Figure Comparative Plot of Tamsulosin PK Parameter Ctau at Day 7 (A vs C) Figure Comparative Plot of Tamsulosin PK Parameter Cmin at Day 7 (A vs C) Figure Comparative Plot of Tamsulosin PK Parameter Cmin at Day 7 (B vs C) Figure Comparative Plot of Tamsulosin PK Parameter T1/2 at Day 7 (A vs C) Figure Comparative Plot of Tamsulosin PK Parameter T1/2 at Day 7 (B vs C) Table 10.1 Summary of Serum Tamsulosin Pharmacokinetic Concentration (ng/ml) - Time Data (PK Concentration Population) Table 10.2 Summary Statistics of Transformed Derived Tamsulosin Pharmacokinetic Parameters (PK Parameter Population) Table 10.3 Summary Statistics of Untransformed Derived Tamsulosin Pharmacokinetic Parameters (PK Parameter Population) Table 10.4 Summary Statistics of Pre-dose Concentration (ng/ml) for Each Subject at Day 5 - Day 7 (PK Concentration Population) Table 10.5 Assessment of Steady State (Pharmacokinetic Population) Table 10.6 Assessment of Steady State (Outliers Removed) (Pharmacokinetic Population) Table 10.7 Parametric Analysis Results of Comparisons of Interest of the log-transformed PK parameters for the Evaluation of Bioequivalence in Tamsulosin at Steady State (Pharmacokinetic Population) Table 10.8 Parametric Analysis Results for AUC(0-24)-ss, Cmin-ss and Ctau (Outliers Removed) (Pharmacokinetic Population)

41 CONFIDENTIAL ZM2008/00081/00 Table 10.9 Nonparametric Analysis Results for Tmax-ss (Pharmacokinetic Population)

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112 112 Protocol: Page 1 of 5 Population: PK Concentration Table 10.1 Summary of Serum Tamsulosin Pharmacokinetic Concentration (ng/ml) - Time Data No. Treatment N Visit Day Pl. Time n Imputed Mean SD Median Min. Max A 23 DAY 1 PREDOSE H H H H H H H H H H H DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H H H H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

113 113 Protocol: Page 2 of 5 Population: PK Concentration Table 10.1 Summary of Serum Tamsulosin Pharmacokinetic Concentration (ng/ml) - Time Data No. Treatment N Visit Day Pl. Time n Imputed Mean SD Median Min. Max A 23 DAY 7 6 H H H H H H H H H H B 24 DAY 1 PREDOSE H H H H H H H H H H H DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

114 114 Protocol: Page 3 of 5 Population: PK Concentration Table 10.1 Summary of Serum Tamsulosin Pharmacokinetic Concentration (ng/ml) - Time Data No. Treatment N Visit Day Pl. Time n Imputed Mean SD Median Min. Max B 24 DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H H H H H H H H H H H H H H H C 23 DAY 1 PREDOSE H H H H H H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

115 115 Protocol: Page 4 of 5 Population: PK Concentration Table 10.1 Summary of Serum Tamsulosin Pharmacokinetic Concentration (ng/ml) - Time Data No. Treatment N Visit Day Pl. Time n Imputed Mean SD Median Min. Max C 23 DAY 1 8 H H H H DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H H H H H H H H H H H H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

116 Protocol: Page 5 of 5 Population: PK Concentration Table 10.1 Summary of Serum Tamsulosin Pharmacokinetic Concentration (ng/ml) - Time Data No. Treatment N Visit Day Pl. Time n Imputed Mean SD Median Min. Max C 23 DAY 7 48 H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

117 117 Protocol: Page 1 of 8 Population: PK Parameter Table 10.2 Summary Statistics of Transformed Derived Tamsulosin Pharmacokinetic Parameters Parameter Visit Day A B C AUC(0-24) DAY 1 N (ng*hr/ml) n Geom. Mean % CI ( , ) ( , ) ( , ) SD Logs Arith. Mean % CI ( , ) ( , ) ( , ) SD %CVb Median Min Max DAY 7 N n Geom. Mean % CI ( , ) ( , ) ( , ) SD Logs Arith. Mean % CI ( , ) ( , ) ( , ) SD %CVb Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

118 118 Protocol: Page 2 of 8 Population: PK Parameter Table 10.2 Summary Statistics of Transformed Derived Tamsulosin Pharmacokinetic Parameters Parameter Visit Day A B C Cmax DAY 1 N (ng/ml) n Geom. Mean % CI ( , ) ( , ) ( , ) SD Logs Arith. Mean % CI ( , ) ( , ) ( , ) SD %CVb Median Min Max DAY 7 N n Geom. Mean % CI ( , ) ( , ) ( , ) SD Logs Arith. Mean % CI ( , ) ( , ) ( , ) SD %CVb Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

119 119 Protocol: Page 3 of 8 Population: PK Parameter Table 10.2 Summary Statistics of Transformed Derived Tamsulosin Pharmacokinetic Parameters Parameter Visit Day A B C Cmin DAY 7 N (ng/ml) n Geom. Mean % CI (2.2723,3.4101) (2.2721,3.6029) (2.1900,3.3523) SD Logs Arith. Mean % CI (2.4189,3.7938) (2.5473,3.9702) (2.1966,3.5742) SD %CVb Median Min Max Cpd DAY 1 N (ng/ml) n Geom. Mean % CI (0.0538,0.0830) (0.0344,0.5112) (0.0324,0.3603) SD Logs Arith. Mean % CI (0.0112,0.0431) ( ,0.0623) ( ,0.0548) SD %CVb Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

120 120 Protocol: Page 4 of 8 Population: PK Parameter Table 10.2 Summary Statistics of Transformed Derived Tamsulosin Pharmacokinetic Parameters Parameter Visit Day A B C Cpd DAY 2 N (ng/ml) n Geom. Mean % CI (1.8332,2.7709) (1.7990,2.8352) (1.7693,2.7871) SD Logs Arith. Mean % CI (2.0344,2.9365) (1.9924,3.2052) (1.9721,3.0580) SD %CVb Median Min Max DAY 3 N n Geom. Mean % CI (2.2938,3.3991) (2.3477,3.6196) (2.3213,3.4921) SD Logs Arith. Mean % CI (2.5129,3.6100) (2.5887,4.0023) (2.5376,3.7565) SD %CVb Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

121 121 Protocol: Page 5 of 8 Population: PK Parameter Table 10.2 Summary Statistics of Transformed Derived Tamsulosin Pharmacokinetic Parameters Parameter Visit Day A B C Cpd DAY 4 N (ng/ml) n Geom. Mean % CI (2.6979,3.9230) (2.6348,4.0813) (2.5415,3.9426) SD Logs Arith. Mean % CI (2.9227,4.1567) (2.8841,4.5894) (2.8372,4.2534) SD %CVb Median Min Max DAY 5 N n Geom. Mean % CI (2.5448,3.8608) (2.7064,4.1187) (2.6527,4.0476) SD Logs Arith. Mean % CI (2.7349,4.2773) (3.0270,4.3858) (2.9017,4.4288) SD %CVb Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

122 122 Protocol: Page 6 of 8 Population: PK Parameter Table 10.2 Summary Statistics of Transformed Derived Tamsulosin Pharmacokinetic Parameters Parameter Visit Day A B C Cpd DAY 6 N (ng/ml) n Geom. Mean % CI (2.5005,3.9957) (2.5227,3.9347) (2.5182,3.9476) SD Logs Arith. Mean % CI (2.7643,4.5037) (2.8147,4.3302) (2.5731,4.2303) SD %CVb Median Min Max DAY 7 N n Geom. Mean % CI (2.5969,3.7901) (2.5021,3.8310) (2.6279,3.8483) SD Logs Arith. Mean % CI (2.7719,4.0990) (2.7613,4.1796) (2.6142,4.0106) SD %CVb Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

123 123 Protocol: Page 7 of 8 Population: PK Parameter Table 10.2 Summary Statistics of Transformed Derived Tamsulosin Pharmacokinetic Parameters Parameter Visit Day A B C Ctau DAY 7 N (ng/ml) n Geom. Mean % CI (2.4974,3.8341) (2.4125,3.8556) (2.3486,3.5544) SD Logs Arith. Mean % CI (2.6664,4.3393) (2.7287,4.2288) (2.5117,3.9289) SD %CVb Median Min Max Fluctuation DAY 7 N (%) n Geom. Mean % CI ( , ) ( , ) ( , ) SD Logs Arith. Mean % CI ( , ) ( , ) ( , ) SD %CVb Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

124 124 Protocol: Page 8 of 8 Population: PK Parameter Table 10.2 Summary Statistics of Transformed Derived Tamsulosin Pharmacokinetic Parameters Parameter Visit Day A B C t1/2 DAY 7 N (hr) n Geom. Mean % CI ( , ) ( , ) ( , ) SD Logs Arith. Mean % CI ( , ) ( , ) ( , ) SD %CVb Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

125 125 Protocol: Page 1 of 2 Population: PK Parameter Table 10.3 Summary Statistics of Untransformed Derived Tamsulosin Pharmacokinetic Parameters Parameter Visit Day A B C lambda-z DAY 7 N (1/hr) n Arith. Mean % CI ( , ) ( , ) ( , ) %CVb SD Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

126 126 Protocol: Page 2 of 2 Population: PK Parameter Table 10.3 Summary Statistics of Untransformed Derived Tamsulosin Pharmacokinetic Parameters Parameter Visit Day A B C tmax DAY 1 N (hr) n Arith. Mean % CI (4.692,5.569) (4.730,5.526) (4.501,5.423) %CVb SD Median Min Max DAY 7 N n Arith. Mean % CI (4.530,5.470) (4.857,5.811) (4.686,5.401) %CVb SD Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

127 Protocol: Page 1 of 4 Population: PK Concentration Table 10.4 Summary Statistics of Pre-dose Concentration (ng/ml) for Each Subject at Day 5 - Day 7 Subj. Period Treatment Mean SD %CV 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 GSK Clincal Study Register. 127 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

128 Protocol: Page 1 of 1 Population: Pharmacokinetic Table 10.5 Assessment of Steady State Point Estimate 90% CI Parameter Effect Regimen of Slope of Slope CVw (%) Cpd (ng/ml) time A 1.00 (0.96,1.04) 12.7 B 0.96 (0.92,1.00) 16.8 C 0.98 (0.93,1.04) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

129 Protocol: Page 1 of 1 Population: Pharmacokinetic Table 10.6 Assessment of Steady State (Outliers Removed) Point Estimate 90% CI Parameter Effect Regimen of Slope of Slope CVw (%) Cpd (ng/ml) time C 0.97 (0.92,1.02) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

130 133 Protocol: Page 1 of 1 Population: Pharmacokinetic Table 10.7 Parametric Analysis Results of Comparisons of Interest of the log-transformed PK parameters for the Evaluation of Bioequivalence in Tamsulosin at Steady State LS GeoMean PK Ratio Parameter Comparison Test Ref. Test vs. Ref. 90% CI CVw (%) CVb (%) AUC(0-24)-ss (ng*hr/ml) A : C (0.93,1.11) B : C (0.85,1.02) Cmax-ss (ng/ml) A : C (0.91,1.06) B : C (0.85,0.98) Cmin-ss (ng/ml) A : C (0.90,1.19) B : C (0.91,1.20) Ctau (ng/ml) A : C (0.95,1.23) B : C (0.91,1.18) T1/2 (hr) A : C (0.94,1.04) B : C (0.97,1.08) Fluctuation (%) A : C (0.90,1.01) B : C (0.89,1.00) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

131 134 Protocol: Page 1 of 1 Population: Pharmacokinetic Table 10.8 Parametric Analysis Results for AUC(0-24)-ss, Cmin-ss and Ctau (Outliers Removed) LS Mean PK Parameter Comparison Test Ref Ratio 90% CI CVw (%) CVb (%) AUC(0-24)-ss (ng*hr/ml) A : C (0.95,1.11) B : C (0.89,1.05) Cmin-ss (ng/ml) A : C (0.94,1.18) B : C (1.00,1.26) Ctau (ng/ml) A : C (0.98,1.21) B : C (1.00,1.24) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

132 Protocol: Page 1 of 1 Population: Pharmacokinetic Table 10.9 Nonparametric Analysis Results for Tmax-ss Median Estimated Median Parameter Comparison Test Ref. Difference 90% CI Tmax-ss (hr) A - C (-0.50,0.50) B - C (0.00,0.50) 135 Rigimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

133 CONFIDENTIAL ZM2008/00081/00 Safety Data Source Figures and Tables Page Table Summary of Exposure to Study Drug (Safety Population) Table Summary of All Adverse Events (Safety Population) Table Summary of Drug Related Adverse Events (Safety Population). 142 Table Summary of Adverse Events Leading to Withdrawal (Safety Population) Table Summary of Adverse Events by Maximum Intensity (Safety Population) Table Listing of Adverse Events Leading to Withdrawal (Safety Population) Table Summary of Hematology Data (Safety Population) Table Listing of Chemistry Values of Potential Clinical Importance (Safety Population) Table Listing of All Chemistry Data for Subjects with Abnormalities of Potential Clinical Importance (Safety Population) Table Listing of Hematology Values of Potential Clinical Importance (Safety Population) Table Listing of All Hematology Data for Subjects with Abnormalities of Potential Clinical Importance (Safety Population) Table Summary of Vital Signs (Safety Population) Table Summary of Change from Baseline for Vital Signs (Safety Population) Table Listing of All Vital Signs for Subjects with Values of Potential Clinical Importance (Safety Population) Table Listing of Vital Signs of Potential Clinical Importance (Safety Population) Table Summary of ECG Values (Safety Population) Table Summary of ECG Findings (Safety Population) Table Summary of Chemistry Data (Safety Population) Table Listing of ECG Values of Potential Clinical Importance (Safety Population)

134 CONFIDENTIAL ZM2008/00081/00 Table Listing of Abnormal ECG Findings (Safety Population) Table Summary Table of Subjects Who Demonstrated Orthostatic Hypotension (Safety Population) Table Summary Table of Subjects Who Demonstrated Orthostatic Hypotension by Visit (Safety Population) Table Summary of Urinalysis for Dipstick Results by Planned Relative Time (Safety Population) Table Summary of Urinalysis for Dipstick Results by Visit and Planned Relative Time (Safety Population) Table Summary of Vital Signs by Visit Day (Safety Population) Table Listing of All ECG Values for Subjects with a Value of Potential Clinical Importance (Safety Population)

135 138 Protocol: Page 1 of 1 Population: Safety Table Summary of Exposure to Study Drug A B C Period (N=23) (N=24) (N=23) Cumulative PERIOD 1 n Duration (day) Mean SD Median Min Max PERIOD 2 n Mean SD Median Min Max PERIOD 3 n Mean SD Median Min Max Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

136 139 Protocol: Page 1 of 3 Population: Safety Table Summary of All Adverse Events System Organ Class A B C Total Preferred Term (N=23) (N=24) (N=23) (N=24) ANY EVENT 15 (65%) 10 (42%) 9 (39%) 20 (83%) Nervous system disorders Any event 6 (26%) 6 (25%) 6 (26%) 12 (50%) Headache 4 (17%) 5 (21%) 4 (17%) 8 (33%) Dizziness 1 (4%) 2 (8%) 3 (13%) 5 (21%) Dizziness postural 2 (9%) 1 (4%) 0 3 (13%) Respiratory, thoracic and mediastinal disorders Any event 2 (9%) 4 (17%) 2 (9%) 7 (29%) Nasal congestion 1 (4%) 3 (13%) 0 4 (17%) Cough 0 2 (8%) 1 (4%) 3 (13%) Epistaxis 0 1 (4%) 0 1 (4%) Pharyngolaryngeal pain (4%) 1 (4%) Respiratory tract congestion 1 (4%) (4%) Musculoskeletal and connective tissue disorders Any event 2 (9%) 1 (4%) 2 (9%) 4 (17%) Pain in extremity 2 (9%) (8%) Musculoskeletal pain 1 (4%) 1 (4%) 0 1 (4%) Back pain (4%) 1 (4%) Musculoskeletal discomfort 0 1 (4%) 0 1 (4%) Myalgia (4%) 1 (4%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

137 140 Protocol: Page 2 of 3 Population: Safety Table Summary of All Adverse Events System Organ Class A B C Total Preferred Term (N=23) (N=24) (N=23) (N=24) Psychiatric disorders Any event 0 1 (4%) 2 (9%) 3 (13%) Abnormal dreams 0 1 (4%) 2 (9%) 3 (13%) Gastrointestinal disorders Any event 2 (9%) 1 (4%) 1 (4%) 2 (8%) Abdominal pain upper 1 (4%) (4%) Diarrhoea 1 (4%) (4%) Flatulence 0 1 (4%) 0 1 (4%) Toothache (4%) 1 (4%) General disorders and administration site conditions Any event 1 (4%) 1 (4%) 0 2 (8%) Hyperthermia 1 (4%) (4%) Pyrexia 0 1 (4%) 0 1 (4%) Eye disorders Any event 1 (4%) (4%) Ocular hyperaemia 1 (4%) (4%) Injury, poisoning and procedural complications Any event 1 (4%) (4%) Post procedural complication 1 (4%) (4%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

138 Protocol: Page 3 of 3 Population: Safety Table Summary of All Adverse Events System Organ Class A B C Total Preferred Term (N=23) (N=24) (N=23) (N=24) Metabolism and nutrition disorders Any event 0 1 (4%) 0 1 (4%) Anorexia 0 1 (4%) 0 1 (4%) Reproductive system and breast disorders Any event 0 1 (4%) 0 1 (4%) Epididymitis 0 1 (4%) 0 1 (4%) 141 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

139 142 Protocol: Page 1 of 1 Population: Safety Table Summary of Drug Related Adverse Events System Organ Class A B C Total Preferred Term (N=23) (N=24) (N=23) (N=24) ANY EVENT 7 (30%) 4 (17%) 5 (22%) 12 (50%) Nervous system disorders Any event 5 (22%) 3 (13%) 3 (13%) 8 (33%) Dizziness 1 (4%) 1 (4%) 3 (13%) 5 (21%) Headache 3 (13%) 2 (8%) 0 4 (17%) Dizziness postural 2 (9%) 1 (4%) 0 3 (13%) Psychiatric disorders Any event 0 1 (4%) 2 (9%) 3 (13%) Abnormal dreams 0 1 (4%) 2 (9%) 3 (13%) Gastrointestinal disorders Any event 1 (4%) (4%) Abdominal pain upper 1 (4%) (4%) Respiratory, thoracic and mediastinal disorders Any event 1 (4%) (4%) Nasal congestion 1 (4%) (4%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

140 Protocol: Page 1 of 1 Population: Safety Table Summary of Adverse Events Leading to Withdrawal System Organ Class A B C Preferred Term (N=23) (N=24) (N=23) ANY EVENT 0 1 (4%) 0 Reproductive system and breast disorders Any event 0 1 (4%) 0 Epididymitis 0 1 (4%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

141 144 Protocol: Page 1 of 6 Population: Safety Table Summary of Adverse Events by Maximum Intensity System Organ Class A (N=23) B (N=24) Preferred Term Mild Moderate Severe Mild Moderate Severe ANY EVENT 13 (57%) 2 (9%) 0 9 (38%) 0 1 (4%) Nervous system disorders Any Event 4 (17%) 2 (9%) 0 6 (25%) 0 0 Headache 2 (9%) 2 (9%) 0 5 (21%) 0 0 Dizziness 1 (4%) (8%) 0 0 Dizziness postural 2 (9%) (4%) 0 0 Respiratory, thoracic and mediastinal disorders Any Event 2 (9%) (17%) 0 0 Nasal congestion 1 (4%) (13%) 0 0 Cough (8%) 0 0 Epistaxis (4%) 0 0 Pharyngolaryngeal pain Respiratory tract congestion 1 (4%) Musculoskeletal and connective tissue disorders Any Event 2 (9%) (4%) 0 0 Musculoskeletal pain 1 (4%) (4%) 0 0 Pain in extremity 2 (9%) Back pain Musculoskeletal discomfort (4%) 0 0 Myalgia Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

142 145 Protocol: Page 2 of 6 Population: Safety Table Summary of Adverse Events by Maximum Intensity System Organ Class C (N=23) Preferred Term Mild Moderate Severe ANY EVENT 9 (39%) 0 0 Nervous system disorders Any Event 6 (26%) 0 0 Headache 4 (17%) 0 0 Dizziness 3 (13%) 0 0 Dizziness postural Respiratory, thoracic and mediastinal disorders Any Event 2 (9%) 0 0 Nasal congestion Cough 1 (4%) 0 0 Epistaxis Pharyngolaryngeal pain 1 (4%) 0 0 Respiratory tract congestion Musculoskeletal and connective tissue disorders Any Event 2 (9%) 0 0 Musculoskeletal pain Pain in extremity Back pain 1 (4%) 0 0 Musculoskeletal discomfort Myalgia 1 (4%) 0 0 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

143 146 Protocol: Page 3 of 6 Population: Safety Table Summary of Adverse Events by Maximum Intensity System Organ Class A (N=23) B (N=24) Preferred Term Mild Moderate Severe Mild Moderate Severe Psychiatric disorders Any Event (4%) 0 0 Abnormal dreams (4%) 0 0 Gastrointestinal disorders Any Event 2 (9%) (4%) 0 0 Abdominal pain upper 1 (4%) Diarrhoea 1 (4%) Flatulence (4%) 0 0 Toothache General disorders and administration site conditions Any Event 1 (4%) (4%) 0 0 Hyperthermia 1 (4%) Pyrexia (4%) 0 0 Eye disorders Any Event 1 (4%) Ocular hyperaemia 1 (4%) Injury, poisoning and procedural complications Any Event 1 (4%) Post procedural complication 1 (4%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

144 147 Protocol: Page 4 of 6 Population: Safety Table Summary of Adverse Events by Maximum Intensity System Organ Class C (N=23) Preferred Term Mild Moderate Severe Psychiatric disorders Any Event 2 (9%) 0 0 Abnormal dreams 2 (9%) 0 0 Gastrointestinal disorders Any Event 1 (4%) 0 0 Abdominal pain upper Diarrhoea Flatulence Toothache 1 (4%) 0 0 General disorders and administration site conditions Any Event Hyperthermia Pyrexia Eye disorders Any Event Ocular hyperaemia Injury, poisoning and procedural complications Any Event Post procedural complication Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

145 Protocol: Page 5 of 6 Population: Safety Table Summary of Adverse Events by Maximum Intensity System Organ Class A (N=23) B (N=24) Preferred Term Mild Moderate Severe Mild Moderate Severe Metabolism and nutrition disorders Any Event (4%) 0 0 Anorexia (4%) 0 0 Reproductive system and breast disorders Any Event (4%) Epididymitis (4%) 148 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

146 Protocol: Page 6 of 6 Population: Safety Table Summary of Adverse Events by Maximum Intensity System Organ Class C (N=23) Preferred Term Mild Moderate Severe Metabolism and nutrition disorders Any Event Anorexia Reproductive system and breast disorders Any Event Epididymitis Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

147 Protocol: Page 1 of 1 Population: Safety Table Listing of Adverse Events Leading to Withdrawal Outcome/ Time Since Age(y)/ Onset Date/ Study 1st Sex/ System Organ Onset Time/ Dose/ Maximum Frequency/ Inv./ Race/ Treat- Class/ Resolve Date/ Period 1st Intensity/ Action Take/ Subj./ Weight ment/ Preferred Term/ Resolve Time/ Dose/ Serious/ Relation to Seq. (Kg) Period VERBATIM TERM Duration Last Dose 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 GSK Clincal Study Register. 150 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

148 151 Protocol: Page 1 of 10 Population: Safety Table Summary of Hematology Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Basophils SCREENING 24 SCREENING (GI/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Basophils SCREENING 24 SCREENING (percentage) (%) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

149 152 Protocol: Page 2 of 10 Population: Safety Table Summary of Hematology Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Eosinophils SCREENING 24 SCREENING (GI/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Eosinophils SCREENING 24 SCREENING (percentage) (%) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

150 153 Protocol: Page 3 of 10 Population: Safety Table Summary of Hematology Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Hematocrit (1) SCREENING 24 SCREENING A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Hemoglobin SCREENING 24 SCREENING (G/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

151 154 Protocol: Page 4 of 10 Population: Safety Table Summary of Hematology Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Lymphocytes SCREENING 24 SCREENING (GI/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Lymphocytes SCREENING 24 SCREENING (percentage) (%) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

152 155 Protocol: Page 5 of 10 Population: Safety Table Summary of Hematology Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Mean Corpuscle SCREENING 24 SCREENING Hemoglobin (PG) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Mean Corpuscle SCREENING 24 SCREENING Hemoglobin Concentration (G/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

153 156 Protocol: Page 6 of 10 Population: Safety Table Summary of Hematology Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Mean Corpuscle SCREENING 24 SCREENING Volume (FL) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Mean Platelet SCREENING 24 SCREENING Volume (FL) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

154 157 Protocol: Page 7 of 10 Population: Safety Table Summary of Hematology Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Monocytes SCREENING 24 SCREENING (GI/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Monocytes SCREENING 24 SCREENING (percentage) (%) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

155 158 Protocol: Page 8 of 10 Population: Safety Table Summary of Hematology Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Platelet count SCREENING 24 SCREENING (GI/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP RDW - Red Cell SCREENING 24 SCREENING Distribution Width (%) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

156 159 Protocol: Page 9 of 10 Population: Safety Table Summary of Hematology Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Red Blood Cell SCREENING 24 SCREENING Count (TI/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Total SCREENING 24 SCREENING Neutrophils (GI/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

157 160 Protocol: Page 10 of 10 Population: Safety Table Summary of Hematology Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Total SCREENING 24 SCREENING Neutrophils (percentage) (%) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP White Blood SCREENING 24 SCREENING Cell Count (GI/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

158 Protocol: Page 1 of 1 Population: Safety Table Listing of Chemistry Values of Potential Clinical Importance Study Inv./ Age(y)/ Treat- Visit/ Day/ Subj./ Sex/ ment/ Lab Test Date/ Period Converted Data Flag[1] Seq. Race Period (Units) Time Day Value Normal Range NR CC 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 GSK Clincal Study Register. 161 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg [1] NR for Normal range flag, CC for Clinical Concern flag; H=Above range, L=Below range

159 Protocol: Page 1 of 18 Population: Safety Table Listing of All Chemistry Data for Subjects with Abnormalities of Potential Clinical Importance Study Inv./ Age(y)/ Treat- Visit/ Day/ Subj./ Sex/ ment/ Lab Test Date/ Period Converted Data Flag[1] Seq. Race Period (Units) Time Day Value Normal Range NR CC 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 GSK Clincal Study Register. 162 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg [1] NR for Normal range flag, CC for Clinical Concern flag; H=Above range, L=Below range, I=Normal, N=No F3 criteria.

160 Protocol: Page 1 of 1 Population: Safety Table Listing of Hematology Values of Potential Clinical Importance Study Inv./ Age(y)/ Treat- Visit/ Day/ Subj./ Sex/ ment/ Lab Test Date/ Period Converted Data Flag[1] Seq. Race Period (Units) Time Day Value Normal Range NR CC 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 GSK Clincal Study Register. 180 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg [1] NR for Normal range flag, CC for Clinical Concern flag; H=Above range, L=Below range

161 Protocol: Page 1 of 56 Population: Safety Table Listing of All Hematology Data for Subjects with Abnormalities of Potential Clinical Importance Study Inv./ Age(y)/ Treat- Visit/ Day/ Subj./ Sex/ ment/ Lab Test Date/ Period Converted Data Flag[1] Seq. Race Period (Units) Time Day Value Normal Range NR CC 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 GSK Clincal Study Register. 181 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg [1] NR for Normal range flag, CC for Clinical Concern flag; H=Above range, L=Below range, I=Normal, N=No F3 criteria.

162 237 Protocol: Page 1 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) SCREENING 24 SCREENING SCREENING 1ST R SCREENING 2ND R SCREENING 3RD R SCREENING AVE R SCREENING R2 OR R A 23 SESSION 1 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 2 PREDOSE SESSION 1 DAY 3 PREDOSE SESSION 1 DAY 4 PREDOSE SESSION 1 DAY 5 PREDOSE SESSION 1 DAY 6 PREDOSE SESSION 1 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

163 238 Protocol: Page 2 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) A 23 SESSION 1 DAY 7 6 H R2 OR R SESSION 1 DAY 8 PREDOSE SESSION 1 DAY 9 PREDOSE SESSION 1 DAY 10 PREDOSE SESSION 2 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 2 PREDOSE SESSION 2 DAY 3 PREDOSE SESSION 2 DAY 4 PREDOSE SESSION 2 DAY 5 PREDOSE SESSION 2 DAY 6 PREDOSE SESSION 2 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 8 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

164 239 Protocol: Page 3 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) A 23 SESSION 2 DAY 9 PREDOSE SESSION 2 DAY 10 PREDOSE SESSION 3 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 2 PREDOSE SESSION 3 DAY 3 PREDOSE SESSION 3 DAY 4 PREDOSE SESSION 3 DAY 5 PREDOSE SESSION 3 DAY 6 PREDOSE SESSION 3 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 8 PREDOSE SESSION 3 DAY 9 PREDOSE SESSION 3 DAY 10 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

165 240 Protocol: Page 4 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) B 24 SESSION 1 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 2 PREDOSE SESSION 1 DAY 3 PREDOSE SESSION 1 DAY 4 PREDOSE SESSION 1 DAY 5 PREDOSE SESSION 1 DAY 6 PREDOSE SESSION 1 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 8 PREDOSE SESSION 1 DAY 9 PREDOSE SESSION 1 DAY 10 PREDOSE SESSION 2 DAY 1 PREDOSE H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

166 241 Protocol: Page 5 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) B 24 SESSION 2 DAY 1 4 H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 2 PREDOSE SESSION 2 DAY 3 PREDOSE SESSION 2 DAY 4 PREDOSE SESSION 2 DAY 5 PREDOSE SESSION 2 DAY 6 PREDOSE SESSION 2 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 8 PREDOSE SESSION 2 DAY 9 PREDOSE SESSION 2 DAY 10 PREDOSE SESSION 3 DAY 1 PREDOSE H H H 1ST R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

167 242 Protocol: Page 6 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) B 24 SESSION 3 DAY 1 6 H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 2 PREDOSE SESSION 3 DAY 3 PREDOSE SESSION 3 DAY 4 PREDOSE SESSION 3 DAY 5 PREDOSE SESSION 3 DAY 6 PREDOSE SESSION 3 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 8 PREDOSE SESSION 3 DAY 9 PREDOSE SESSION 3 DAY 10 PREDOSE C 23 SESSION 1 DAY 1 PREDOSE H H H 1ST R H 2ND R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

168 243 Protocol: Page 7 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) C 23 SESSION 1 DAY 1 6 H 3RD R H AVE R H R2 OR R SESSION 1 DAY 2 PREDOSE SESSION 1 DAY 3 PREDOSE SESSION 1 DAY 4 PREDOSE SESSION 1 DAY 5 PREDOSE SESSION 1 DAY 6 PREDOSE SESSION 1 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 8 PREDOSE SESSION 1 DAY 9 PREDOSE SESSION 1 DAY 10 PREDOSE SESSION 2 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

169 244 Protocol: Page 8 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) C 23 SESSION 2 DAY 1 6 H R2 OR R SESSION 2 DAY 2 PREDOSE SESSION 2 DAY 3 PREDOSE SESSION 2 DAY 4 PREDOSE SESSION 2 DAY 5 PREDOSE SESSION 2 DAY 6 PREDOSE SESSION 2 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 8 PREDOSE SESSION 2 DAY 9 PREDOSE SESSION 2 DAY 10 PREDOSE SESSION 3 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 2 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

170 245 Protocol: Page 9 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) C 23 SESSION 3 DAY 3 PREDOSE SESSION 3 DAY 4 PREDOSE SESSION 3 DAY 5 PREDOSE SESSION 3 DAY 6 PREDOSE SESSION 3 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 8 PREDOSE SESSION 3 DAY 9 PREDOSE SESSION 3 DAY 10 PREDOSE FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP Heart Rate (BPM) SCREENING 24 SCREENING SCREENING 1ST R SCREENING 2ND R SCREENING 3RD R SCREENING AVE R SCREENING R2 OR R A 23 SESSION 1 DAY 1 PREDOSE H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

171 246 Protocol: Page 10 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) A 23 SESSION 1 DAY 1 4 H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 2 PREDOSE SESSION 1 DAY 3 PREDOSE SESSION 1 DAY 4 PREDOSE SESSION 1 DAY 5 PREDOSE SESSION 1 DAY 6 PREDOSE SESSION 1 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 8 PREDOSE SESSION 1 DAY 9 PREDOSE SESSION 1 DAY 10 PREDOSE SESSION 2 DAY 1 PREDOSE H H H 1ST R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

172 247 Protocol: Page 11 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) A 23 SESSION 2 DAY 1 6 H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 2 PREDOSE SESSION 2 DAY 3 PREDOSE SESSION 2 DAY 4 PREDOSE SESSION 2 DAY 5 PREDOSE SESSION 2 DAY 6 PREDOSE SESSION 2 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 8 PREDOSE SESSION 2 DAY 9 PREDOSE SESSION 2 DAY 10 PREDOSE SESSION 3 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

173 248 Protocol: Page 12 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) A 23 SESSION 3 DAY 1 6 H AVE R H R2 OR R SESSION 3 DAY 2 PREDOSE SESSION 3 DAY 3 PREDOSE SESSION 3 DAY 4 PREDOSE SESSION 3 DAY 5 PREDOSE SESSION 3 DAY 6 PREDOSE SESSION 3 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 8 PREDOSE SESSION 3 DAY 9 PREDOSE SESSION 3 DAY 10 PREDOSE B 24 SESSION 1 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

174 249 Protocol: Page 13 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) B 24 SESSION 1 DAY 1 6 H R2 OR R SESSION 1 DAY 2 PREDOSE SESSION 1 DAY 3 PREDOSE SESSION 1 DAY 4 PREDOSE SESSION 1 DAY 5 PREDOSE SESSION 1 DAY 6 PREDOSE SESSION 1 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 8 PREDOSE SESSION 1 DAY 9 PREDOSE SESSION 1 DAY 10 PREDOSE SESSION 2 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 2 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

175 250 Protocol: Page 14 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) B 24 SESSION 2 DAY 3 PREDOSE SESSION 2 DAY 4 PREDOSE SESSION 2 DAY 5 PREDOSE SESSION 2 DAY 6 PREDOSE SESSION 2 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 8 PREDOSE SESSION 2 DAY 9 PREDOSE SESSION 2 DAY 10 PREDOSE SESSION 3 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 2 PREDOSE SESSION 3 DAY 3 PREDOSE SESSION 3 DAY 4 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

176 251 Protocol: Page 15 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) B 24 SESSION 3 DAY 5 PREDOSE SESSION 3 DAY 6 PREDOSE SESSION 3 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 8 PREDOSE SESSION 3 DAY 9 PREDOSE SESSION 3 DAY 10 PREDOSE C 23 SESSION 1 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 2 PREDOSE SESSION 1 DAY 3 PREDOSE SESSION 1 DAY 4 PREDOSE SESSION 1 DAY 5 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

177 252 Protocol: Page 16 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) C 23 SESSION 1 DAY 6 PREDOSE SESSION 1 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 8 PREDOSE SESSION 1 DAY 9 PREDOSE SESSION 1 DAY 10 PREDOSE SESSION 2 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 2 PREDOSE SESSION 2 DAY 3 PREDOSE SESSION 2 DAY 4 PREDOSE SESSION 2 DAY 5 PREDOSE SESSION 2 DAY 6 PREDOSE SESSION 2 DAY 7 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

178 253 Protocol: Page 17 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) C 23 SESSION 2 DAY 7 2 H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 8 PREDOSE SESSION 2 DAY 9 PREDOSE SESSION 2 DAY 10 PREDOSE SESSION 3 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 2 PREDOSE SESSION 3 DAY 3 PREDOSE SESSION 3 DAY 4 PREDOSE SESSION 3 DAY 5 PREDOSE SESSION 3 DAY 6 PREDOSE SESSION 3 DAY 7 PREDOSE H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

179 254 Protocol: Page 18 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) C 23 SESSION 3 DAY 7 6 H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 8 PREDOSE SESSION 3 DAY 9 PREDOSE SESSION 3 DAY 10 PREDOSE FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP Systolic BP (mmhg) SCREENING 24 SCREENING SCREENING 1ST R SCREENING 2ND R SCREENING 3RD R SCREENING AVE R SCREENING R2 OR R A 23 SESSION 1 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 2 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

180 255 Protocol: Page 19 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) A 23 SESSION 1 DAY 3 PREDOSE SESSION 1 DAY 4 PREDOSE SESSION 1 DAY 5 PREDOSE SESSION 1 DAY 6 PREDOSE SESSION 1 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 8 PREDOSE SESSION 1 DAY 9 PREDOSE SESSION 1 DAY 10 PREDOSE SESSION 2 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 2 PREDOSE SESSION 2 DAY 3 PREDOSE SESSION 2 DAY 4 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

181 256 Protocol: Page 20 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) A 23 SESSION 2 DAY 5 PREDOSE SESSION 2 DAY 6 PREDOSE SESSION 2 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 8 PREDOSE SESSION 2 DAY 9 PREDOSE SESSION 2 DAY 10 PREDOSE SESSION 3 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 2 PREDOSE SESSION 3 DAY 3 PREDOSE SESSION 3 DAY 4 PREDOSE SESSION 3 DAY 5 PREDOSE SESSION 3 DAY 6 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

182 257 Protocol: Page 21 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) A 23 SESSION 3 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 8 PREDOSE SESSION 3 DAY 9 PREDOSE SESSION 3 DAY 10 PREDOSE B 24 SESSION 1 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 2 PREDOSE SESSION 1 DAY 3 PREDOSE SESSION 1 DAY 4 PREDOSE SESSION 1 DAY 5 PREDOSE SESSION 1 DAY 6 PREDOSE SESSION 1 DAY 7 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

183 258 Protocol: Page 22 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) B 24 SESSION 1 DAY 7 2 H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 8 PREDOSE SESSION 1 DAY 9 PREDOSE SESSION 1 DAY 10 PREDOSE SESSION 2 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 2 PREDOSE SESSION 2 DAY 3 PREDOSE SESSION 2 DAY 4 PREDOSE SESSION 2 DAY 5 PREDOSE SESSION 2 DAY 6 PREDOSE SESSION 2 DAY 7 PREDOSE H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

184 259 Protocol: Page 23 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) B 24 SESSION 2 DAY 7 6 H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 8 PREDOSE SESSION 2 DAY 9 PREDOSE SESSION 2 DAY 10 PREDOSE SESSION 3 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 2 PREDOSE SESSION 3 DAY 3 PREDOSE SESSION 3 DAY 4 PREDOSE SESSION 3 DAY 5 PREDOSE SESSION 3 DAY 6 PREDOSE SESSION 3 DAY 7 PREDOSE H H H 1ST R H 2ND R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

185 260 Protocol: Page 24 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) B 24 SESSION 3 DAY 7 6 H 3RD R H AVE R H R2 OR R SESSION 3 DAY 8 PREDOSE SESSION 3 DAY 9 PREDOSE SESSION 3 DAY 10 PREDOSE C 23 SESSION 1 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 1 DAY 2 PREDOSE SESSION 1 DAY 3 PREDOSE SESSION 1 DAY 4 PREDOSE SESSION 1 DAY 5 PREDOSE SESSION 1 DAY 6 PREDOSE SESSION 1 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

186 261 Protocol: Page 25 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) C 23 SESSION 1 DAY 7 6 H AVE R H R2 OR R SESSION 1 DAY 8 PREDOSE SESSION 1 DAY 9 PREDOSE SESSION 1 DAY 10 PREDOSE SESSION 2 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 2 DAY 2 PREDOSE SESSION 2 DAY 3 PREDOSE SESSION 2 DAY 4 PREDOSE SESSION 2 DAY 5 PREDOSE SESSION 2 DAY 6 PREDOSE SESSION 2 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

187 262 Protocol: Page 26 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) C 23 SESSION 2 DAY 8 PREDOSE SESSION 2 DAY 9 PREDOSE SESSION 2 DAY 10 PREDOSE SESSION 3 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 2 PREDOSE SESSION 3 DAY 3 PREDOSE SESSION 3 DAY 4 PREDOSE SESSION 3 DAY 5 PREDOSE SESSION 3 DAY 6 PREDOSE SESSION 3 DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R SESSION 3 DAY 8 PREDOSE SESSION 3 DAY 9 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

188 Protocol: Page 27 of 27 Population: Safety Table Summary of Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) C 23 SESSION 3 DAY 10 PREDOSE FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

189 264 Protocol: Page 1 of 6 Population: Safety Table Summary of Change from Baseline for Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) A 23 SESSION 1 DAY 1 2 H H SESSION 1 DAY 7 2 H H SESSION 2 DAY 1 2 H H SESSION 2 DAY 7 2 H H SESSION 3 DAY 1 2 H H SESSION 3 DAY 7 2 H H B 24 SESSION 1 DAY 1 2 H H SESSION 1 DAY 7 2 H H SESSION 2 DAY 1 2 H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

190 265 Protocol: Page 2 of 6 Population: Safety Table Summary of Change from Baseline for Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Diastolic BP (mmhg) B 24 SESSION 2 DAY 7 2 H H SESSION 3 DAY 1 2 H H SESSION 3 DAY 7 2 H H C 23 SESSION 1 DAY 1 2 H H SESSION 1 DAY 7 2 H H SESSION 2 DAY 1 2 H H SESSION 2 DAY 7 2 H H SESSION 3 DAY 1 2 H H SESSION 3 DAY 7 2 H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

191 266 Protocol: Page 3 of 6 Population: Safety Table Summary of Change from Baseline for Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) A 23 SESSION 1 DAY 1 2 H H SESSION 1 DAY 7 2 H H SESSION 2 DAY 1 2 H H SESSION 2 DAY 7 2 H H SESSION 3 DAY 1 2 H H SESSION 3 DAY 7 2 H H B 24 SESSION 1 DAY 1 2 H H SESSION 1 DAY 7 2 H H SESSION 2 DAY 1 2 H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

192 267 Protocol: Page 4 of 6 Population: Safety Table Summary of Change from Baseline for Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart Rate (BPM) B 24 SESSION 2 DAY 7 2 H H SESSION 3 DAY 1 2 H H SESSION 3 DAY 7 2 H H C 23 SESSION 1 DAY 1 2 H H SESSION 1 DAY 7 2 H H SESSION 2 DAY 1 2 H H SESSION 2 DAY 7 2 H H SESSION 3 DAY 1 2 H H SESSION 3 DAY 7 2 H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

193 268 Protocol: Page 5 of 6 Population: Safety Table Summary of Change from Baseline for Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) A 23 SESSION 1 DAY 1 2 H H SESSION 1 DAY 7 2 H H SESSION 2 DAY 1 2 H H SESSION 2 DAY 7 2 H H SESSION 3 DAY 1 2 H H SESSION 3 DAY 7 2 H H B 24 SESSION 1 DAY 1 2 H H SESSION 1 DAY 7 2 H H SESSION 2 DAY 1 2 H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

194 269 Protocol: Page 6 of 6 Population: Safety Table Summary of Change from Baseline for Vital Signs Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Systolic BP (mmhg) B 24 SESSION 2 DAY 7 2 H H SESSION 3 DAY 1 2 H H SESSION 3 DAY 7 2 H H C 23 SESSION 1 DAY 1 2 H H SESSION 1 DAY 7 2 H H SESSION 2 DAY 1 2 H H SESSION 2 DAY 7 2 H H SESSION 3 DAY 1 2 H H SESSION 3 DAY 7 2 H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

195 Protocol: Page 1 of 120 Population: Safety Table Listing of All Vital Signs for Subjects with Values of Potential Clinical Importance Study Inv./ Age(y)/ Planned Day/ Systolic Diastolic Heart Subj./ Sex/ Treatment/ Relative Subject Actual Date/ Period BP BP Rate Seq. Race Visit Time Position Time Day (mmhg) (mmhg) (bpm) 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 GSK Clincal Study Register. 270 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

196 Protocol: Page 1 of 8 Population: Safety Table Listing of Vital Signs of Potential Clinical Importance Study Inv./ Age(y)/ Planned Day/ Systolic Diastolic Heart Subj./ Sex/ Treatment/ Relative Actual Date/ Period BP BP Rate Seq. Race Visit Time Time Day (mmhg) (mmhg) (bpm) 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 GSK Clincal Study Register. 390 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

197 Protocol: Page 1 of 2 Population: Safety Table Summary of ECG Values Planned Relative Treatment N Visit Time n Mean SD Median Min. Max Heart rate SCREENING 24 SCREENING SCREENING (BPM) FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP PR Interval SCREENING 24 SCREENING SCREENING (MSEC) FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP QRS Duration SCREENING 24 SCREENING SCREENING (MSEC) FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP QT Interval SCREENING 24 SCREENING SCREENING (MSEC) FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP QTc Interval SCREENING 24 SCREENING SCREENING (MSEC) FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

198 Protocol: Page 2 of 2 Population: Safety Table Summary of ECG Values Planned Relative Treatment N Visit Time n Mean SD Median Min. Max QTcB (MSEC) SCREENING 24 SCREENING SCREENING FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP QTcF (MSEC) SCREENING 24 SCREENING SCREENING FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP RR Interval SCREENING 24 SCREENING SCREENING (MSEC) FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

199 Protocol: Page 1 of 1 Population: Safety Table Summary of ECG Findings SCREENING FOLLOW-UP Category (N=24) (N=24) n Normal 21 (87.5%) 23 (95.8%) Abnormal - Not clinically significant 3 (12.5%) 1 (4.2%) Abnormal - Clinically significant Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

200 401 Protocol: Page 1 of 8 Population: Safety Table Summary of Chemistry Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Alanine Amino SCREENING 24 SCREENING Transferase (IU/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Albumin (G/L) SCREENING 24 SCREENING A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

201 402 Protocol: Page 2 of 8 Population: Safety Table Summary of Chemistry Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Alkaline SCREENING 24 SCREENING Phosphatase (IU/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Aspartate SCREENING 24 SCREENING Amino Transferase (IU/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

202 403 Protocol: Page 3 of 8 Population: Safety Table Summary of Chemistry Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Blood Urea SCREENING 24 SCREENING Nitrogen (MMOL/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Calcium SCREENING 24 SCREENING (MMOL/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

203 404 Protocol: Page 4 of 8 Population: Safety Table Summary of Chemistry Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Carbon SCREENING 24 SCREENING Dioxide content / Bicarbonate (MMOL/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Chloride SCREENING 24 SCREENING (MMOL/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

204 405 Protocol: Page 5 of 8 Population: Safety Table Summary of Chemistry Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Creatinine SCREENING 24 SCREENING (UMOL/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Direct SCREENING 24 SCREENING Bilirubin (UMOL/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

205 406 Protocol: Page 6 of 8 Population: Safety Table Summary of Chemistry Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Gamma SCREENING 24 SCREENING Glutamyl Transferase (IU/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Glucose SCREENING 24 SCREENING (MMOL/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

206 407 Protocol: Page 7 of 8 Population: Safety Table Summary of Chemistry Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Potassium SCREENING 24 SCREENING (MMOL/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Sodium SCREENING 24 SCREENING (MMOL/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

207 408 Protocol: Page 8 of 8 Population: Safety Table Summary of Chemistry Data Planned Lab Test Relative (Units) Treatment N Time n Mean SD Median Min. Max Total Protein SCREENING 24 SCREENING (G/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Total SCREENING 24 SCREENING Bilirubin (UMOL/L) A 23 DAY B 24 DAY C 23 DAY FOLLOW-UP 24 FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

208 Protocol: Page 1 of 1 Population: Safety Table Listing of ECG Values of Potential Clinical Importance Study QTc Day/ Visit/ QTc Interval Inv./ Age(y)/ Per- Planned Heart PR QRS QT Interval (Frideri Subj./ Sex/ Treatment/ iod ECG Date/ Relative Rate Interval Duration Interval (Bazett) cia) Seq. Race Period Day Time Time (BPM) (msec) (msec) (msec) (msec) (msec) 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 GSK Clincal Study Register. 409 Regimenn Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

209 Protocol: Page 1 of 1 Population: Safety Table Listing of Abnormal ECG Findings Visit/ Planned Relative Study Inv./ Age(y)/ Time/ Day/ Clinically Subj./ Sex/ Treatment/ ECG Date/ Period Significant Seq. Race Period Time Day Result Abnormality 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 GSK Clincal Study Register. 410 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

210 Protocol: Page 1 of 1 Population: Safety Table Summary Table of Subjects Who Demonstrated Orthostatic Hypotension A B C (N=23) (N=24) (N=23) SBP (mmhg) Orthostatic Hypotension 6 (26%) 3 (13%) 5 (22%) DBP (mmhg) Orthostatic Hypotension 5 (22%) 3 (13%) 3 (13%) Total 8 (35%) 5 (21%) 6 (26%) 411 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: Orthostatic hypotension will be defined as a reduction in SBP of 20 mmhg or more and/or a reduction in DBP of 10 mmhg or more for the standing measurement compared to the average 3 supine measurements.

211 412 Protocol: Page 1 of 1 Population: Safety Table Summary Table of Subjects Who Demonstrated Orthostatic Hypotension by Visit Hypotension A B C Visit (N=23) (N=24) (N=23) SBP (mmhg) Orthostatic Hypotension Any event 6 (26%) 3 (13%) 5 (22%) SESSION 1 DAY 1 2 (9%) 1 (4%) 2 (9%) SESSION 1 DAY 7 2 (9%) 1 (4%) 1 (4%) SESSION 2 DAY (4%) 0 SESSION 2 DAY (4%) SESSION 3 DAY (4%) 1 (4%) SESSION 3 DAY 7 2 (9%) 1 (4%) 1 (4%) DBP (mmhg) Orthostatic Hypotension Any event 5 (22%) 3 (13%) 3 (13%) SESSION 1 DAY 1 2 (9%) 0 1 (4%) SESSION 1 DAY 7 4 (17%) 0 0 SESSION 2 DAY (8%) 0 SESSION 3 DAY 1 1 (4%) 1 (4%) 0 SESSION 3 DAY 7 1 (4%) 0 2 (9%) Total Any event 8 (35%) 5 (21%) 6 (26%) SESSION 1 DAY 1 2 (9%) 1 (4%) 2 (9%) SESSION 1 DAY 7 5 (22%) 1 (4%) 1 (4%) SESSION 2 DAY (8%) 0 SESSION 2 DAY (4%) SESSION 3 DAY 1 1 (4%) 2 (8%) 1 (4%) SESSION 3 DAY 7 3 (13%) 1 (4%) 2 (9%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

212 413 Protocol: Page 1 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Planned Relative Time Labtest: Urine Bilirubin (dipstick) SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING n 24 NEGATIVE 24 (100%) DAY -1 n NEGATIVE 23 (100%) 24 (100%) 23 (100%) FOLLOW-UP n 24 NEGATIVE 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

213 414 Protocol: Page 2 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Planned Relative Time Labtest: Urine Glucose (dipstick) SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING n 24 NEGATIVE 24 (100%) DAY -1 n NEGATIVE 23 (100%) 24 (100%) 22 (96%) 100 MG/DL 1 (4%) FOLLOW-UP n 24 NEGATIVE 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

214 415 Protocol: Page 3 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Planned Relative Time Labtest: Urine Ketones (dipstick) SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING n 24 NEGATIVE 24 (100%) DAY -1 n NEGATIVE 23 (100%) 24 (100%) 22 (96%) TRACE 1 (4%) FOLLOW-UP n 24 NEGATIVE 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

215 416 Protocol: Page 4 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Planned Relative Time Labtest: Urine Leukocyte Esterase (dipstick) SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING n 24 NEGATIVE 23 (96%) TRACE 1 (4%) DAY -1 n NEGATIVE 23 (100%) 24 (100%) 23 (100%) FOLLOW-UP n 24 NEGATIVE 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

216 417 Protocol: Page 5 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Planned Relative Time Labtest: Urine Nitrite (dipstick) SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING n 24 NEGATIVE 24 (100%) DAY -1 n NEGATIVE 23 (100%) 24 (100%) 23 (100%) FOLLOW-UP n 24 NEGATIVE 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

217 418 Protocol: Page 6 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Planned Relative Time Labtest: Urine Occult Blood (dipstick) SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING n 24 NEGATIVE 22 (92%) TRACE 2 (8%) DAY -1 n NEGATIVE 21 (91%) 24 (100%) 21 (91%) TRACE 2 (9%) 1+ (SMALL) 2 (9%) FOLLOW-UP n 24 NEGATIVE 20 (83%) TRACE 2 (8%) 1+ (SMALL) 2 (8%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

218 419 Protocol: Page 7 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Planned Relative Time Labtest: Urine Protein (dipstick) SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING n 24 NEGATIVE 24 (100%) DAY -1 n NEGATIVE 21 (91%) 20 (83%) 20 (87%) TRACE (15 MG/DL) 2 (9%) 4 (17%) 3 (13%) FOLLOW-UP n 24 NEGATIVE 20 (83%) TRACE (15 MG/DL) 4 (17%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

219 420 Protocol: Page 8 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Planned Relative Time Labtest: Urine Urobilinogen (dipstick) SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING n 24 <= 1MG/DL 24 (100%) DAY -1 n <= 1MG/DL 21 (91%) 23 (96%) 23 (100%) 1MG/DL 1 (4%) 1 MG/DL 1 (4%) 2 MG/DL 1 (4%) FOLLOW-UP n 24 <= 1MG/DL 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

220 421 Protocol: Page 1 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Visit and Planned Relative Time Labtest: Urine Bilirubin (dipstick) Visit SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING SCREENING n 24 NEGATIVE 24 (100%) SESSION 1 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 8 (100%) SESSION 2 DAY -1 DAY -1 n NEGATIVE 7 (100%) 8 (100%) 8 (100%) SESSION 3 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 7 (100%) FOLLOW-UP FOLLOW-UP n 24 NEGATIVE 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

221 422 Protocol: Page 2 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Visit and Planned Relative Time Labtest: Urine Glucose (dipstick) Visit SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING SCREENING n 24 NEGATIVE 24 (100%) SESSION 1 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 8 (100%) SESSION 2 DAY -1 DAY -1 n NEGATIVE 7 (100%) 8 (100%) 8 (100%) SESSION 3 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 6 (86%) 100 MG/DL 1 (14%) FOLLOW-UP FOLLOW-UP n 24 NEGATIVE 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

222 423 Protocol: Page 3 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Visit and Planned Relative Time Labtest: Urine Ketones (dipstick) Visit SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING SCREENING n 24 NEGATIVE 24 (100%) SESSION 1 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 7 (88%) TRACE 1 (13%) SESSION 2 DAY -1 DAY -1 n NEGATIVE 7 (100%) 8 (100%) 8 (100%) SESSION 3 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 7 (100%) FOLLOW-UP FOLLOW-UP n 24 NEGATIVE 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

223 424 Protocol: Page 4 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Visit and Planned Relative Time Labtest: Urine Leukocyte Esterase (dipstick) Visit SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING SCREENING n 24 NEGATIVE 23 (96%) TRACE 1 (4%) SESSION 1 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 8 (100%) SESSION 2 DAY -1 DAY -1 n NEGATIVE 7 (100%) 8 (100%) 8 (100%) SESSION 3 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 7 (100%) FOLLOW-UP FOLLOW-UP n 24 NEGATIVE 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

224 425 Protocol: Page 5 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Visit and Planned Relative Time Labtest: Urine Nitrite (dipstick) Visit SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING SCREENING n 24 NEGATIVE 24 (100%) SESSION 1 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 8 (100%) SESSION 2 DAY -1 DAY -1 n NEGATIVE 7 (100%) 8 (100%) 8 (100%) SESSION 3 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 7 (100%) FOLLOW-UP FOLLOW-UP n 24 NEGATIVE 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

225 426 Protocol: Page 6 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Visit and Planned Relative Time Labtest: Urine Occult Blood (dipstick) Visit SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING SCREENING n 24 NEGATIVE 22 (92%) TRACE 2 (8%) SESSION 1 DAY -1 DAY -1 n NEGATIVE 7 (88%) 8 (100%) 7 (88%) TRACE 1 (13%) 1+ (SMALL) 1 (13%) SESSION 2 DAY -1 DAY -1 n NEGATIVE 6 (86%) 8 (100%) 7 (88%) TRACE 1 (13%) 1+ (SMALL) 1 (14%) SESSION 3 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 7 (100%) FOLLOW-UP FOLLOW-UP n 24 NEGATIVE 20 (83%) TRACE 2 (8%) 1+ (SMALL) 2 (8%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

226 427 Protocol: Page 7 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Visit and Planned Relative Time Labtest: Urine Protein (dipstick) Visit SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING SCREENING n 24 NEGATIVE 24 (100%) SESSION 1 DAY -1 DAY -1 n NEGATIVE 8 (100%) 7 (88%) 7 (88%) TRACE (15 MG/DL) 1 (13%) 1 (13%) SESSION 2 DAY -1 DAY -1 n NEGATIVE 5 (71%) 5 (63%) 7 (88%) TRACE (15 MG/DL) 2 (29%) 3 (38%) 1 (13%) SESSION 3 DAY -1 DAY -1 n NEGATIVE 8 (100%) 8 (100%) 6 (86%) TRACE (15 MG/DL) 1 (14%) FOLLOW-UP FOLLOW-UP n 24 NEGATIVE 20 (83%) TRACE (15 MG/DL) 4 (17%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

227 428 Protocol: Page 8 of 8 Population: Safety Table Summary of Urinalysis for Dipstick Results by Visit and Planned Relative Time Labtest: Urine Urobilinogen (dipstick) Visit SCREENING A B C FOLLOW-UP Planned Relative Time Result (N=24) (N=23) (N=24) (N=23) (N=24) SCREENING SCREENING n 24 <= 1MG/DL 24 (100%) SESSION 1 DAY -1 DAY -1 n <= 1MG/DL 7 (88%) 8 (100%) 8 (100%) 1MG/DL 1 (13%) SESSION 2 DAY -1 DAY -1 n <= 1MG/DL 6 (86%) 7 (88%) 8 (100%) 1 MG/DL 1 (13%) 2 MG/DL 1 (14%) SESSION 3 DAY -1 DAY -1 n <= 1MG/DL 8 (100%) 8 (100%) 7 (100%) FOLLOW-UP FOLLOW-UP n 24 <= 1MG/DL 24 (100%) Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

228 429 Protocol: Page 1 of 10 Population: Safety Table Summary of Vital Signs by Visit Day Planned Visit Relative Treatment N Day Time n Mean SD Median Min. Max Diastolic BP (mmhg) SCREENING 24 SCREENING SCREENING 1ST R SCREENING 2ND R SCREENING 3RD R SCREENING AVE R SCREENING R2 OR R A 23 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

229 430 Protocol: Page 2 of 10 Population: Safety Table Summary of Vital Signs by Visit Day Planned Visit Relative Treatment N Day Time n Mean SD Median Min. Max Diastolic BP (mmhg) A 23 DAY 7 6 H R2 OR R DAY 8 PREDOSE DAY 9 PREDOSE DAY 10 PREDOSE B 24 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

230 431 Protocol: Page 3 of 10 Population: Safety Table Summary of Vital Signs by Visit Day Planned Visit Relative Treatment N Day Time n Mean SD Median Min. Max Diastolic BP (mmhg) B 24 DAY 8 PREDOSE DAY 9 PREDOSE DAY 10 PREDOSE C 23 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 8 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

231 432 Protocol: Page 4 of 10 Population: Safety Table Summary of Vital Signs by Visit Day Planned Visit Relative Treatment N Day Time n Mean SD Median Min. Max Diastolic BP (mmhg) C 23 DAY 9 PREDOSE DAY 10 PREDOSE FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP Heart Rate (BPM) SCREENING 24 SCREENING SCREENING 1ST R SCREENING 2ND R SCREENING 3RD R SCREENING AVE R SCREENING R2 OR R A 23 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

232 433 Protocol: Page 5 of 10 Population: Safety Table Summary of Vital Signs by Visit Day Planned Visit Relative Treatment N Day Time n Mean SD Median Min. Max Heart Rate (BPM) A 23 DAY 7 4 H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 8 PREDOSE DAY 9 PREDOSE DAY 10 PREDOSE B 24 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H H Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

233 434 Protocol: Page 6 of 10 Population: Safety Table Summary of Vital Signs by Visit Day Planned Visit Relative Treatment N Day Time n Mean SD Median Min. Max Heart Rate (BPM) B 24 DAY 7 6 H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 8 PREDOSE DAY 9 PREDOSE DAY 10 PREDOSE C 23 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H H H 1ST R Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

234 435 Protocol: Page 7 of 10 Population: Safety Table Summary of Vital Signs by Visit Day Planned Visit Relative Treatment N Day Time n Mean SD Median Min. Max Heart Rate (BPM) C 23 DAY 7 6 H 2ND R H 3RD R H AVE R H R2 OR R DAY 8 PREDOSE DAY 9 PREDOSE DAY 10 PREDOSE FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP Systolic BP (mmhg) SCREENING 24 SCREENING SCREENING 1ST R SCREENING 2ND R SCREENING 3RD R SCREENING AVE R SCREENING R2 OR R A 23 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 2 PREDOSE DAY 3 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

235 436 Protocol: Page 8 of 10 Population: Safety Table Summary of Vital Signs by Visit Day Planned Visit Relative Treatment N Day Time n Mean SD Median Min. Max Systolic BP (mmhg) A 23 DAY 4 PREDOSE DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 8 PREDOSE DAY 9 PREDOSE DAY 10 PREDOSE B 24 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

236 437 Protocol: Page 9 of 10 Population: Safety Table Summary of Vital Signs by Visit Day Planned Visit Relative Treatment N Day Time n Mean SD Median Min. Max Systolic BP (mmhg) B 24 DAY 5 PREDOSE DAY 6 PREDOSE DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 8 PREDOSE DAY 9 PREDOSE DAY 10 PREDOSE C 23 DAY 1 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 2 PREDOSE DAY 3 PREDOSE DAY 4 PREDOSE DAY 5 PREDOSE Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

237 438 Protocol: Page 10 of 10 Population: Safety Table Summary of Vital Signs by Visit Day Planned Visit Relative Treatment N Day Time n Mean SD Median Min. Max Systolic BP (mmhg) C 23 DAY 6 PREDOSE DAY 7 PREDOSE H H H 1ST R H 2ND R H 3RD R H AVE R H R2 OR R DAY 8 PREDOSE DAY 9 PREDOSE DAY 10 PREDOSE FOLLOW-UP 24 FOLLOW-UP FOLLOW-UP Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg Note: R1: supine position; R2 or R4: stitting or standing position; AVE R1: the average of the first, the second and third supine measurements.

238 Protocol: Page 1 of 1 Population: Safety Table Listing of All ECG Values for Subjects with a Value of Potential Clinical Importance Study QTc Day/ Visit/ QTc Interval Inv./ Age(y)/ Per- Planned Heart PR QRS QT Interval (Frideri Subj./ Sex/ Treatment/ iod ECG Date/ Relative Rate Interval Duration Interval (Bazett) cia) Seq. Race Period Day Time Time (BPM) (msec) (msec) (msec) (msec) (msec) 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 GSK Clincal Study Register. 439 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg

239 CONFIDENTIAL ZM2008/00081/00 Attachment 1: Study Administration Institutional Review Board (IRB) Activities Outsourced to Other CROs/Companies Monitor Name and Address Covance Laboratories, Madison, WI, USA Cape Carteret, NC Role/Responsibilities PK analyses Clinical study conduct 1 440

240 441 Attachment 2: Time and Events Table for Protocol Procedure / Time (hrs) Screen Day -1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Follow Up (up to 30 days prior to Day 1) (10-14 days postlast dose) Visit (V); Admission (A); Discharge (DC) V A DC V V Informed Consent X Medical History X Medication/Concomitant Med History X X X Demographics X Full Physical Exam X X Clinical Laboratory Tests X X X Serology for HIV, Hep B and Hep C X 2D6 Pharmacogenetic Typing X Drug and Alcohol Screen X X 1 Vital Signs X 2 X 3 X 3 X 3 X 3 X 3 X 2 X X X X Orthostatic Vital Signs X X 4 X 4 12-Lead ECG X X Baseline Signs & Symptoms/Adverse Events X X X X X X X X X X X X X Administer Study Drug X X X X X X X Subjects to remain semirecumbent X 5 X 5 Meals 6 X X 7 X X X X X X 7 X X X 8 Pharmacokinetic Blood Sample X 9 X 10 X 10 X 10 X 10 X 10 X 9 X 11 X 11 X 11 1

241 1. Drug and alcohol screen must be negative prior to dosing 2. To be taken within 1 hour prior to dosing and at 2 and 4 hours post dose 3. To be taken within 1 hour prior to dosing 4. To be taken at 6 hours post-dose 5. Subjects to remain semi-recumbent for 6 hours post-dose 6. Meals should be served at approximately the same time on all days. 7. Subjects will not receive breakfast 8. Meals are optional 9. PK sample times: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 16 hour post-dose 10. Pre-dose sample only 11. PK sample times: 24, 36, 48, 72 hours post-dose 442 2

242 CONFIDENTIAL ZM2008/00081/00 Synopsis Identifier: ZM2008/00081/00 Study Number: Title: An open-label, randomized, repeat dose, 3 period crossover study to determine the bioequivalence of 3 different formulations of tamsulosin at steady state in healthy male volunteers. Investigator(s): MD and PharmD Study center(s): USA Publication(s): None at the time of this report. Study period: Initiation Date: 26 FEB 2008 Completion Date: 23 APR 2008 Phase of development: I Objectives: Primary 1. To investigate the bioequivalence of tamsulosin at steady state of a Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg under fasting conditions. 2. To investigate the bioequivalence of tamsulosin at steady state of a Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg under fasting conditions. Secondary 1. To assess the safety and tolerability of dosing with the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg, the Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg, and concomitant dosing of AVODART 0.5 mg and the U.S.- sourced Flomax 0.4 mg. Methodology: Clinical data exist to support that tamsulosin (an alpha-1-adrenoceptor antagonist), when used in combination with dutasteride (a 5-alpha reductase inhibitor), offers a more effective treatment for the symptoms of benign prostatic hyperplasia than either drug used alone. For patients who have been prescribed both dutasteride and tamsulosin, it is more desirable to have a single capsule formulation that could deliver both of these drugs 1 1

243 CONFIDENTIAL ZM2008/00081/00 simultaneously. Depending on the results this study and completed studies as well as the results of ongoing formulation development work, the decision will be made to move forward with either the 10% or the 15% enteric coated formulation of tamsulosin in the combination capsule. There is concern that tamsulosin may accumulate after repeat dosing, therefore, this study aimed to establish bioequivalence at steady state of tamsulosin only. Each subject was to receive one of the three treatment regimens in each dosing session. Subjects were randomized to one of 6 treatment sequences ABC, ACB, BAC, BCA, CAB, or CBA. Regimen A B C Description Dutasteride and Tamsulosin Hydrochloride Combination Capsule, 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride (test) Dutasteride and Tamsulosin Hydrochloride Combination Capsule, 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride (test) Flomax 0.4 mg (sustained release capsule commercially available in United States) and AVODART 0.5 mg (reference) Eligible subjects were admitted to the research unit the evening prior to dosing (Day -1) and remained in the unit until approximately 48 hours after dosing on Day 7. The subjects returned to the research unit for an outpatient visit at approximately 72 hours post-dose Day 7 after each treatment session. On days when full PK sampling took place (Days 1 and 7) subjects were fasted for 10 hours prior to drug administration and for 4 hours after. There was an approximately 5-7 day washout between dosing of each session. Subjects were to participate in 3 dosing sessions. Subjects returned to the research unit 10 days after the last dose for follow-up and were subsequently discharged from the study. The total duration of each subject's participation from screening to follow-up was approximately 9 weeks. Number of subjects: 24 subjects were enrolled and 23 subjects completed the study. Subject Disposition and Demographics: All subjects were male, the majority were African American (46%) or White (42%) and subjects had a mean age of 24 years. 2 2

244 Number of Subjects Number of subjects planned, N: 24 Number of subjects randomized, N: 24 Number of subjects included in All subjects (safety) population, n (%): 24 (100) Number of subjects included in PK population, n (%): 24 (100) Number of subjects completed as planned, n (%): 23 (96) Number of subjects withdrawn (any reason), n (%): 1 (4) Reasons for subject withdrawal, n (%) Serious Adverse Event 1 (4) Demographics Age in Years, Mean (Range) 24 (19-45) Sex, n (%) Female: 0 Male: 24 (100) BMI, Mean (Range) 26.0 ( ) Height, Mean (Range) 177 ( ) Weight, Mean (Range) 81.4 ( ) Ethnicity, n (%) Hispanic or Latino: 2 (8) Not Hispanic or Latino: 22 (92) Race, n (%) African American/African Heritage 11 (46) Asian South East Asian Heritage 2 (8) White White/Caucasian/European Heritage 10 (42) Mixed Race 1 (4) Diagnosis and main criteria for inclusion: Healthy male subjects aged years (inclusive), with a body weight 55 kg and body mass index between kg/m 2 (inclusive), who were not CYP2D6 poor metabolizers were eligible for the study. Treatment administration: CONFIDENTIAL ZM2008/00081/00 In each of the 3 sessions, subjects received Regimen A, B, or C as per the randomization schedule. Subjects were fasted for 10 hours prior to dosing on Days 1 and 7, with the exception of water, which will be allowed freely except for 1 hour before and 1 hour after dosing. On other study days, subjects were dosed approximately 30 minutes after the start of breakfast. Following dosing, subjects were not allowed food for 4 hours. Study medication was swallowed, without chewing, with 240 ml of water at room temperature. 3 3

245 CONFIDENTIAL ZM2008/00081/00 Drug Dose/Form/Route Frequency /Duration Flomax 0.4 mg tamsulosin/ sustained Once daily / 7 release capsule / oral days AVODART (GI198745) 0.5 mg dutasteride/ capsule / oral Once daily / 7 days Dutasteride and Tamsulosin Hydrochloride (10%) Combination Capsule Dutasteride and Tamsulosin Hydrochloride (15%) Combination Capsule 0.5 mg dutasteride, 0.4 mg tamsulosin HCl / capsules / oral 0.5 mg dutasteride, 0.4 mg tamsulosin HCl / capsules / oral Once daily / 7 days Once daily / 7 days Lot or Batch Number Lot # Batch # Batch # Batch # All study medication was supplied by GlaxoSmithKline. Criteria for evaluation: Primary Endpoints: 1. AUC (0-24) and Cmax of tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg after a single dose and at steady state. 2. AUC (0-24) and Cmax of tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg after a single dose and at steady state. 3. AUC (0-24) and Cmax of tamsulosin in concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg. Secondary Endpoints: 1. C(tau) (defined as the concentration at 24 hours after the Day 7 dose), t1/2, tmax, λ, Cmin and fluctuation [(Cmax Cmin)/(AUC(0-24)/24)] of tamsulosin, as data permit. 2. Safety and tolerability of all treatments as assessed by blood pressure and pulse rate measurements, adverse events and clinical laboratory safety tests. Statistical methods: There were no interim analyses planned or conducted in this study. The final PK analyses were performed as follows: 1. A linear regression analysis was performed for the log e -transformed Cτ s in Days 4, 5 and 6 (i.e. pre-dose concentration data in Days 5, 6 and 7) versus day, to check the achievement of the steady state for each regimen. 2. To assess the bioequivalence of the test and reference treatments of tamsulosin, log e - transformed values of PK parameter AUC(0-24)-ss, Cmax-ss, Cmin-ss, Cτ, t1/2 and fluctuation were analyzed by analysis of variance (ANOVA) using mixed effects model, fitting the fixed effects for treatment sequence, period and regimen, and 4 4

246 fitting subject within sequence as a random effect. Point estimates and 90% confidence intervals for the test-to-reference ratios A:C and B:C were constructed. 3. Tmax-ss was analyzed nonparametrically using the Wilcoxon Matched Pairs Method to compute the point estimate and 90% confidence interval for the median difference for each comparison of interest. Summary: Safety: CONFIDENTIAL There were no deaths or partner pregnancies reported during this study. There was one SAE which lead to withdrawal from the study. ZM2008/00081/00 The most commonly reported AEs in any regimen (>10%) were headache, dizziness and nasal congestion. A slightly higher proportion of AEs were seen with Regimen A (Dutasteride and Tamsulosin Hydrochloride (10%) Combination Capsule) than with either Regimens B or C. All adverse events were considered by the investigator to be mild or moderate in intensity. The investigator was unable to reach the subject after the end of the study for follow-up. Regimen A (n=23) Regimen B (n=24) Regimen C (n=23) Total (n=24) Subjects with any AE, 15 (65) 10 (42) 9 (39) 20 (83) n (%) Subjects with any AE related to 7 (30) 4 (17) 5 (22) 12 (50) study medication, n (%) Dizziness 1 (4) 2 (8) 3 (13) 5 (21) Headache 4 (17) 5 (21) 4 (17) 8 (33) Regimens: A 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C Flomax 0.4 mg and AVODART 0.5 mg 5 5

247 CONFIDENTIAL ZM2008/00081/00 Pharmacokinetics: Statistical methods: Following loge-transformation, AUC(0-24) Cmax,,Cmin, t1/2, FL, and Cτ of tamsulosin were separately analyzed using a mixed effects model with fixed effect terms for sequence, period and regimen. Subject within sequence was treated as a random effect in the model. Point estimates and their associated 90% confidence intervals were constructed for the differences, [A- C and B - C]. The point estimates and their associated 90% confidence intervals were back-transformed to provide point estimates and 90% confidence intervals for the ratios, [A:C and B:C]. Tmax was analyzed non-parametrically using the Wilcoxon's Matched Pairs Method. Point estimates and 90% confidence intervals were constructed for the estimated median differences, [A C and B C]. Table 1 Point Estimates and 90% Confidence Intervals for Comparisons of Interests of Pharmacokinetic Parameters for Evaluation of Bioequivalence of Tamsulosin at Steady State Parameter Comparison Least Square Geometric Mean Test Reference Point Estimate of Ratio 90% CI AUC(0-24)-ss 1 A : C (0.93,1.11) (ng*hr/ml) B : C (0.85,1.02) Cmax-ss 1 A : C (0.91,1.06) (ng/ml) B : C (0.85,0.98) Cmin-ss 1 A : C (0.90,1.19) (ng/ml) B : C (0.91,1.20) Cτ 1 (ng/ml) A : C (0.95,1.23) B : C (0.91,1.18) t1/2 1 (hr) A : C (0.94,1.04) B : C (0.97,1.08) Fluctuation 1 (%) A : C (0.90,1.01) B : C (0.89,1.00) tmax 2 (hr) A - C (-0.50,0.50) B - C (0.00,0.50) Source data: Pharmacokinetic Table 10.7 and Table Point estimate is the ratio of adjusted geometric means between regimens 2. Point estimate represents the estimated median difference between regimens 3. CVw% represents a pooled estimate of within-subject variability across regimens 4. CVb% represents a pooled estimate of between-subject variability across regimens Regimens: A 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C Flomax 0.4 mg and AVODART 0.5 mg CVw 3 (%) CVb 4 (%) Conclusions: The tamsulosin component of the combination capsule formulations of dutasteride 0.5 mg and either 10% or 15% enteric coated tamsulosin HCl 0.4 mg is bioequivalent to the concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg at steady-state. 6 6

248 Administration of the combination capsule formulations of dutasteride 0.5 mg/tamsulosin HCl 0.4 mg to healthy adult male volunteers was generally well tolerated under the conditions of this study. Date of Report: October 2008 CONFIDENTIAL ZM2008/00081/00 7 7

249 ZM2007/00164/00 CONFIDENTIAL CONFIDENTIAL ZM2007/00164/00 GlaxoSmithKline The GlaxoSmithKline group of companies group of companies Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Pharmacology Protocol ZM2008/00081/00 Title: An open-label, randomized, repeat dose, 3 period crossover study to determine the bioequivalence of 3 different formulations of tamsulosin at steady state in healthy male volunteers. Compound Number: GI Effective Date: 30-JAN-2008 Description: This will be an open-label, randomized, repeat dose, 3 period crossover study to assess the bioequivalence of tamsulosin when given in the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin 0.4 mg or the modified Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S. commercially available Flomax 0.4 mg capsules at steady state. In each dosing session, subjects will receive one regimen for 7 days. Pharmacokinetic blood draws for the assessment of serum tamsulosin will be taken on Day 1 and Day 7 with trough serum tamsulosin PK drawn on Days 2-6. There will be an approximately 5-7 day washout period between dosing in each session. Subjects will participate in 3 dosing sessions. Safety will be assessed by measurement of blood pressure, heart rate, laboratory safety screens, and collection of adverse events. The study will enroll approximately 24 healthy male subjects in order to complete approximately 16 evaluable subjects. Subject: AVODART, dutasteride, Flomax, tamsulosin hydrochloride, GI198745, healthy subject, steady state, bioequivalence Author(s): CSSO, CPDM CSSO, CPDM CPKMS, CPDM DB, DDS DM, CPDM GSO, PCD Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited. 1 1

250 ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/00 2

251 ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL ZM2007/00164/00 SPONSOR/MEDICAL MONITOR INFORMATION PAGE Medical Monitor and Sponsor Contact Information: Role Name Day Time Phone Number Primary Medical Monitor MD After-hours Phone/Cell/ Pager Number Fax Number GSK Address 709 Swedeland Road King of Prussia, PA Secondary Medical Monitor Tertiary Medical Monitor MD, MSc. MD 709 Swedeland Road King of Prussia, PA Swedeland Road King of Prussia, PA Sponsor Registered Address: GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). If applicable, the details of the alternative Sponsor and contact person in the territory will be provided to the relevant regulatory authority as part of the clinical trial application. Regulatory Agency Identifying Number(s): 47,

252 ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL ZM2007/00164/00 INVESTIGATOR PROTOCOL AGREEMENT PAGE I confirm agreement to conduct the study in compliance with the protocol. I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study. I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receive the appropriate information throughout the study. Investigator Name: Investigator Address: Investigator Phone Number: Investigator Signature Date 4 4

253 ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/00 TABLE OF CONTENTS Page ABBREVIATIONS INTRODUCTION Background Dutasteride Tamsulosin Rationale Study Rationale Dose Rationale Risk Assessment OBJECTIVE(S) Primary Secondary ENDPOINT(S) Primary Secondary STUDY DESIGN Design Description Treatment Assignment Investigational Product Dosage/Administration Investigational Product Dosage/Administration (Continued) Time and Events Table Time and Events Table (Continued) STUDY POPULATION Number of Subjects Eligibility Criteria Inclusion Criteria Exclusion Criteria Other Eligibility Criteria Considerations DATA ANALYSIS AND STATISTICAL CONSIDERATIONS Hypotheses and Treatment Comparisons Sample Size Considerations Sample Size Assumptions Sample Size Sensitivity Sample Size Re-estimation Data Analysis Considerations Interim Analysis

254 ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/ Final Analyses STUDY ASSESSMENTS AND PROCEDURES Demographic/Medical History Assessments Safety Pregnancy Time period for collecting pregnancy information Action to be taken if pregnancy occurs in a female partner of a male study subject Pharmacokinetics Blood Sample Collection Sample Analysis LIFESTYLE AND/OR DIETARY RESTRICTIONS Contraception Requirements Meals and Dietary Restrictions Caffeine, Alcohol, and Tobacco Activity CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES Permitted Medications Prohibited Medications Non-Drug Therapies COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS Subject Completion Subject Withdrawal Criteria Subject Withdrawal Procedures Treatment After the End of the Study Screen and Baseline Failures INVESTIGATIONAL PRODUCT(S) Blinding Packaging and Labeling Preparation/Handling/Storage/Accountability Bioequivalence Retention Samples Assessment of Compliance Treatment of Investigational Product Overdose ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) Definition of Adverse Events Definition of Serious Adverse Events Method of Detecting AEs and SAEs Recording of AEs and SAEs Evaluating AEs and SAEs

255 ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/ Assessment of Intensity Assessment of Causality Follow-up of AEs and SAEs Prompt Reporting of SAEs to GSK Regulatory Reporting Requirements For SAEs STUDY CONDUCT CONSIDERATIONS Regulatory and Ethical Considerations, Including the Informed Consent Process Quality Control (Study Monitoring) Quality Assurance Study and Site Closure Records Retention Provision of Study Results and Information to Investigators Data Management REFERENCES

256 ZM2007/00164/00 CONFIDENTIAL ABBREVIATIONS ZM2008/00081/00 CONFIDENTIAL ZM2007/00164/00 AE ALT (SGPT) AST (SGOT) AUC(0- ) AUC(0-24) AUC(0-t) BMI BPH BP BUN CDER Cmax Cmin Ctau CPDM CPKMS CRF CSSO CV CVU CYP DB DDS DHT DM ECG FDA FDC GCP GGT GI GLP GSK GSO HBsAg HCl HR hrs HIV ICF IND IP Adverse Event Alanine aminotransferase Aspartate aminotransferase Area under the serum drug concentration versus time curve extrapolated to infinity Area under the serum drug concentration versus time curve over 24 hours Area under the serum drug concentration from time zero to the last measurable drug concentration Body mass index Benign prostatic hyperplasia Blood pressure Blood urea nitrogen Center for Drug Evaluation and Research Maximum observed drug concentration Minimum observed drug concentration Pre-dose concentrations determined immediately before a dose at steady state Clinical Pharmacology and Discovery Medicine Clinical Pharmacokinetics Modelling & Simulation Case report form Clinical Science and Study Operations Coefficient of variation Cardiovascular and Urology Cytochrome P450 Discovery Biometrics Drug Development Sciences Dihydrotestosterone Discovery Medicine Electrocardiogram Food and Drug Administration Fixed dose combination Good Clinical Practice Gamma glutamyl transferase Gastrointestinal Good Laboratory Practice GlaxoSmithKline Global Supply Operations Hepatitis B surface antigen Hydrochloride Heart rate Hours Human immunodeficiency virus Informed consent form Investigational New Drug application Investigational product 8 8

257 ZM2007/00164/00 CONFIDENTIAL CONFIDENTIAL ZM2007/00164/00 IRB Institutional Review Board IUD Intrauterine device kg Kilogram L Liter m Meters MCH Mean corpuscular hemoglobin MCHC Mean corpuscular hemoglobin concentration MCV Mean corpuscular volume mg Milligram ml Milliliter mmhg Millimeters of mercury MSDS Material Safety Data Sheet msec Millisecond MTOPS Medical Therapy of Prostatic Symptoms oz Ounce PCD Pre-clinical Development PGx Pharmacogenetics PK Pharmacokinetics QTcB Corrected QT interval by Bazett s formula QTcF Corrected QT interval by Fridericia s formula RBC Red blood cells Ro Accumulation ratio, observed SAE Serious adverse event SD Standard deviation SOP Standard operating procedure SPM Study procedures manual ss Steady state t1/2 Elimination half-life Tmax Time at which Cmax was observed tsp Teaspoon ULN Upper limit of normal U.S. United States WBC White blood cells w/w Weight-to-weight ration Trademark Information ZM2008/00081/00 Trademarks of the GlaxoSmithKline group of companies AVODART Trademarks not owned by the GlaxoSmithKline group of companies Flomax Inform Omnic Synthon WinNonlin 9 9

258 ZM2007/00164/00 CONFIDENTIAL 1. INTRODUCTION 1.1. Background CONFIDENTIAL ZM2007/00164/00 Data from a large, multi-centre National Institutes of Health-sponsored Medical Therapy of Prostatic Symptoms (MTOPS) study have demonstrated greater benefits of combination alpha-1-adrenergic receptor antagonist and 5-alpha-reductase inhibitor therapy compared with either drug used as monotherapy in males with benign prostatic hyperplasia (BPH) [McConnell, 2002]. For patients who have been prescribed both dutasteride and tamsulosin, it is more desirable to have a single capsule formulation that could deliver both of these drugs simultaneously. In order to facilitate adherence among patients who are prescribed a combination therapy with both these drugs, a fixed dose combination formulation of dutasteride 0.5 mg and tamsulosin hydrochloride 0.4 mg is being developed for the treatment of males with symptomatic BPH Dutasteride Dutasteride (AVODART ) is an approved potent 5-alpha-reductase inhibitor indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve symptoms, reduce the risk of acute urinary retention and reduce the risk of the need for BPH-related surgery. In humans, dutasteride is well-tolerated in single doses up to 40 mg/day, multiple doses up to 40 mg/day administered for 7 days, and 5 mg/day administered for 24 weeks. The overall incidence and type of adverse events (AEs) was similar across the dutasteride, placebo, and finasteride treatment groups. Details of preclinical and clinical studies can be found in the Dutasteride Investigator Brochure, v07 [GlaxoSmithKline Document Number GM1999/00294/07] Tamsulosin Tamsulosin (Flomax) is an alpha-1-adrenocepter blocking agent approved for the treatment of signs and symptoms of benign prostatic hyperplasia. ZM2008/00081/00 In GSK study ARI10021, the bioequivalence of Flomax or Omnic (tamsulosin HCl formulations marketed in U.S. and Germany, respectively) was assessed in 27 healthy male subjects (age 18-45) in an open-label, two-way crossover study. In this study, 2 of 27 (7%) subjects experienced drug-related syncope of one minute duration occurring 4-8 hours following administration of tamsulosin 0.4 mg, and one subject experienced a nondrug related vaso-vagal event one hour after dosing which lasted 6 minutes [Study ARI10021, GlaxoSmithKline Document Number JM2004/00005/00]. In two U.S. placebo-controlled Flomax trials, the incidence of syncope was 0.2% (1 of 502) of patients taking Flomax 0.4 mg and 0.6% (3 of 493) of patients taking placebo [Flomax Package Insert, 2007]

259 ZM2007/00164/00 CONFIDENTIAL CONFIDENTIAL ZM2007/00164/00 Safety data from two U.S. placebo-controlled trials show the most common treatment emergent adverse drug reactions (>5%) when Flomax was given as 0.4 mg daily were: headache (19.3%), dizziness (14.9%), rhinitis (13.1%), infection (9.0%), abnormal ejaculation (8.4%), asthenia (7.8%), back pain (7.0%), diarrhea (6.2%) and pharyngitis (5.8%) [Flomax Package Insert, 2007] Rationale Study Rationale To support the product label for the combination dutasteride/tamsulosin hydrochloride product, there is one ongoing bioequivalence study [Study ARI109882, GlaxoSmithKline Document Number ZM2007/00022/00] and another bioequivalence study planned [Study ARI110282, GlaxoSmithKline Document Number ZM2007/00036/00] to evaluate the combination of dutasteride and a 10% and 15% enteric coated formulations of tamsulosin, respectively. Depending on the results of the ongoing studies as well as the results of ongoing formulation development work, the decision will be made to move forward with either the 10% or the 15% enteric coated formulation of tamsulosin in the combination capsule. This current study will establish bioequivalence of the 10% enteric coated tamsulosin in the combination product and the 15% enteric coated tamsulosin in the modified combination product relative to concomitant dosing with separate capsules of dutasteride and tamsulosin commercial formulations at steady state, with respect to tamsulosin. There is concern that tamsulosin may accumulate after repeat dosing, therefore, this study will establish bioequivalence at steady state of tamsulosin only Dose Rationale ZM2008/00081/00 Dutasteride 0.5 mg and tamsulosin hydrochloride 0.4 mg are the lowest available dosage forms, as well as the starting doses for therapy, approved in the U.S. for the treatment of males with symptomatic benign prostatic hyperplasia, and therefore are the doses being employed in this study. In a healthy volunteer study, single doses of dutasteride up to 40 mg/day (80 times the therapeutic dose) for 7 days have been administered without significant safety concerns [Study ARI10019, GlaxoSmithKline Document Number RM2001/00128/01]. It is therefore expected that the dose of dutasteride administered in this study (0.5 mg) will be safe. The dose of tamsulosin for this study (0.4 mg) has been administered to healthy volunteers in previous studies and found to be safe and well-tolerated [Study ARI106263, GlaxoSmithKline Document Number ZM2007/00042/00]. It is therefore expected to be safe to administer to the volunteers in this study

260 ZM2007/00164/00 CONFIDENTIAL CONFIDENTIAL ZM2007/00164/00 The pharmacokinetic and pharmacodynamic interaction of tamsulosin on dutasteride was assessed in study ARIA1011. There were no differences in PK parameters when tamsulosin was given individually or concomitantly with dutasteride, levels of DHT were reduced 93% from baseline when these drugs were given concomitantly and testosterone increased 21% from baseline when these drugs were given concomitantly [Study ARIA1011, GlaxoSmithKline Document Number RM1999/00360/00]. Due to the long half life of dutasteride and evidence that a drug interaction is unlikely, a study to determine the effects of tamsulosin on dutasteride is not planned at this time. Dutasteride is a substrate of CYP3A4/5, but there are no data which suggest that tamsulosin will inhibit either of these enzymes. This makes a drug-drug interaction between tamsulosin and dutasteride unlikely [Dutasteride Investigator Brochure, 2007, GlaxoSmithKline Document Number GM1999/00294/07], [Flomax Package Insert, 2007] Risk Assessment Because tamsulosin can cause orthostasis [Flomax Package Insert, 2007], orthostatic vital sign measurements will be taken at the times indicated in the Time and Events Table (Section 4.4). If a subject is found to have protocol-defined orthostasis (see Section 7.2), that subject may be treated at the discretion of the investigator. Dutasteride is Pregnancy Category X and therefore will not be administered to female subjects and should not be handled by women who are pregnant or who could become pregnant. Men must agree to the contraception requirements in Section 8.1 and may not donate blood for 6 months after the final dose of study medication to avoid a blood transfusion to pregnant females. 2. OBJECTIVE(S) 2.1. Primary 1. To investigate the bioequivalence of tamsulosin at steady state of a Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg under fasting conditions. 2. To investigate the bioequivalence of tamsulosin at steady state of a Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg under fasting conditions Secondary ZM2008/00081/00 1. To assess the safety and tolerability of dosing with the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg, the Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg, and concomitant dosing of AVODART 0.5 mg and the U.S.- sourced Flomax 0.4 mg

261 ZM2007/00164/00 CONFIDENTIAL 3. ENDPOINT(S) 3.1. Primary CONFIDENTIAL ZM2007/00164/00 1. AUC (0-24) and Cmax of tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg after a single dose and at steady state. 2. AUC (0-24) and Cmax of tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg after a single dose and at steady state. 3. AUC (0-24) and Cmax of tamsulosin in concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg Secondary 1. C(tau) (defined as the concentration at 24 hours after the Day 7 dose), t1/2, tmax, λ, Cmin and fluctuation [(Cmax Cmin)/(AUC(0-24)/24)] of tamsulosin, as data permit. 2. Safety and tolerability of all treatments as assessed by blood pressure and pulse rate measurements, adverse events and clinical laboratory safety tests. 4. STUDY DESIGN 4.1. Design Description ZM2008/00081/00 This will be an open-label, randomized, repeat dose, 3 period crossover study in healthy males. Each subject will receive one of the three treatment regimens in each dosing session. There will be an approximately 5-7 day washout between dosing of each session. Subjects will participate in 3 dosing sessions. In order to minimize the potential impact of genetic variability to the pharmacokinetics of tamsulosin, poor CYP2D6 metabolizers will be excluded from this study. Eligible subjects will be admitted to the research unit the evening prior to dosing (Day -1) and will remain in the unit until approximately 48 hours after dosing on Day 7. The subjects will return to the research unit for an outpatient visit at approximately 72 hours post-dose Day 7 after each treatment session. On days when full PK sampling will take place (Days 1 and 7) subjects will be fasted for 10 hours prior to drug administration and for 4 hours after. Subjects will undergo a washout period of approximately 5-7 days after the last dose in each treatment session. Subjects will return to the research unit approximately days after the last dose for follow-up and will be subsequently discharged from the study. The total duration of each subject's participation from screening to follow-up will be approximately 8-13 weeks

262 ZM2007/00164/00 CONFIDENTIAL 4.2. Treatment Assignment CONFIDENTIAL ZM2007/00164/00 Subjects will be assigned to ABC, ACB, BAC, BCA, CAB, or CBA in accordance with the randomization schedule generated by Discovery Biometrics, prior to the start of the study, using validated internal software (RandAll). A description of each regimen is provided in Table 1: ZM2008/00081/00 Table 1 Regimen A B C Study Medication Dosing Treatments Description Dutasteride and Tamsulosin Hydrochloride Modified Combination Capsule, 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride (test) Dutasteride and Tamsulosin Hydrochloride Modified Combination Capsule, 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride (test) Flomax 0.4 mg (sustained release capsule commercially available in United States) and AVODART 0.5 mg (reference) Once a randomization number has been assigned to a subject, it cannot be re-assigned to any other subject at the site. Withdrawn subjects may be replaced at the discretion of GSK to ensure the required number of subjects complete the study. In the event that a withdrawn subject is replaced, the replacement subject will be assigned to the same treatment sequence Investigational Product Dosage/Administration Product name: Formulation description: Investigational Product (IP) Dutasteride and Tamsulosin (10%) Hydrochloride Combination Capsules Dutasteride Soft Gelatin Capsule (300 mg Capmul) overencapsulated with Tamsulosin HCl Pellets, 0.224% w/w in an orange/brown hypromellose capsule shell (size 00). Dutasteride and Tamsulosin (15%) Hydrochloride Combination Capsules Dutasteride Soft Gelatin Capsule (300 mg Capmul) overencapsulated with Tamsulosin HCl Pellets, 0.214% w/w in an orange/brown hypromellose capsule shell (size 00). AVODART Commercial product formulation without print. Flomax Commercial product. Continued 14 14

263 ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL ZM2007/00164/ Investigational Product Dosage/Administration (Continued) Product name: Batch Numbers: Investigational Product (IP) Dutasteride and Dutasteride and Tamsulosin (10%) Tamsulosin (15%) Hydrochloride Hydrochloride Combination Combination Capsules Capsules Bulk drug: Bulk drug: AVODART Bulk drug: Flomax Packaged product: Comet: Packaged product: Comet: Packaged product: Comet: Dosage form: Capsule Capsule Capsule Capsule Unit dose 0.5 mg dutasteride, 0.5 mg dutasteride, strength(s)/dosage 0.4 mg tamsulosin 0.4 mg tamsulosin level(s): hydrochloride hydrochloride Route/ Administration/ Duration: Dosing instructions: Physical description: Manufacturer/ source of procurement: Administer orally, daily for 7 days Study medication will be administered by study personnel on the dosing days with 240 ml of water. On Days 1 and 7, drug will be administered in the fasted state. On all other days, drug will be administered ~30 minutes after the start of a standard low-fat breakfast. Capsules have orange cap and brown body; capsules are imprinted with GS 7CZ in black ink on the cap. PLEASE NOTE: Combination capsules have the SAME imprint code. Administer orally, daily for 7 days Study medication will be administered by study personnel on the dosing days with 240 ml of water. On Days 1 and 7, drug will be administered in the fasted state. On all other days, drug will be administered ~30 minutes after the start of a standard low-fat breakfast. Capsules have orange cap and brown body; capsules are imprinted with GS 7CZ in black ink on the cap. PLEASE NOTE: Combination capsules have the SAME imprint code. 0.5 mg dutasteride 0.4 mg tamsulosin HCl Administer orally, daily for 7 days Study medication will be administered by study personnel on the dosing days with 240 ml of water. On Days 1 and 7, drug will be administered in the fasted state. On all other days, drug will be administered ~30 minutes after the start of a standard low-fat breakfast. Oblong, dull yellow, soft gelatin capsules identical to the commercially available AVODART except plain (no print). Administer orally, daily for 7 days Study medication will be administered by study personnel on the dosing days with 240 ml of water. On Days 1 and 7, drug will be administered in the fasted state. On all other days, drug will be administered ~30 minutes after the start of a standard low-fat breakfast. Elongated hard gelatin capsules with an olive green cap and orange body imprinted on one side with Flomax 0.4mg and on the other side with BI 58 in black ink. GSK GSK GSK Boehringer Ingleheim; Commercial product sourced by GSK

264 CONFIDENTIAL ZM2007/00164/ Time and Events Table Procedure / Time (hrs) Screen Day -1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 (up to 30 days prior to Day 1) Visit (V); Admission (A); Discharge (DC) Informed Consent X Medical History X Medication/Concomitant Med V A DC V V X X X History Demographics X Full Physical Exam X X Clinical Laboratory Tests X X X Serology for HIV, Hep B and X Hep C 2D6 Pharmacogenetic Typing X Drug and Alcohol Screen X X 1 Vital Signs X 2 X 3 X 3 X 3 X 3 X 3 X 2 X X X X Orthostatic Vital Signs X X 4 X 4 12-Lead ECG X X Baseline Signs & Symptoms/Adverse Events X X X X X X X X X X X X X Administer Study Drug X X X X X X X Subjects to remain semirecumbent X 5 X 5 Meals 6 X X 7 X X X X X X 7 X X X 8 Pharmacokinetic Blood Sample X 9 X 10 X 10 X 10 X 10 X 10 X 9 X 11 X 11 X Follow Up (10-14 days postlast dose) ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/00

265 Time and Events Table (Continued) 1. Drug and alcohol screen must be negative prior to dosing 2. To be taken within 1 hour prior to dosing and at 2 and 4 hours post dose 3. To be taken within 1 hour prior to dosing 4. To be taken at 6 hours post-dose 5. Subjects to remain semi-recumbent for 6 hours post-dose 6. Meals should be served at approximately the same time on all days. Please refer to Section 8.2 for more details. 7. Subjects will not receive breakfast 8. Meals are optional 9. PK sample times: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 16 hour post-dose 10. Pre-dose sample only 11. PK sample times: 24, 36, 48, 72 hours post-dose CONFIDENTIAL ZM2007/00164/00 ZM2007/00164/00 CONFIDENTIAL 17 ZM2008/00081/00

266 ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL ZM2007/00164/00 5. STUDY POPULATION 5.1. Number of Subjects Approximately 24 subjects will be enrolled such that approximately 16 subjects complete dosing and critical assessments Eligibility Criteria Inclusion Criteria A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Subjects with orthostasis at screening should be excluded from enrollment. 1. Males between 18 and 45 years of age (inclusive). 2. Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until follow-up from the study. 3. Body weight 55 kg and BMI within the range kg/m2 (inclusive). 4. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. 5. QTcB or QTcF < 450 msec. 6. Subjects must agree not to donate blood and blood products for 6 months after the last dose of study medication Exclusion Criteria A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1. The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines. 2. Slow metabolizer for CYP2D6 as determined by screening PGx analysis. 3. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening

267 ZM2007/00164/00 CONFIDENTIAL 4. A positive test for HIV antibody. CONFIDENTIAL ZM2007/00164/00 5. History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 drinks/week. One drink is equivalent to: 12 g alcohol = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits. 6. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). 7. Exposure to more than four new chemical entities within 12 months prior to the first dosing day. 8. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John s Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication and until collection of the final PK sample from the study, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. 9. History of sensitivity to any of the study medications, or components thereof, including sulfonamides, or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. 10. History of postural hypotension, dizziness, poor hydration, vertigo, vaso-vagal reactions or any other signs and symptoms of orthostasis, which in the opinion of the investigator could be exacerbated by tamsulosin and result in putting the subject at risk of injury. 11. Orthostatic hypotension at screening, defined as a reduction in systolic blood pressure of 20 mmhg or more and/or a reduction in diastolic blood pressure of 10 mmhg or more for standing vs. supine measurements. 12. Where participation in the study would result in donation of blood or blood products in excess of 500 ml within a 56 day period. 13. Unwillingness or inability to follow the procedures outlined in the protocol. 14. History of sensitivity to heparin or heparin-induced thrombocytopenia. ZM2008/00081/ Consumption of red wine, seville oranges, grapefruit, grapefruit juice or cruciferous vegetables (watercress, broccoli, cabbage, Brussels sprouts) from 7 days prior to the first dose of study medication and until collection of the final PK sample in the study

268 ZM2007/00164/00 CONFIDENTIAL Other Eligibility Criteria Considerations CONFIDENTIAL ZM2007/00164/00 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: [Dutasteride Investigator Brochure v07 dated 14-Aug-2007 GlaxoSmithKline Document Number GM1999/00294/07], and the approved product label for tamsulosin HCl (Flomax) [Flomax Package Insert, 2007] and dutasteride (AVODART) [AVODART Package Insert, 2007]. 6. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 6.1. Hypotheses and Treatment Comparisons Bioequivalence This study is designed to test the bioequivalence of regimen A - tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg (test) and regimen B - tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg (test) relative to regimen C - concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg (reference) at steady state. The null hypothesis is that the true ratio of the geometric mean of the test treatment to the geometric mean of the reference treatment, µ(test)/µ(reference), for AUC(0-24), is either less than 0.80 or greater than The alternate hypothesis is that the true ratio of the test treatment geometric mean to the reference treatment geometric mean is at least 0.80 and no greater than Symbolically, this is expressed as follows: H(0): µ(test)/µ(reference) < 0.80 or µ(test)/µ(reference) > 1.25, i.e., treatments are not bioequivalent. Versus H(1) : 0.80 µ(test)/µ(reference) 1.25, i.e., treatments are bioequivalent. ZM2008/00081/00 For PK parameter AUC(0-24), a two one-sided t-test (TOST) procedure [Schuirmann, 1987] with α=0.05 for each one-sided test will be used to test this set of hypotheses. This is equivalent to requiring that a 90% interval for the true ratio of test to reference geometric means falls entirely within the range of 0.80 to

269 ZM2007/00164/00 CONFIDENTIAL 6.2. Sample Size Considerations Sample Size Assumptions CONFIDENTIAL ZM2007/00164/00 The table below summarizes the observed estimates of within subject CV and observed ratio of geometric means for the primary endpoints AUC(0-t) and Cmax from the first pilot study of Synthon: CVw: within subject Point Estimate (PE) of Ratio Cmax 16.13% 1.04 AUC(0-t) 11.65% 0.98 The within subject CV estimate, 11.65% for AUC(0-t), translates to a standard deviation (SD) of 0.12 on the natural log scale. Based on this SD, a sample size of 16 statistically evaluable subjects will have at least 90% power to demonstrate bioequivalence. This calculation assumes: a true ratio of 1, the within-subject variability from the current study will not be larger than that used in the sample size calculations, data are log-normally distributed, and each t-test is made at the 5% level Sample Size Sensitivity A sensitivity analysis was conducted in the event that the variability is greater than expected and the point estimate of ratio is not 1. Based on the first pilot study from Synthon, the upper bound of 90% confidence interval of CVw% for AUC(0-t) of tamsulosin (details on file, GSK) is 15.6%. With a sample size of 16 subjects, the power to conclude bioequivalence of AUC(0-t) is still over 90% assuming the point estimate of the ratio is Sample Size Re-estimation No sample size re-estimation will be performed Data Analysis Considerations Interim Analysis No interim analysis is planned. ZM2008/00081/

270 ZM2007/00164/00 CONFIDENTIAL Final Analyses ZM2008/00081/00 CONFIDENTIAL ZM2007/00164/ Safety Analyses Safety data will be presented in tabular and/or graphical format and summarized descriptively according to GSK s Integrated Data Standards Library (IDSL) standards Pharmacokinetic Analyses Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics Modeling and Simulation Department, CPDM, GlaxoSmithKline. Plasma tamsulosin concentration-time data will be analyzed by non-compartmental methods with WinNonlin [4.1]. Calculations will be based on the actual sampling times recorded during the study. From the plasma concentration-time data, the following pharmacokinetic parameters will be determined, as data permit: Day 1: AUC(0-24), Cmax, tmax, Day 7: AUC(0-24)ss, Cmax,ss. Tmax,ss, t½ Trough concentration (Cτ) samples collected on the specified days may be used to assess attainment of steady state. To estimate the extent of accumulation after repeat dosing, the observed accumulation ratio (Ro) will be determined. R 0 = AUC( 0 τ ) AUC( 0 τ ) ss SD Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively according to the following guidance document from Health Canada: GUIDANCE FOR INDUSTRY Conduct and Analysis of Bioavailability andbioequivalence Studies - Part B: Oral Modified Release Formulations (1996). All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D. Statistical analyses of the pharmacokinetic parameter data will be the responsibility of Discovery Biometrics, GlaxoSmithKline. Steady state will be checked with C(tau) data (the last three pre-dose concentrations) as indicated in the guidance document from Health Canada. Following loge-transformation, AUC(0-24) Cmax, and Cmin of tamsulosin will be separately analyzed using a mixed effects model with fixed effect terms for sequence, period and regimen. Subject within sequence will be treated as a random effect in the model. Point estimates and their associated 90% confidence intervals will be constructed for the differences, [A- C and B - C]. The point estimates and their associated 90% confidence intervals will then be back-transformed to provide point estimates and 90% confidence intervals for the ratios, [A:C and B:C]. Results corrected for measured drug content will also be presented

271 ZM2007/00164/00 CONFIDENTIAL CONFIDENTIAL ZM2007/00164/00 Tmax and fluctuation of tamsulosin will be analysed using the same model as above with data in raw scale and the point estimates and their associated 90% confidence intervals will be constructed for the differences, [A- C and B - C]. 7. STUDY ASSESSMENTS AND PROCEDURES This section lists the parameters of each planned study assessment. The exact timing of each assessment is listed in the Time and Events Table (Section 4.4). Detailed procedures for obtaining each assessment are provided in the Study Procedures Manual (SPM). Whenever vitals signs, 12-lead ECGs and blood draws are scheduled for the same nominal time, the 12-lead ECG will be obtained first, followed by vital signs and then blood draws (with the blood draw occurring at the planned nominal time). The timing and number of planned study assessments, including safety and pharmacokinetic assessments may be altered during the course of the study based on newly available data (e.g. to obtain data closer to the time of peak serum concentrations) to ensure appropriate monitoring. The change in timing or addition of time points for any planned study assessments must be approved and documented by GSK, but this will not constitute a protocol amendment. The IRB will be informed of any safety issues that require alteration of the safety monitoring scheme. No more than 500 ml of blood will be collected over the duration of the study, including any extra assessments that may be required Demographic/Medical History Assessments The following demographic parameters will be captured: date of birth, gender, race and ethnicity. Medical/medication/alcohol history will be assessed as related to the eligibility criteria listed in Section Safety Planned timepoints for all safety assessments are listed in the Time and Events Table (Section 4.4). Additional time points for safety tests (such as vital signs, physical exams and laboratory safety tests) may be added during the course of the study based on newly available data to ensure appropriate safety monitoring. Physical Exams ZM2008/00081/00 A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. Height and weight will also be measured and recorded

272 ZM2007/00164/00 CONFIDENTIAL Vital Signs CONFIDENTIAL ZM2007/00164/00 Vital sign measurements will include supine systolic and diastolic blood pressure and pulse rate. Orthostatic Vital Signs Orthostatic vital signs will be taken at the time points outlined in Section 4.4, Time and Events Table and will include supine and standing blood pressure and heart rate. In order to obtain orthostatic vital signs, patients will undergo the procedures defined in the SPM. Subjects meeting the following criteria assessed during orthostatic testing (from supine to standing) will have protocol defined orthostatic hypotension: a decrease in systolic blood pressure of > 20mmHg, or a decrease in diastolic blood pressure > 10mmHg, or any symptoms of faintness, light headedness, dizziness, spinning sensation, or vertigo If orthostatic hypotension occurs, it should be treated at the discretion of the investigator. All readings will be recorded in the CRF. Electrocardiogram (ECG) Single 12-lead ECGs will be obtained at screening and follow-up from the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. Subjects are required to rest for at least 5 minutes before the ECG is recorded. Clinical Laboratory Assessments Hematology, clinical chemistry and urinalysis parameters to be tested are listed below: Hematology Platelet Count RBC Indices: Automated WBC Differential: RBC Count MCV Neutrophils WBC Count (absolute) MCH Lymphocytes Hemoglobin MCHC Monocytes Eosinophils Basophils ZM2008/00081/00 Clinical Chemistry BUN Potassium AST (SGOT) Total and direct bilirubin Creatinine Chloride ALT (SGPT) Glucose, fasting Total CO 2 GGT Albumin (Screening only) Sodium Calcium Alkaline phosphatase Total Protein (Screening only) 24 24

273 ZM2007/00164/00 CONFIDENTIAL Routine Urinalysis Specific gravity ph, glucose, protein, blood and ketones by dipstick Microscopic examination (if blood or protein is abnormal) ZM2008/00081/00 CONFIDENTIAL ZM2007/00164/00 Other tests (Screening Visit Only) HIV Hepatitis B (HBsAg) Hepatitis C (Hep C antibody -- if second generation Hepatitis C antibody positive, a hepatitis C antibody Chiron RIBA immunoblot assay should be reflexively performed on the same sample to confirm the result) 7.3. Pregnancy Time period for collecting pregnancy information All pregnancies in female partners of male subjects will be collected after the start of dosing and until follow-up from the study Action to be taken if pregnancy occurs in a female partner of a male study subject The investigator will attempt to collect pregnancy information on any female partner of a male study subject who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of the partner s pregnancy. The partner 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 Pharmacokinetics Blood Sample Collection Blood samples for pharmacokinetic analysis of tamsulosin will be collected at the time points indicated in Section 4.4, Time and Events Table. The actual date and time of each blood sample collection will be recorded. The timing of PK samples may be altered and/or PK samples may be obtained at additional time points to ensure thorough PK monitoring. Details of PK blood sample collection (including volume to be collected), processing, storage and shipping procedures are provided in the Study Procedures Manual (SPM)

274 ZM2007/00164/00 CONFIDENTIAL Sample Analysis CONFIDENTIAL ZM2007/00164/00 Serum analysis will be performed under the management of Worldwide Bioanalysis, DMPK, GlaxoSmithKline. Concentrations of tamsulosin will be determined in serum samples using the currently approved analytical methodology. Raw data will be stored in the GLP Archives, GlaxoSmithKline. Once the serum has been analyzed for tamsulosin, any remaining serum may be analyzed qualitatively for other circulating metabolites and the results reported under a separate DMPK protocol. 8. LIFESTYLE AND/OR DIETARY RESTRICTIONS 8.1. Contraception Requirements Male subjects must be willing to abstain from or use a condom during sexual intercourse with a pregnant or lactating female. Subjects must also use a condom with spermicide, plus another form of contraception (e.g., IUD, birth control pills taken by female partner, tubal ligation or diaphragm with spermicide) if engaging in sexual intercourse with a woman who could become pregnant. Male subjects must adhere to these contraceptive criteria from administration of the first dose of study medication until follow-up from the study. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring subjects understand how to properly use these methods of contraception 8.2. Meals and Dietary Restrictions Subjects will be required to fast for approximately 10 hours prior to the start of breakfast (Days 2-6 and 8-10) or prior to dosing (Days 1 and 7), with the exception of water, which will be allowed freely except for 1 hour before and 1 hour after dosing. Subjects will be given breakfast on Days 2-6 and Days 8, 9 and 10 (Day 10 is optional). Subjects will be given approximately 25 minutes to complete breakfast and must finish within this 25 minute period. Administration of study medication will occur approximately 30 minutes after the start of breakfast. Subjects should receive a standard low-fat breakfast on these days. Subjects will not receive breakfast on Days 1 and 7. ZM2008/00081/00 Following dosing, subjects will not be allowed food until 4 hours post dose. Meals will be served as outlined in the Time and Events Table (Section 4.4). Meals will be served at approximately the same time on each day. Meals on Day 10 are optional

275 ZM2007/00164/00 CONFIDENTIAL CONFIDENTIAL ZM2007/00164/00 Subjects will not be allowed to consume the following foods or drinks within 7 days prior to the first dose of study medication until after collection of the final pharmacokinetic blood sample has been collected for the study: grapefruit juice; red wine; seville oranges; grapefruit or cruciferous vegetables (watercress, broccoli, cabbage, Brussels sprouts) Caffeine, Alcohol, and Tobacco During each dosing session, subjects will abstain from ingesting caffeine- or xanthinecontaining products (e.g. coffee, tea, cola drinks, chocolate) for 24 hours prior to the start of dosing until collection of the final pharmacokinetic sample during each session. During each dosing session, subjects will abstain from alcohol for 24 hours prior to the start of dosing until collection of the final pharmacokinetic during each session. Subjects who use tobacco products will be instructed that use of nicotine-containing products (including nicotine patches) will not be permitted while they are in the Clinical Unit Activity Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection for clinical laboratory tests. Subjects may participate in light recreational activities during studies (e.g., watch television, read) Subjects will be required to remain semi-recumbent for 6 hours post-dose on Day 1 and Day 7 of each dosing session. 9. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES 9.1. Permitted Medications Acetaminophen, at doses of 2 grams/day is permitted. Other concomitant medication may be considered on a case by case basis by the GSK Medical Monitor Prohibited Medications ZM2008/00081/00 Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until the collection of the final PK sample from the study, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study

276 ZM2007/00164/00 CONFIDENTIAL 9.3. Non-Drug Therapies CONFIDENTIAL ZM2007/00164/00 Subjects must abstain from taking any vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until the collection of the final PK sample from the study, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study. 10. COMPLETION OR EARLY WITHDRAWAL OF SUBJECTS Subject Completion A completed subject is one who has completed Sessions 1, 2 and Subject Withdrawal Criteria A subject may withdraw from investigational product at any time at his/her own request, or may be withdrawn at any time at the discretion of the investigator for safety, behavioral or administrative reasons Subject Withdrawal Procedures For subjects withdrawn from the study, the following should be performed if appropriate: 12-lead ECG, clinical safety labs and AE assessment. Relevant sections of the CRF will be completed by the Investigator (or designated staff) Treatment After the End of the Study This is not a therapeutic study; therefore, subjects will not receive any additional treatment after completion of the study Screen and Baseline Failures Data for screen and baseline failures will not be collected. 11. INVESTIGATIONAL PRODUCT(S) Investigational product dosage and administration details are listed in Section Blinding This will be an open-label study. ZM2008/00081/

277 ZM2007/00164/00 CONFIDENTIAL Packaging and Labeling CONFIDENTIAL ZM2007/00164/00 The contents of the label will be in accordance with all applicable regulatory requirements Preparation/Handling/Storage/Accountability No special preparation of investigational product is required. Investigational product should not be handled by women who are pregnant or who could become pregnant due to potential risk of fetal anomaly in a male fetus. Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product. Only authorized site staff (site staff trained to administer investigational product in accordance with the site s SOPs) 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. Investigational product is to be stored at stored up to 25 C (77 F). Maintenance of a temperature log (manual or automated) is required. The investigator, institution, or the head of the medical institution (where applicable) is responsible for investigational product accountability, reconciliation, and record maintenance. The investigator or the head of the medical institution (where applicable), or designated site staff (e.g., storage manager, where applicable) must maintain investigational product accountability records throughout the course of the study. The responsible person(s) will document the amount of investigational product received from and returned to GSK and the amount administered to the subjects. The required accountability unit for this study will be capsules. Discrepancies are to be reconciled or resolved. Procedures for final disposition of unused investigational product are listed in the SPM. Investigational product is not expected to pose significant occupational safety risk to site staff under normal conditions of use and administration. A Material Safety Data Sheet (MSDS)/equivalent document 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 Bioequivalence Retention Samples ZM2008/00081/00 As this study is a pivotal bioequivalence study, sufficient additional clinical supplies of test and reference study drugs will be provided to the clinical study sites to allow for retention samples, per FDA regulations [FDA/CDER Guidance for Industry, 2004}. Refer to the SPM for details regarding the selection and storage of these bioequivalence retention samples

278 ZM2007/00164/00 CONFIDENTIAL Assessment of Compliance CONFIDENTIAL ZM2007/00164/00 When subjects are dosed at the study site, they will receive investigational products directly from the investigator or designee, under medical supervision. The date and time of each dose administered in the clinic will be recorded in the source documents. The dose of investigational product(s) will be confirmed prior to dosing by a member of the study site staff other than the person administering the investigational product. Study site personnel will examine each subject s mouth to ensure that the investigational product was ingested Treatment of Investigational Product Overdose For this study, any dose of dutasteride > 0.5 mg or tamsulosin > 0.4 mg within a 24 hour time period [±1 hour] will be considered an overdose. GSK does not recommend specific treatment for an overdose. The investigator will use clinical judgment to treat any overdose. 12. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ZM2008/00081/00 The investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE. AEs will be collected from the start of Investigational Product and until the follow-up contact. Medical occurrences that begin prior to the start of investigational product but after obtaining informed consent may be recorded on the Medical History/Current Medical Conditions CRF. SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g. investigational product, protocolmandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact. All SAEs will be recorded and reported to GSK within 24 hours, as indicated in Section 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 or study participation, the investigator would promptly notify GSK

279 ZM2007/00164/00 CONFIDENTIAL Definition of Adverse Events CONFIDENTIAL ZM2007/00164/00 An AE is 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. Note: 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. Events meeting the definition of an AE include: Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator. 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 concomitant medication (overdose per se will not be reported as an AE/SAE). Events that do not meet the definition of an AE include: Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject s condition. 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 Definition of Serious Adverse Events ZM2008/00081/00 If an event is not an AE per Section 12.1, then it can not be an SAE even if serious conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of disease, etc)

280 ZM2007/00164/00 CONFIDENTIAL An SAE is any untoward medical occurrence that, at any dose: CONFIDENTIAL ZM2007/00164/00 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 ZM2008/00081/00 f. Medical or scientific judgment 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

281 ZM2007/00164/00 CONFIDENTIAL Method of Detecting AEs and SAEs CONFIDENTIAL ZM2007/00164/00 Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. Appropriate questions include: How are you feeling? Have you had any (other) medical problems since your last visit/contact? Have you taken any new medicines, other than those provided in this study, since your last visit/contact? 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 AE/SAE in the appropriate data collection tool. It is not acceptable for the investigator to send photocopies of the subject s medical records to GSK in lieu of completion of the GSK, AE/SAE data collection tool. However, there may be instances when copies of medical records for certain cases are requested by GSK. In this instance, all subject identifiers, with the exception of the subject number, 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 will 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 and will assign it 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. ZM2008/00081/

282 ZM2007/00164/00 CONFIDENTIAL CONFIDENTIAL ZM2007/00164/00 An AE that is assessed as severe will not be confused with an 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 at least one of the predefined outcomes as described in the definition of an SAE Assessment of Causality The investigator is obligated to assess the relationship between investigational product and the occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. The investigator will use clinical judgment 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 Investigator Brochure (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 the initial transmission of the SAE data to GSK. The investigator may change his/her opinion of causality in light of follow-up information, amending the SAE data collection tool accordingly. The causality assessment is one of the criteria used when determining regulatory reporting requirements Follow-up of AEs and SAEs ZM2008/00081/00 After the initial AE/SAE report, the investigator is required to proactively follow each subject 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. The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as fully as possible the nature and/or causality of the AE or SAE. The investigator is obligated to assist. This may include additional laboratory tests or investigations, histopathological examinations or consultation with other health care professionals. If a subject dies during participation in the study or during a recognized follow-up period, the investigator will provide GSK with a copy of any post-mortem findings, including histopathology. New or updated information will be recorded in the originally completed data collection tool. The investigator will submit any updated SAE data to GSK within the designated reporting time frames

283 ZM2007/00164/00 CONFIDENTIAL Prompt Reporting of SAEs to GSK CONFIDENTIAL ZM2007/00164/00 Once the investigator determines that an event meets the protocol definition of an SAE, the SAE will be reported to GSK within 24 hours. Any follow-up information on a previously reported SAE will also be reported to GSK within 24 hours. 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 appropriate data collection tool. The investigator will always provide an assessment of causality at the time of the initial report as described in Section , Assessment of Causality. The primary mechanism for reporting SAEs to GSK will be the electronic data collection tool (e.g., InForm system). If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE data collection tool and fax it to the GSK Medical Monitor. Then the site will enter the serious adverse event data into the electronic system as soon as it becomes available. After the study is completed at a given site, the electronic data collection tool (e.g., InForm system) will be taken off-line to prevent the entry of new data or changes to existing data. If a site receives a report of a new SAE from a study participant or receives updated data on a previously reported SAE after the electronic data collection tool has been taken off-line, the site can report this information on a paper SAE form or to their GSK protocol contact by telephone. GSK contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical Monitor Contact Information page Regulatory Reporting Requirements For SAEs Prompt notification of SAEs by the investigator to GSK is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met. ZM2008/00081/00 GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. GSK will comply with country specific regulatory requirements relating to safety reporting to regulatory authorities, IRBs and investigators. Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to investigators as necessary. An investigator who receives an investigator safety report describing an SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the IRB, if appropriate according to local requirements

284 ZM2007/00164/00 CONFIDENTIAL CONFIDENTIAL ZM2007/00164/ STUDY CONDUCT CONSIDERATIONS Regulatory and Ethical Considerations, Including the Informed Consent Process GSK will obtain favorable opinion/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. The study will be conducted in accordance with all applicable regulatory requirements, including an U.S. IND. The study will also be conducted in accordance with "good clinical practice" (GCP), all applicable subject privacy requirements, and, the guiding principles of the Declaration of Helsinki. This includes, but is not limited to, the following: IRB review and favorable opinion/approval to conduct the study and of any subsequent relevant amended documents Written informed consent (and any amendments) to be obtained for each subject before participation in the study Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB) Quality Control (Study Monitoring) In accordance with applicable regulations including GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will also include identification, agreement and documentation of data items for which the CRF will serve as the source document. GSK will monitor the study and site activity to verify that the: ZM2008/00081/00 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 other study agreements, GCP, and all applicable regulatory requirements. The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents 36 36

285 ZM2007/00164/00 CONFIDENTIAL Quality Assurance CONFIDENTIAL ZM2007/00164/00 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 Study and Site Closure Upon completion or premature discontinuation of the study, the monitor will conduct site closure activities with the investigator or site staff, as appropriate, in accordance with applicable regulations including GCP, and GSK procedures. In addition, GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. For multicenter studies, this can occur at one or more or at all sites. If GSK determines such action is needed, GSK will discuss this with the investigator or the head of the medical institution (where applicable), including the reasons for taking such action. When feasible, GSK will provide advance notification to the investigator or the head of the medical institution, where applicable, of the impending action prior to it taking effect. If the study is suspended or prematurely discontinued for safety reasons, GSK will promptly inform investigators or the head of the medical institution (where applicable) and the regulatory authorities of the suspension or premature discontinuation of the study and the reason(s) for the action. If required by applicable regulations, the investigator or the head of the medical institution (where applicable) must inform the IRB promptly and provide the reason for the suspension or premature discontinuation Records Retention ZM2008/00081/00 Following closure of the study, the investigator or the head of the medical institution (where applicable) must maintain all site study records, except for those required by local regulations to be maintained by someone else, 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 ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions

286 ZM2007/00164/00 CONFIDENTIAL CONFIDENTIAL ZM2007/00164/00 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, archival at an off-site facility or transfer of ownership of the records in the event the investigator leaves the site Provision of Study Results and Information to Investigators When required by applicable regulations, the investigator signatory for the clinical study report will be determined at the time the report is written. When the clinical study report is completed, GSK will provide the investigator with a full summary of the study results. The investigator is encouraged to share the summary results with the subjects, as appropriate. In addition, the investigator will be given reasonable access to review the relevant statistical tables, figures, and reports and will be able to review the results for the entire study at a GSK site or other mutually agreeable location. GSK will provide the investigator with the randomization codes for their site after the statistical analysis for the entire study has been completed Data Management ZM2008/00081/00 GSK Data Management will identify and implement the most effective data acquisition and management strategy for each clinical trial protocol and deliver datasets which support the protocol objectives. Subject data will be entered into GSK defined CRFs and combined with data provided from other sources (e.g. diary data, laboratory data) in a validated data system. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures with the objective of removing errors and inconsistencies in the data which would otherwise impact on the analysis and reporting objectives, or the credibility of the Clinical Study Report. Adverse events and concomitant medications terms will be coded using validated dictionaries. Original CRFs will be retained by GSK, while the investigator will retain a copy. In all cases, subject initials will not be collected nor transmitted to GSK

287 ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL ZM2007/00164/ REFERENCES AVODART (Dutasteride) Product Information. October FDA/CDER Guidance for Industry: Handling and Retention of BA and BE Testing Samples, May Flomax (Tamsulosin) Product Information. October GlaxoSmithKline Document Number GM1999/00294/07. Dutasteride Investigator Brochure. August GlaxoSmithKline Document Number RM2001/00128/01. ARI A Double-Blind, Placebo Controlled, Randomized, Parallel Group Study To Investigate The Changes In The Corrected QT Interval Following Repeat Oral Doses Of GI In Healthy Male Volunteers. October GlaxoSmithKline Document Number ZM2007/00042/00. ARI An Open-Label, Randomized, Single Dose 6-Way Crossover Study to Investigate the Pharmacokinetics, Safety and Tolerability of 5 Different Tamsulosin Hydrochloride Formulations in Healthy Male Subjects. May GlaxoSmithKline Document Number JM2004/00005/00. ARI An open-label, single dose, 2-way crossover study to investigate the pharmacokinetics, safety, and tolerability of oral Flomax (tamsulosin hydrochloride 0.4mg capsule U.S.) and Omnic (tamsulosin hydrochloride 0.4mg capsule Germany) in healthy male volunteers. February GlaxoSmithKline Document Number ZM2007/00022/00. ARI An Open-Label, Randomized, Single Dose Three-Period Partial Crossover Study to Determine the Bioequivalence and Food Effect of a Combination Capsule Formulation of Dutasteride and Tamsulosin Hydrochloride (0.5mg/0.4mg) Compared to Concomitant Dosing of AVODART 0.5mg and Flomax 0.4mg Commercial Capsules in Healthy Male Subjects. August GlaxoSmithKline Document Number ZM2007/00036/00. ARI An Open-Label, Randomized, Single Dose, Three-Period Incomplete block, Crossover Study to Determine the Bioequivalence and Food Effect of a Modified Combination Capsule Formulation of Dutasteride and Tamsulosin Hydrochloride (0.5mg/0.4mg) Compared to Concomitant Dosing of AVODART 0.5mg and Flomax 0.4mg Commercial Capsules in Healthy Male Subjects. December GlaxoSmithKline Document Number RM1999/00360/00. ARIA1011. An Open-Label, Crossover Study to Investigate the Pharmacokinetic-Pharmacodynamic Interaction Between (1) Tamsulosin and GI and (2) Terazosin and GI When Co- Administered to Healthy Male Subjects for 14 Days. May

288 ZM2007/00164/00 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL ZM2007/00164/00 McConnell JD. The long term effects of medical therapy on the progression of BPH: Results from the MTOPS Trial (abstract 1042). J. Urology 167 (4):265, Schuirmann DJ A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet and Biopharm, 15,

289 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/00 The GlaxoSmithKline group of companies Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Pharmacology Reporting and Analysis Plan Title: Clinical Pharmacology Reporting and Analysis Plan for An open-label, randomized, repeat dose, 3 period crossover study to determine the bioequivalence of 3 different formulations of tamsulosin at steady state in healthy male volunteers. Compound Number: GI Effective Date: 16-Apr-2008 Description: The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses and output to be included in the Clinical Pharmacology Study Report for Protocol ZM2007/00164/00. This RAP is intended to describe the pharmacokinetics and safety analyses required for the study. This document will be provided to the study team members to convey the content of the Statistical Analysis Complete (SAC) deliverable. Identifier/Version Number: RM2008/00073/00 Subject: AVODART, dutasteride, Flomax, tamsulosin hydrochloride, GI198745, healthy subject, steady state, bioequivalence Author s Name and Functional Area: Discovery Biometrics Approved by: The Discovery Biometrics Director (or designee) will give final approval Discovery Biometrics (Manager, Statistics and Programming) 16-Apr-2008 Copyright 2008 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 1 1

290 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/00 TABLE OF CONTENTS PAGE 1. INTRODUCTION STUDY OBJECTIVE(S) AND ENDPOINT(S) Study Objective(s) Primary Objective(s) Secondary Objective(s) Study Endpoint(s) Primary Endpoint(s) Secondary Endpoints(s) STUDY DESIGN PLANNED ANALYSES Interim Analyses Final Analyses Decision Critical Results ANALYSIS POPULATIONS HYPOTHESES AND TREATMENT COMPARISONS TREATMENT AND OTHER SUB-GROUP DESCRIPTIONS FOR DATA DISPLAYS GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING Reporting Conventions Data Management Premature Withdrawal and Missing Data Baseline Definition Derived and Transformed Data Change from Baseline Pharmacokinetic Parameters Multiple Measurements at One Timepoint Calculation of Spirometry Screening Parameters Values of Potential Clinical Importance STUDY POPULATION SAFETY ANALYSES PHARMACOKINETIC ANALYSES Drug Concentration Measures Deriving and Summarizing Pharmacokinetic Parameters Statistical Analyses Population Pharmacokinetic Analyses PHARMACODYNAMIC AND BIOMARKERS ANALYSES Pharmacodynamic Analyses

291 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/ Biomarker Analyses PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES PHARMACOGENETIC, VIRAL GENOTYPING AND PHENOTYPING ANALYSES EFFICACY ANALYSES HEALTH OUTCOMES ANALYSES REFERENCES ATTACHMENTS Table of Contents for Data Display Specifications Standard Displays Study Population Data Source Tables and Listings Safety Data Source Tables and Listings Pharmacokinetic Date Source Tables, Figures and ListingsPharmacokinetic Data Source Tables, Figures and Listings Data Display Specifications (Example Shells)

292 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/00 LIST OF ABBREVIATIONS AE Adverse Event AUC(0-24) Area under the concentration-time curve from zero (pre-dose) to some fixed nominal time 24 hours BE Bioequivalence BMI Body mass index BPH Benign prostatic hyperplasia Cmax Maximum observed concentration at Day 1 Cmax,ss Maximum observed concentration at Day 7 (Steady State) Cmin Minimum observed concentration at Day 1 Cmin,ss Minimum observed concentration at Day 7 (Steady State) Cτ Pre-dose (trough) concentration at the end of the dosing interval CPDM Clinical Pharmacology and Discovery Medicine CPDS Clinical Pharmacology Data Science CPKMS Clinical Pharmacokinetics Modelling & Simulation CRF Case Report Form CV Coefficient of variance CYP Cytochrome P450 DB Discovery Biometrics DDS Drug Development Sciences ECG Electrocardiogram FDA Food and Drug Administration GI Gestrointestinal GSK GlaxoSmithKline HCI Hydrochloride hrs hours IRB Institutional Review Board Kg Kilogram L Liter m Meters mg Milligram ml Milliliter mmhg Millimeters of mercury msec Milliseconds MTOPS Medical Therapy of Prostatic Symptoms oz Ounce PGx Pharmacogenetics PK Pharmacokinetic RAP Reporting Analysis Plan Ro Accumulation ratio, observed SAE Serious adverse event(s) SD Standard deviation SOP Standard Operating Procedure ss Steady state SUSAR Suspected, Unexpected, Serious Adverse drug Reaction 4 4

293 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/00 t½ Terminal phase half-life tmax Time of occurrence of Cmax at Day 1 Tmax,ss Time of occurrence of Cmax at Day 7 (Steady State) US United States Trademark Information Trademarks of the GlaxoSmithKline group of companies AVODART Trademarks not owned by the GlaxoSmithKline group of companies Flomax 5 5

294 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/00 1. INTRODUCTION The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be included in the Clinical Pharmacology Study Report for Protocol: Revision Chronology: ZM2007/00164/ JAN-30 Original All decisions regarding the final analysis, as defined in this RAP document, have been made prior to Database Freeze. 2. STUDY OBJECTIVE(S) AND ENDPOINT(S) 2.1. Study Objective(s) Primary Objective(s) 1. To investigate the bioequivalence of tamsulosin at steady state of a Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg under fasting conditions. 2. To investigate the bioequivalence of tamsulosin at steady state of a Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg relative to concomitant dosing of AVODART 0.5 mg and the U.S.- sourcedflomax 0.4 mg under fasting conditions Secondary Objective(s) 1. To assess the safety and tolerability of dosing with the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg, the Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg, and concomitant dosing of AVODART 0.5 mg and the U.S. sourced Flomax 0.4 mg Study Endpoint(s) Primary Endpoint(s) 1. AUC (0-24) and Cmax of tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg after a single dose and at steady state. 2. AUC (0-24) and Cmax of tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg after a single dose and at steady state. 6 6

295 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/00 3. AUC (0-24) and Cmax of tamsulosin in concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg Secondary Endpoints(s) 1. Cτ (defined as the predose concentration determined immediately before dose at steady state), t1/2, tmax, λ, Cmin,ss and fluctuation [(Cmax,ss Cmin,ss)/(AUC(0-24),ss/24)] of tamsulosin, as data Permit, where subscript ss means steady state. 2. Safety and tolerability of all treatments as assessed by blood pressure and pulse rate measurements, adverse events and clinical laboratory safety tests. 3. STUDY DESIGN This will be an open-label, randomized, repeat dose, 3 period crossover study in healthy males. Each subject will receive one of the three treatment regimens in each dosing session. There will be an approximately 5-7 day washout between dosing of each session. Subjects will participate in 3 dosing sessions. In order to minimize the potential impact of genetic variability to the pharmacokinetics of tamsulosin, poor CYP2D6 metabolizers will be excluded from this study. Eligible subjects will be admitted to the research unit the evening prior to dosing (Day -1) and will remain in the unit until approximately 48 hours after dosing on Day 7. The subjects will return to the research unit for an outpatient visit at approximately 72 hours post-dose Day 7 after each treatment session. On days when full PK sampling will take place (Days 1 and 7) subjects will be fasted for 10 hours prior to drug administration and for 4 hours after. Subjects will undergo a washout period of approximately 5-7 days after the last dose in each treatment session. Subjects will return to the research unit approximately days after the last dose for follow-up and will be subsequently discharged from the study. The total duration of each subject's participation from screening to follow-up will be approximately 8-13 weeks. Subjects will be assigned to ABC, ACB, BAC, BCA, CAB, or CBA in accordance with the randomization schedule generated by Discovery Biometrics, prior to the start of the study, using validated internal software (RandAll). Regimen Description A Dutasteride and Tamsulosin Hydrochloride Modified Combination Capsule, 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride (test) B Dutasteride and Tamsulosin Hydrochloride Modified Combination Capsule, 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride (test) C Flomax 0.4 mg (sustained release capsule commercially available in United States) and AVODART 0.5 mg (reference) 7 7

296 CONFIDENTIAL ZM2008/00081/00 4. PLANNED ANALYSES 4.1. Interim Analyses No interim analysis is planned Final Analyses CONFIDENTIAL RM2008/00073/00 The final planned analyses will be performed after all subjects have completed the study and after database freeze/unblinding. See Section 10 to Section 16 for all final planned analyses for this study Decision Critical Results The reporting of pharmacokinetic parameters data will be performed after the database has been frozen. See Section 10 to Section 16 for details regarding the planned analyses and Section 18 for the data displays for decision critical results. 5. ANALYSIS POPULATIONS Safety Population: All subjects who received at least one dose of study drug will be included in the safety population. This population will be used in the evaluation of safety and tolerability. PK Concentration Population: Subjects for whom a pharmacokinetic sample was obtained and analysed. PK Parameter Population: All subjects in the PK Concentration Population who provide pharmacokinetic parameter data for at least one regimen. 6. HYPOTHESES AND TREATMENT COMPARISONS Bioequivalence This study is designed to test the bioequivalence of regimen A tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 10% enteric coated tamsulosin HCl 0.4 mg (test) and regimen B - tamsulosin in the Combination Capsule formulation of dutasteride 0.5 mg/ 15% enteric coated tamsulosin HCl 0.4 mg (test) relative to regimen C - concomitant dosing of AVODART 0.5 mg and the U.S.-sourced Flomax 0.4 mg (reference) at steady state. The null hypothesis is that the true ratio of the geometric mean of the test treatment to the geometric mean of the reference treatment, µ(test)/µ(reference), for each primary PK endpoint, is either less than 0.80 or greater than The alternate hypothesis is that the true ratio of the test treatment geometric mean to the reference treatment geometric mean is at least 0.80 and no greater than Symbolically, this is expressed as follows: H 0 : µ(test)/µ(reference) 0.80 or µ(test)/µ(reference) 1.25, 8 8

297 CONFIDENTIAL ZM2008/00081/00 i.e., treatments are not bioequivalent. Versus H 1 : 0.80 < µ(test)/µ(reference) < 1.25, i.e., treatments are bioequivalent. CONFIDENTIAL RM2008/00073/00 For each PK parameter designated as a primary endpoint at steady state, a two one-sided t-test (TOST) procedure [Schuirmann, 1987] with α=0.05 for each one-sided test will be used to test this set of hypotheses. This is equivalent to requiring that a 90% interval for the true ratio of test to reference geometric means falls entirely within the range of 0.80 to TREATMENT AND OTHER SUB-GROUP DESCRIPTIONS FOR DATA DISPLAYS Randomisation Final Data Display (i.e. HARP / other) Code Treatment Description Treatment Description A Dutasteride and Tamsulosin Hydrochloride Modified Combination Capsule, 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride (test) 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B C Dutasteride and Tamsulosin Hydrochloride Modified Combination Capsule, 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride (test) Flomax 0.4 mg (sustained release capsule commercially available in United States) and AVODART 0.5 mg (reference) 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride Flomax 0.4 mg and AVODART 0.5 mg 8. GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING 8.1. Reporting Conventions All data collected and databased will be presented in data listings. All data from withdrawn subjects will be included in listings. Time window checks will be performed on the actual sample times. Data collected at unscheduled time points will not be used to calculate any of the derived parameters or used in any analyses or summary tables. However these data will be listed in the appropriate listing. 9 9

298 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/ Data Management Data Type Source Format of Planned Date Responsibility Data of Final File 1 PK SMS 2000 CSV DMPK 1. This is for study teams to determine upfront if there is a possibility of not meeting the completion of the CPSR within 6 months of LSLV (i.e. novel data that may not be available until several months after LSLV) Premature Withdrawal and Missing Data A subject may withdraw from investigational product at any time at his/her own request, or may be withdrawn at any time at the discretion of the investigator for safety, behavioral or administrative reasons. All subjects who withdraw prematurely form the study/study drug will be documented and the reason for their withdrawal recorded in the final Clinical Pharmacology Study Report (CPSR). All available data from subjects who withdraw will be listed and all available planned data will be included in the summaries according to the populations defined in Section 5. For subjects withdrawn from the study, the following should be performed if appropriate: 12-lead ECG, clinical safety labs and AE assessment. Relevant sections of the CRF will be completed by the Investigator (or designated staff). Missing data will be indicated as blank in the output and no missing data imputation will be performed Baseline Definition The baseline is the last observation before the start of the study drug at Day 1 of Period Derived and Transformed Data Change from Baseline Change from baseline for each patient will be computed as the post-baseline minus the baseline value Pharmacokinetic Parameters For the purposes of calculating summary statistics and for statistical analysis, all PK parameters with the exception of tmax, λ, and fluctuation of tamsulosin (FL) will be log e transformed. Between-subject coefficient of variation (%CVb) will be calculated according to the following methods: 10 10

299 CONFIDENTIAL ZM2008/00081/00 Untransformed Data : 100 * (SD/Mean) CONFIDENTIAL RM2008/00073/00 Transformed Data : 100 * (sqrt exp(sd of log e -transformed ) 2-1)) Fluctuation of tamsulosin (FL) is defined as (Cmax,ss Cmin,ss)/(AUC(0-24),ss/24) at steady state (day 7 of each period). Cτ was defined as the predose concentration determined immediately before dose at or near steady state Multiple Measurements at One Timepoint Where multiple measurements are recorded for a particular time point, the mean of the measurements will be calculated and used in any derivation of summary statistics. However all available data will be listed. Where more than the specified number of measurements have been taken, the most recently recorded values will be used in the derivation of the appropriate summary measure (i.e. mean or maximum) Calculation of Spirometry Screening Parameters N/A 8.6. Values of Potential Clinical Importance IDSL PCI values for healthy volunteers will be used. 9. STUDY POPULATION Study population data will be summarised by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline. The precise format and content of Study Population tables are shown in Section 18.2 of the RAP. The tables will use the Safety population unless otherwise specified. 10. SAFETY ANALYSES Safety data will be summarised and listed by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline. The precise format and content of Safety figures, tables and listings are shown in Section 18.2 of the RAP. The tables will use the safety population

300 CONFIDENTIAL ZM2008/00081/ PHARMACOKINETIC ANALYSES CONFIDENTIAL RM2008/00073/00 The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be performed by, or under the direct auspices of, Clinical Pharmacology Data Sciences (CPDS), GlaxoSmithKline. The merge of PK concentration data, randomisation and CRF data will be performed by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline. Derivation of pharmacokinetic parameters will be performed by, or under the direct auspices of, Clinical Pharmacokinetic Modelling Simulation (CPKMS), GlaxoSmithKline. Statistical analysis of pharmacokinetic parameters will be performed by, or under the direct auspices of, Discovery Biometrics (Statistician), GlaxoSmithKline Drug Concentration Measures Concentrations of tamsulosin will be listed and summarised by treatment group and nominal time. Standard summary statistics will be calculated (i.e. mean, standard deviation, median, minimum and maximum). Refer to the standard operating procedure, SOP-CPK-0001, for more information regarding the treatment of concentrations below the assay s lower limit of quantification (NQ). Individual concentration-time profiles and median/mean profiles by treatment group will be plotted. Each of the figures will contain one plot on the untransformed scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear plot). See Section 18.3 Data Display Specifications (Example Shells) for details Deriving and Summarizing Pharmacokinetic Parameters Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacokinetics Modeling and Simulation Department, CPDM, GlaxoSmithKline. The pharmacokinetic parameters will be calculated by standard non-compartmental analysis according to current working practices and using Win Nonlin Pro. All calculations of noncompartmental parameters will be based on actual sampling times. From the plasma concentration-time data, the following pharmacokinetic parameters will be determined, as data permit: Day 1: AUC(0-24), Cmax, Cmin, tmax, Day 7: AUC(0-24),ss, Cmax,ss, Cmin,ss, tmax,ss, t½, Cτ λ can be derived by following formulae: λ= log e 2/ t½ 12 12

301 CONFIDENTIAL ZM2008/00081/ Statistical Analyses CONFIDENTIAL RM2008/00073/00 Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively according to the following guidance document from Health Canada: GUIDANCE FOR INDUSTRY Conduct and Analysis of Bioavailability And Bioequivalence Studies - Part B: Oral Modified Release Formulations (1996). All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D. Statistical analyses of the pharmacokinetic parameter data will be the responsibility of Discovery Biometrics, GlaxoSmithKline. Following log e -transformation, AUC(0-24),ss, Cmax,ss, Cmin,ss (as data permit) will be separately analyzed by a mixed effects model, fitting fixed effect terms for sequence, period, and regimen, and fitting subject within sequence as a random effect. Point estimates and associated 90% confidence intervals for the differences A-C and B-C will be separately constructed for each parameter using the residual variance. Results corrected for measured drug content will also be presented. These point estimates and confidence intervals will then be exponentially back transformed to obtain point estimates and 90% confidence intervals for the ratios A:C and B:C. Within-subject and between-subject CVs will be calculated for each endpoint using the following equations: CVw=100*sqrt(exp(MSE)-1) CVb=100*sqrt(exp(RSubject) - 1) where MSE is the mean squared residual error, and RSubject is the estimate of random subject effect. The following approximation of within and between subject CVs will be calculated also: CVintra=100*sqrt(MSE) CVinter=100*sqrt(RSubject) Tmax, fluctuation of tamsulosin, and λ will be analysed using the same model as above with data in raw scale and the point estimates and their associated 90% confidence intervals will be constructed for the differences, [A- C and B - C]. Within and between subject SDs (standard deviation) will be provided from the model. To estimate the extent of accumulation after repeat dosing, the observed accumulation ratio ( R 0 ) will be determined. AUC(0 24) ss R0 =, where AUC ( 0 24) ss is AUC from time zero to 24 hours under AUC (0 24) steady state and AUC ( 0 24) is AUC from time zero to 24 hours at day

302 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/00 Steady state will be checked with Cτ data (the last three pre-dose concentrations) as indicated in the guidance document from Health Canada. A repeated measures analysis of the last three pre-dose concentrations will be provided. Following log e transformation, Cτ will be analyzed by a repeated measures model, fitting terms for (SAS proc mixed) sequence, period, regimen, time, time*period, time*regimen as fixed effect and subject within sequence as random effect. The main importance of this analysis is to check time and time * regimen effects. Distributional assumptions underlying the statistical analyses will be assessed by visual inspection of residual plots. Normality will be examined by normal probability plots, while homogeneity of variance will be assessed by plotting the residuals against the predicted values for the model. All the derived parameters will be listed. For each of these parameters, except tmax, tmax,ss, and fluctuation, the following summary statistics will be calculated for each regimen: median, maximum, minimum, arithmetic mean, standard deviation, coefficient of variation, geometric mean, 90% confidence interval for the geometric mean and standard deviation of logarithmically transformed data. For tmax, tmax,ss, and fluctuation, median, maximum, minimum, arithmetic mean and standard deviation will be calculated Population Pharmacokinetic Analyses N/A 12. PHARMACODYNAMIC AND BIOMARKERS ANALYSES N/A Pharmacodynamic Analyses N/A Biomarker Analyses N/A 13. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES N/A 14. PHARMACOGENETIC, VIRAL GENOTYPING AND PHENOTYPING ANALYSES N/A 14 14

303 CONFIDENTIAL ZM2008/00081/ EFFICACY ANALYSES N/A 16. HEALTH OUTCOMES ANALYSES N/A CONFIDENTIAL RM2008/00073/

304 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/ REFERENCES GlaxoSmithKline Document Number ZM2007/00164/00 Study ID. An openlabel, randomized, repeat dose, 3 period crossover study to determine the bioequivalence of 3 different formulations of tamsulosin at steady state in healthy male volunteers. Schuirmann DJ A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet and Biopharm, 15, Steinijans V.W, Diletti E. Statistical Analysis of Bioavailability Studies: Parametric and Nonparametric Confidence Intervals. Eur J Clin Pharmacol 1983; 24:

305 CONFIDENTIAL ZM2008/00081/00 CONFIDENTIAL RM2008/00073/ ATTACHMENTS Table of Contents for Data Display Specifications Contributions from Statistics: Minimum set of output/data displays to be included in the Statistical Contribution to the Clinical Report (SCCR). 1. Randomization Schedule of Intent and Actual Dosing.(not shown) 2. Main Results for comparisons of interest (See Exhibit A). 3. Summary of Results of Statistical Analyses for Derived Pharmacokinetic Parameters (See Exhibits B & C & D). 4. Appendix of Statistical analysis details (not shown) 5. Summary Statistics of Derived Pharmacokinetic Parameters (not shown) 6. Data listings of Derived Pharmacokinetic Parameters (not shown) Note: Data will be tabulated to the same degree of accuracy as given in the original data Important programming note on numbering of PK, Safety and Study Population Related outputs: Study Population related tables and/or figures should be numbered as Table x and/or Figure x. PK related tables and/or figures should be numbered as x and/or Figure x. Safety related tables and/or figures should be numbering as x and/or Figure x

306 CONFIDENTIAL RM2008/00073/ Standard Displays Study Population Data Source Tables and Listings Type Number Description IDSL /ex no Responsibility T 9.xx Summary of Demographic Characteristics DM1 P T 9.xx Summary of Race and Racial Characteristics DM6 P T 9.xx Summary of Subject Disposition ES1 P 18 T L L L L L 9.xx 9.xx 9.xx 9.xx 9.xx 9.xx Summary of Concomitant Medications CM1 P Listing of Demographic Characteristics DM4 P Listing of Race DM10 P Listing of Concomitant Medications CP_CM4 P Listing of Reason for Withdrawal ES3 P Listing of Subjects with Inclusion/exclusion Criteria Deviations IE4 P 18

307 CONFIDENTIAL RM2008/00073/ Safety Data Source Tables and Listings Type LTG? Number Ref Description IDSL/ ex no Responsibility Exp T 11.xx Summary of Exposure data Ex1 P Exp L 11.xx Listing of Exposure Data EX4 P AE T 11.xx Summary of All Adverse Events AE1 P AE T 11.xx Summary of Drug Related Adverse Events AE1 P 19 AE T 11.xx AE T 11.xx AE L 11.xx AE L 11.xx AE L 11.xx AE L 11.xx AE L 11.xx LAB T 11.xx Summary of AEs Leading to Withdrawal AE1 P Summary of Adverse Events by Maximum Intensity AE1 P Relationship Between System Organ Class and Verbatim Text AE2 P Listing of Subject Numbers for Individual Adverse Events AE7 P Listing of all Adverse Events AE9 P Listing of Serious Adverse Events AE9a P Listing of AEs with No Resolution Date AE9a P Summary of Chemistry Data LB1 P 19

308 CONFIDENTIAL RM2008/00073/00 LAB T 11.xx LAB L 11.xx Summary of Hematology Data LB1 P Listing of Clinical Chemistry of Potential Clinical Importance CP_LB6 P LAB L 11.xx Listing of all Clinical Chemistry Laboratory Data for Subjects with Abnormalities of Potential Clinical Importance LB2 P LAB L 11.xx Listing of Clinical Hematology of Potential Clinical Importance CP_LB6 P LAB L 11.xx Listing of all Clinical Hematology Laboratory Data for Subjects with Abnormalities of Potential Clinical Importance LB2 P 20 Vital T 11.xx Summary of Vital Signs VS1 P Vitals T 11.xx Summary of Change from Baseline for Vital Signs VS1 P Vital L 11.xx Listing of All Vital Signs for Subjects with Values of Potential Clinical Importance CP_VS5 P Vital T 11.xx Listing of Vital Signs of Potential Clinical Importance P Vital_O T 11.xx Listing of Orthostatic Vital Signs VS5, Exhibit S P Vital_O T 11.xx Summary table of subjects who demonstrated orthostatic hypotension Exhibit T P ECG T 11.xx Summary of ECG Values EG2 P ECG T 11.xx Summary of ECG Findings EG2 P 20

309 CONFIDENTIAL RM2008/00073/00 ECG L 11.xx Listing of All ECG Values for Subjects with a Value of Potential Clinical Importance CP_EG6a P ECG L 11.xx ECG L 11.xx Listing of ECG Values of Potential Clinical Importance CP_EG16b P Listing of Abnormal ECG Findings CP_EG6b P Pharmacokinetic Date Source Tables, Figures and ListingsPharmacokinetic Data Source Tables, Figures and Listings 21 TLG? Number Ref Description IDSL ex no Responsibility T 10.xx Summary of {Matrix} Tamsulosin Pharmacokinetic Concentration-Time Data PKCT1 P T 10.xx Summary Statistics of Untransformed Derived {Matrix} Tamsulosin Pharmacokinetic Parameters PKPT4 P T 10.xx Summary Statistics of log-transformed Derived {Matrix} Tamsulosin Pharmacokinetic Parameters PKPT4 P T 10.xx Listing of {Matrix} Tamsulosin Pharmacokinetic Concentration-Time Data PKCL1X P T 10.xx Listing of Derived {Matrix} Tamsulosin Pharmacokinetic Parameters PKPL1X P T 10.xx Point Estimates and 90% Confidence Intervals for the Evaluation of Bioequivalence of Tamsulosin at Steady State T 10.xx Point Estimates and 90% Confidence Intervals for the Evaluation of Bioequivalence of Tamsulosin at Steady State for potency corrected data 21 Exhibit A Exhibit A Stats Stats

310 CONFIDENTIAL RM2008/00073/00 T 10.xx Log-transformed Pharmacokinetic Parameter Analysis ANOVA for ln(pk parameter) Exhibit B Stats T 10.xx Untransformed Pharmacokinetic Parameter Analysis ANOVA for PK parameter Exhibit C Stats L 10.xx Listing of SAS Output for Point Estimates and 90% Confidence Intervals for the Evaluation of Bioequivalence of Tamsulosin at Steady State Stats 22 L 10.xx Listing of SAS Output for Point Estimates and 90% Confidence Intervals for the Evaluation of Bioequivalence of Tamsulosin at Steady State for potency corrected data L 10.xx Listing of SAS Output for Log-transformed Pharmacokinetic Parameter Analysis ANOVA for ln(pk parameter) L 10.xx Listing of SAS Output for Untransformed Pharmacokinetic Parameter Analysis ANOVA for PK parameter T 10.xx Repeated Measures Analysis of ln(cτ) L 10.xx Randomization Scheme L 10.xx Listings of Pre-dose Concentration (µg /ml) for Each Subject T 10.xx Summary Statistics of Pre-dose Concentration (ng/ml) for Each Subject L 10.xx Listing of Untransformed Derived Pharmacokinetic Parameters Ratios By Regimen T 10.xx Summary Statistics of Untransformed Derived Pharmacokinetic Parameters Ratios L 10.xx Listing of Log-transformed Derived Pharmacokinetic Parameters By Regimen 22 Exhibit D CP_RD1x Exhibit E Exhibit F Exhibit G Exhibit H Exhibit I Stats Stats Stats Stats Stats P P P P P

311 CONFIDENTIAL RM2008/00073/00 T 10.xx Summary Statistics of Log-transformed Derived Pharmacokinetic Parameters By Regimen P L 10.xx Listings of Derived Pharmacokinetic Parameters λ/tmax/tmax,ss Difference By Regimen T 10.xx Summary Statistics of Derived Pharmacokinetic Parameters Differences Exhibit J Exhibit K P P T 10.xx Estimates Based on Correction for Measured Content Exhibit L Stats F 10.xx Individual Plasma {Matrix} Tamsulosin Concentration-Time Plots at Day 1 (Linear and Semi-Log) (identify and overlay treatments) Exhibit M Exhibit N P 23 F 10.xx Individual Plasma {Matrix} Tamsulosin Concentration-Time Plots at day 7 (Linear and Semi-Log) (identify and overlay treatments) F 10.xx Individual Plasma {Matrix} Tamsulosin ln(concentration)-time Plots at Day 1 (Linear and Semi-Log) (identify and overlay treatments) F 10.xx Individual Plasma {Matrix} Tamsulosin ln(concentration)-time Plots at day 7 (Linear and Semi-Log) (identify and overlay treatments) F 10.xx Mean Plasma {Matrix} Tamsulosin Concentration-Time Plots at day 1 (Linear and Semi-log) (identify and overlay treatments) F 10.xx Mean Plasma {Matrix} Tamsulosin Concentration-Time Plots at Day 7 (Linear and Semi-log) (identify and overlay treatments) F 10.xx Mean Plasma {Matrix} Tamsulosin ln(concentration)-time Plots at day 1 (Linear and Semi-log) (identify and overlay treatments) F 10.xx Mean Plasma {Matrix} Tamsulosin ln(concentration)-time Plots at Day 7 (Linear and Semi-log) (identify and overlay treatments) 23 Exhibit N Exhibit O Exhibit O Exhibit P Exhibit P Exhibit Q Exhibit Q P P P P P P P

312 24 CONFIDENTIAL RM2008/00073/00 F 10.xx Median Plasma {Matrix} Tamsulosin ln(concentration)-time Plots at Day 1 (Linear and Semi-log) (identify PKCF3 P and overlay treatments) F 10.xx Median Plasma {Matrix} Tamsulosin Concentration-Time Plots at Day 7 (Linear and Semi-log) (identify and PKCF3 P overlay treatments) F 10.xx Comparative Plot (Linear and Semii-Log) of Tamsulosin PK parameter AUC(0-24) (units) at Day 1 (A vs C) Exhibit R P F 10.xx Comparative Plot (Linear and Semii-Log) of Tamsulosin PK parameter AUC(0-24) (units) at Day 1 (B vs C) Exhibit R P F 10.xx Comparative Plot (Linear and Semii-Log) of Tamsulosin PK parameter AUC(0-24) (units) at Day 7 (A vs C) Exhibit R P F 10.xx Comparative Plot (Linear and Semii-Log) of Tamsulosin PK parameter AUC(0-24) (units) at Day 7 (B vs C) Exhibit R P {Matrix}= plasma Additional Notes to Programmer: If collected, please report ALL Times, ie, AE, ConMeds, LABs, Vitals, ECGs, Dose. Include Height, Weight, and BMI into the Demography Table and Listing For ConMeds collected, add start/stop times, and Indication to listing Output final reporting datasets for LABS, AEs, Vitals, and ECGs. Use PCI values for healthy volunteers in IDSL. 24

313 CONFIDENTIAL RM2008/00073/ Data Display Specifications (Example Shells) Note: All the example shells follow the guidance document from Health Canada: GUIDANCE FOR INDUSTRY Conduct and Analysis of Bioavailability And Bioequivalence Studies - Part B: Oral Modified Release Formulations (1996)

314 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 2 Exhibit A Point Estimates and 90% Confidence Intervals for the Evaluation of Bioequivalence of Tamsulosin at Steady State 26 Parameter AUC(0-24),ss Comparison LS GeoMean Test 26 LS GeoMean Ref. Ratio Test vs. Ref 90% CI A : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) B : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) Cmax,ss A : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) B : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) Cmin,ss A : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) B : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) C(tau) A : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) B : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) λ A : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) B : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) tmax,ss A : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) B : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) Fluctuation A : C xx.xx xx.xx xx.xx (xx.xx, xx.xx) B : C xx.xx xx.xx xx.xx (xx.xx, xx.xx)

315 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 2 of 2 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg 27 27

316 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit B Log-transformed Pharmacokinetic Parameter Analysis ANOVA for ln(pk parameter) 28 Source Num df Den df F P-value Sequence x x xx.xx x.xx Period x x xx.xx x.xx Regimen x x xx.xx x.xx Intra-subject CV = xx percent, Inter-subject CV= xx percent Note: PK parameters AUC(0-24),ss, Cmax,ss, Cmin,ss, C(tau) need log transformation. 28

317 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit C Untransformed Pharmacokinetic Parameter Analysis ANOVA for PK Parameter 29 Source Num df Den df F P-value Sequence x x xx.xx x.xx Period x x xx.xx x.xx Regimen x x xx.xx x.xx Intra-subject SD = xx percent Note: Raw scale of PK parameters λ, fluctuation, and tmax,ss will be used. 29

318 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit D Repeated Measures Analysis of ln(cτ) 30 Source Num df Den df F P-value Sequence x x xx.xx x.xx Period x x xx.xx x.xx Regimen x x xx.xx x.xx Time x x xx.xx x.xx Time*Period x x xx.xx x.xx Time*Regimen x x xx.xx x.xx 30

319 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Exhibit E Page 1 of 2 Listings of Pre-dose Concentration (µg /ml) for Each Subject 31 Subject Regimen Period Day Conc. (Units) 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 GSK Clincal Study Register. 31

320 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 2 of 2 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg 32 32

321 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Exhibit F Page 1 of 1 Summary Statistics of Pre-dose Concentration (ng/ml) for Each Subject 33 Subject Regimen Period Mean SD CV 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 GSK Clincal Study Register. Note to programmer: Please use pre-dose values from days 5, 6 and 7 to derive Mean, SD and CV. Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg 33

322 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Exhibit G Page 1 of 1 34 Listing of Untransformed Derived Pharmacokinetic Parameters Ratios By Regimen Subject Regimen A Regimen B Regimen C Ratio Ratio A/C (%) B/C (%) 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 GSK Clincal Study Register. Note to programmer: Please refer to IDSL Listing pkkpl2 Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg 34

323 CONFIDENTIAL RM2008/00073/00 Protocol Population Page 1 of 1 : : PK population Exhibit H Summary Statistics of Untransformed Derived Pharmacokinetic Parameters Ratios Param. Ratios N Day n Mean 95% CI (Lower,Upper) SD %CVb Median Min. Max. AUC(0-24) (units) A/C xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 7 24 xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 35 B/C xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx Cmax (units) A/C xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx B/C xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 7 21 xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx Cmin (units) A/C xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx B/C xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 7 21 xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg 35

324 CONFIDENTIAL RM2008/00073/00 Protocol Population : : PK population Page 1 of 1 Exhibit I Listing of Log-transformed Derived Pharmacokinetic Parameters By Regimen 36 Subject Regimen A Regimen B Regimen C 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 GSK Clincal Study Register. Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg 36

325 CONFIDENTIAL RM2008/00073/00 Protocol Population Page 1 of 1 : : PK population Exhibit J Summary Statistics of Log Scale Derived Pharmacokinetic Parameters By Regimen Param. Regimen N Day n Mean 95% CI (Lower,Upper) SD Median Min. Max. AUC(0-24) (units) A xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 7 24 xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 37 B xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx C xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx Cmax (units) A xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx B xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 7 21 xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx C xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx Cmin (units) A xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx B xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 7 21 xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 37

326 CONFIDENTIAL RM2008/00073/00 C xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xxxx.x xxxx xxxx Note to programmer: CV is not required to display in the above summary table Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg 38 38

327 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit K Listings of Derived Pharmacokinetic Parameters λ/tmax/tmax,ss Difference By Regimen 39 Subject Regimen A Regimen B Regimen C Difference Difference 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 GSK Clincal Study Register. 39

328 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit L Summary Statistics of Derived Pharmacokinetic Parameters Differences Param. Difference N Day n Mean 95% CI (Lower,Upper) SD %CVb Median Min. Max. 40 λ A-C xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 7 24 xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx B-C xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx tmax A-C xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 7 23 xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx B-C xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx 7 21 xxxx.x (xxxx.x,xxxx.x) xx.x xx.x xxxx.x xxxx xxxx Regimen Key: A: 0.5 mg dutasteride, 10% enteric coated 0.4 mg tamsulosin hydrochloride B: 0.5 mg dutasteride, 15% enteric coated 0.4 mg tamsulosin hydrochloride C: Flomax 0.4 mg and AVODART 0.5 mg 40

329 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit M Estimates Based on Correction for Measured Content A B C 41 Lot number xxxx xxxx xxxx Expiry date xx/xx xx/xx xx/xx Date of analysis xx/xx xx/xx xx/xx Measured content (% of label claim) xx.xx xx.xx xx.xx Correction factors! raw scale-multiply! log scale-add x.xxxx x.xxxx 41 x.xxxx x.xxxx x.xxxx x.xxxx

330 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit N Concentration-Time Profiles 42 42

331 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit O Ln(Concentration)-Time Profiles 43 Note to programmer: This plot must contain the regression lines from which the terminal disposition rate constants (λ) were estimated. 43

332 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit P Arithmetic means Plasma Tamsulosin Concentration-Time 44 Plot 44

333 Protocol Population : : PK population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit Q Arithmetic means Plasma Tamsulosin ln(concentration)-time Plot 45 45

334 CONFIDENTIAL RM2008/00073/00 Protocol : Population : PK population Page 1 of 1 Exhibit R Figure 11.1 Comparative Plot (Linear and Semi-Log) of PK parameter AUC(0-24) (units) (A vs C) 46 Program ID/programmer ID/date/time Note: Y axis willl be PK parameters : AUC(0-24), Cmax, Cmin, Cτ, of Tamsulosin, if data permit. X axis will be regimen (A vs C). 46

335 CONFIDENTIAL RM2008/00073/00 Protocol : Population : Safety population Page 1 of 1 47 Inv./ Subj. A/ XXX/ XXX Etc. Note to Programmer: Exhibit S Listing of Orthostatic Vital Signs ----Systolic Blood Pressure---- Treatment/ Avg. Period Visit Planned Relative Time Sitting (mmhg) Supine Orthostatic Change (mmhg) XXX/ Day -1 XXXXXXX XXX XXX.XX XXX.XX XXXXXXXXXX Refer to the SAS code (td_vs5.sas) in CRV Continue this table for Diastolic Blood Pressure and Heart Rate. Orthostatic change= standing - avg supine measurements 47

336 Protocol Population : : Safety population CONFIDENTIAL RM2008/00073/00 Page 1 of 1 Exhibit T Summary table of subjects who demonstrated orthostatic hypotension 48 Regimen A (N=xx) Regimen B (N=xx) Regimen C (N=xx) SBP (mm Hg) orthostatic xx xx xx hypotension DBP (mm Hg) orthostatic xx xx xx hypotension Total xx xx xx Note for programmer: This is a mock up table for counting subjects who demonstrated orthostatic hypotension as defined by the protocol during the change in position assessment. Orthostatic hypotension will be defined as a reduction in systolic blood pressure of 20 mmhg or more and/or a reduction in diastolic blood pressure of 10 mmhg or more for the standing measurement compared to the supine measurements (average of the last 2 measurements). 48

337 Annotated Trial Design Page 1 of 51 Annotated Design For Trial: ari111402_nwr_e Protocol: Generated By InForm Architect June 27, :03PM 1

338 Time and Events Schedule For Study: ari111402_nwr_e Annotated Trial Design Page 2 of 51 Assessment CRF Screen Session 1 Session 1 Session 1 Session 1 Session 1 Session 1 Session 1 Session 1 Session 1 Session 1 Session 1 Session 2 Session 2 Session 2 Session 2 Session 2 Session 2 Session 2 Session 2 Session 2 Session 2 Session 2 Session 3 Session 3 Session 3 Session 3 Session 3 Session 3 Session 3 Session 3 Session 3 Session 3 Session 3 Follow- Logs/Repeats Conflict (Screen) Day -1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day -1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day -1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 up (Logs/Rpts) (Conflict) [ S ] (S1D -1) (S1D1) (S1D2) (S1D3) (S1D4) (S1D5) (S1D6) (S1D7) (S1D8) (S1D9) (S1D10) (S2D -1) (S2D1) (S2D2) (S2D3) (S2D4) (S2D5) (S2D6) (S2D7) (S2D8) (S2D9) (S2D10) (S3D -1) (S3D1) (S3D2) (S3D3) (S3D4) (S3D5) (S3D6) (S3D7) (S3D8) (S3D9) (S3D10) (F/U) [ U ] [ U/R/D ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] [ S ] 1 DATE OF VISIT DoV SUBJECT IDENTIFICATION Subj ID 2 3 DEMOGRAPHY Demog LEAD ECG ECG 4 5 ORTHOSTATIC VITAL SIGNS ORTHO VS 5 6 ELECTRONICALLY TRANSFERRED LAB DATA Lab ELIGIBILITY QUESTION ELIG 7 8 RANDOMISATION NUMBER Rand 2 9 MEAL STATUS Meal INVESTIGATIONAL PRODUCT Dose TREATMENT CONFIRMATION Trt Conf VITAL SIGNS VS ORTHOSTATIC VITAL SIGNS ORTHO VS PHARMACOKINETICS BLOOD - GI PK VITAL SIGNS VS PHARMACOKINETICS BLOOD - GI PHARMACOKINETICS BLOOD - GI PK PK VITAL SIGNS VS LEAD ECG ECG 2 2 VITAL SIGNS VS 3 21 STUDY CONCLUSION Conclusion 5 22 PREGNANCY INFORMATION Preg M 6-DF 23 LOGS AND REPEATS Logs/Rpts 1 24 NON-SERIOUS ADVERSE EVENT AE 2-RF-DF 25 SERIOUS ADVERSE EVENTS SAE 3-RF-DF 26 CONCOMITANT MEDICATIONS Con Meds 4-RF-DF LEAD ECG ECG Rpt 5-RF-DF 28 ECG ABNORMALITIES ECG Abn 6-RF-DF 29 VITAL SIGNS VS Rpt 7-RF-DF 3 ORTHO VITAL SIGNS Ortho Rpt 8-RF-DF 31 ELECTRONICALLY TRANSFERRED LAB DATA 32 REPEAT PHARMACOKINETICS BLOOD - GI Lab Rpt 9-RF-DF PK Rpt 1-RF-DF 33 Reg Docs REG 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 2

339 ari111402_nwr_e : INFORM SCREENING (SCREEN) Annotated Trial Design Page 3 of 51 INFORM SCREENING * 1. Subject initials [hidden] A3 (MAPPINGS1:t_SCREEN.txtScrSINIT) (MAPPINGS2:t_SCREEN.txtScrSINIT) 2. Date of birth Req / Req / Req (19-29) (MAPPINGS1:t_SCREEN.BIRTHDT) (MAPPINGS2: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 from screening form CDD: MAPPINGS1 Table: t_screen Key Type: PATIENTVISIT Column Name Column Data Type Design Note txtscrsinit STRING(3) - A3 BIRTHDT DATE - DDMONYYYY CDD: MAPPINGS2 Table: t_screen Key Type: PATIENTVISIT Column Name Column Data Type Design Note txtscrsinit STRING(3) - A3 BIRTHDT DATE - DDMONYYYY 3

340 ari111402_nwr_e : INFORM ENROLMENT (ENROL) Annotated Trial Design Page 4 of 51 SUBJECT NUMBER 1. Subject number A6 (MAPPINGS1:t_ENROL.mtxtSubjectNumber) (MAPPINGS2:t_ENROL.mtxtSubjectNumber) CDD: MAPPINGS1 Table: t_enrol Key Type: PATIENTVISIT Column Name Column Data Type Design Note mtxtsubjectnumber STRING(6) - A6 CDD: MAPPINGS2 Table: t_enrol Key Type: PATIENTVISIT Column Name Column Data Type Design Note mtxtsubjectnumber STRING(6) - A6 4

341 ari111402_nwr_e : DATE OF VISIT (DoV) Annotated Trial Design Page 5 of 51 Adverse Events/Concomitant Medications» Record details of any new serious adverse event or any changes to ongoing serious adverse events in the SAE form in the Logs/Rpts visit.» From (Session 1 Day 1) onwards, record details of any new non-serious adverse event or any changes to ongoing non-serious adverse events in the appropriate AE form in the Logs/Rpts visit» Record any changes to the subject's concomitant medication or any new medication taken since the last visit in the Con Meds form in the Logs/Rpts visit. DATE OF VISIT/ASSESSMENT 1. Date of visit/assessment Req / Req / Req (28-29) (MAPPINGS1:t_VISIT.DOV) (MAPPINGS2:t_VISIT.DOV) CDD: MAPPINGS1 Table: t_visit Key Type: PATIENTVISIT Column Name Column Data Type Design Note DOV DATE - DDMONYYYY CDD: MAPPINGS2 Table: t_visit Key Type: PATIENTVISIT Column Name Column Data Type Design Note DOV DATE - DDMONYYYY 5

342 ari111402_nwr_e : SUBJECT IDENTIFICATION (Subj ID) Annotated Trial Design Page 6 of 51 SUBJECT NUMBER 1. Subject number A6 (MAPPINGS1:t_SUBID.mtxtSubjectNumber) (MAPPINGS2:t_SUBID.mtxtSubjectNumber) CDD: MAPPINGS1 Table: t_subid Key Type: PATIENTVISIT Column Name Column Data Type Design Note mtxtsubjectnumber STRING(6) - A6 CDD: MAPPINGS2 Table: t_subid Key Type: PATIENTVISIT Column Name Column Data Type Design Note mtxtsubjectnumber STRING(6) - A6 6

343 ari111402_nwr_e : DEMOGRAPHY (Demog) Annotated Trial Design Page 7 of 51 DEMOGRAPHY 1. Date of birth Req / Req / Req (19-29) (MAPPINGS1:t_DEMO.BIRTHDT) (MAPPINGS2:t_DEMO.BIRTHDT) 2. Sex (MAPPINGS1:t_DEMO.SEX) (MAPPINGS2:t_DEMO.SEX) [M] Male [F] (MAPPINGS1:t_DEMO.CHDPOTCD) (MAPPINGS2:t_DEMO.CHDPOTCD) Female : Record child-bearing potential [1] Pre-menarcheal [2] Post-menopausal [3] Sterile (of child-bearing age) [4] Potentially able to bear children 3. Ethnicity (MAPPINGS1:t_DEMO.ETHNICCD) (MAPPINGS2:t_DEMO.ETHNICCD) [1] Hispanic or Latino [2] Not Hispanic or Latino 4. Geographic ancestry Check all that apply (MAPPINGS1:t_DEMO.RACECCD11) (MAPPINGS2:t_DEMO.RACECCD11) [11] African American/African Heritage (MAPPINGS1:t_DEMO.RACECCD12) (MAPPINGS2:t_DEMO.RACECCD12) [12] American Indian or Alaskan Native (MAPPINGS1:t_DEMO.RACECCD13) (MAPPINGS2:t_DEMO.RACECCD13) [13] Asian - Central/South Asian Heritage (MAPPINGS1:t_DEMO.RACECCD14) (MAPPINGS2:t_DEMO.RACECCD14) [14] Asian - East Asian Heritage (MAPPINGS1:t_DEMO.RACECCD15) (MAPPINGS2:t_DEMO.RACECCD15) [15] Asian - Japanese Heritage (MAPPINGS1:t_DEMO.RACECCD16) (MAPPINGS2:t_DEMO.RACECCD16) [16] Asian - South East Asian Heritage (MAPPINGS1:t_DEMO.RACECCD17) (MAPPINGS2:t_DEMO.RACECCD17) [17] Native Hawaiian or Other Pacific Islander (MAPPINGS1:t_DEMO.RACECCD18) (MAPPINGS2:t_DEMO.RACECCD18) [18] White - Arabic/North African Heritage (MAPPINGS1:t_DEMO.RACECCD19) (MAPPINGS2:t_DEMO.RACECCD19) [19] White - White/Caucasian/European Heritage Item Design Notes: Item No. Design Note 1. Will be automatically mapped to demography form from screening form 7 CDD: MAPPINGS1 Table: t_demo Key Type: PATIENTVISIT Column Name Column Data Type Design Note BIRTHDT DATE - DDMONYYYY SEX STRING(1) CHDPOTCD STRING(1) ETHNICCD STRING(1) RACECCD11 STRING(255) RACECCD12 STRING(255) RACECCD13 STRING(255) RACECCD14 STRING(255) RACECCD15 STRING(255) RACECCD16 STRING(255) RACECCD17 STRING(255) RACECCD18 STRING(255) RACECCD19 STRING(255) CDD: MAPPINGS2 Table: t_demo Key Type: PATIENTVISIT Column Name Column Data Type Design Note BIRTHDT DATE - DDMONYYYY SEX STRING(1) CHDPOTCD STRING(1) ETHNICCD STRING(1) RACECCD11 STRING(255) RACECCD12 STRING(255) RACECCD13 STRING(255) RACECCD14 STRING(255) RACECCD15 STRING(255) RACECCD16 STRING(255) RACECCD17 STRING(255) RACECCD18 STRING(255) RACECCD19 STRING(255)

344 ari111402_nwr_e : 12-LEAD ECG (ECG) Annotated Trial Design Page 8 of Date and Time of ECG Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_ECG_A_SCR.EGDTTM) (MAPPINGS2:t_ECG_A_SCR.EGDTTM) Req : Req 24-hour clock 2. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_ECG_A_SCR.EGHR) (MAPPINGS2:t_ECG_A_SCR.EGHR) 3. PR Interval xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_A_SCR.PR ) (MAPPINGS2:t_ECG_A_SCR.PR ) 4. QRS Duration xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_A_SCR.QRS ) (MAPPINGS2:t_ECG_A_SCR.QRS ) 5. Uncorrected QT Interval xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_A_SCR.QT ) (MAPPINGS2:t_ECG_A_SCR.QT ) 6. QTc Interval xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_A_SCR.QTC ) (MAPPINGS2:t_ECG_A_SCR.QTC ) 7. Result of the ECG (MAPPINGS1:t_ECG_A_SCR.EGINTPCD) (MAPPINGS2:t_ECG_A_SCR.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE [4] No result (not available) Form Design Note: Screening ECG CDD: MAPPINGS1 Table: t_ecg_a_scr Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR FLOAT - F6. QRS FLOAT - F6. QT FLOAT - F6. QTC FLOAT - F6. EGINTPCD STRING(1) CDD: MAPPINGS2 Table: t_ecg_a_scr Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR FLOAT - F6. QRS FLOAT - F6. QT FLOAT - F6. QTC FLOAT - F6. EGINTPCD STRING(1) 8

345 ari111402_nwr_e : ORTHOSTATIC VITAL SIGNS (ORTHO VS) Annotated Trial Design Page 9 of 51 Supine (first measurement of three) 1. Actual time Hr:Min (:-23:59) NReq / NReq / NReq (28-29) (MAPPINGS1:t_VITALS_X2_A.CDDVSACTTM) (MAPPINGS2:t_VITALS_X2_A.CDDVSACTDTTM) Req : Req 24-hour clock 2. Height xxx ( n >= ) cm (MAPPINGS1:t_VITALS_X2_A.HEIGHT) (MAPPINGS2:t_VITALS_X2_A.HEIGHT) 3. Weight xxx.x ( n >=.) kg (MAPPINGS1:t_VITALS_X2_A.WEIGHT) (MAPPINGS2:t_VITALS_X2_A.WEIGHT) Body mass index 4. Blood pressure (MAPPINGS1:t_VITALS_X2_A.VSBMI) (MAPPINGS2:t_VITALS_X2_A.VSBMI) xxx ( n >= ) / (MAPPINGS1:t_VITALS_X2_A.SYSBP) (MAPPINGS2:t_VITALS_X2_A.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X2_A.DIABP) (MAPPINGS2:t_VITALS_X2_A.DIABP) 5. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X2_A.HEART) (MAPPINGS2:t_VITALS_X2_A.HEART) Supine (second measurement of three) 6. Actual time Hr:Min (:-23:59) NReq / NReq / NReq (28-29) (MAPPINGS1:t_VITALS_X2_A.CDDVSACTTM) (MAPPINGS2:t_VITALS_X2_A.CDDVSACTDTTM) Req : Req 24-hour clock 7. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X2_A.SYSBP) (MAPPINGS2:t_VITALS_X2_A.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X2_A.DIABP) (MAPPINGS2:t_VITALS_X2_A.DIABP) 8. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X2_A.HEART) (MAPPINGS2:t_VITALS_X2_A.HEART) Supine (third measurement of three) 9. Actual time Hr:Min (:-23:59) NReq / NReq / NReq (28-29) (MAPPINGS1:t_VITALS_X2_A.CDDVSACTTM) (MAPPINGS2:t_VITALS_X2_A.CDDVSACTDTTM) Req : Req 24-hour clock 1. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X2_A.SYSBP) (MAPPINGS2:t_VITALS_X2_A.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X2_A.DIABP) (MAPPINGS2:t_VITALS_X2_A.DIABP) 11. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X2_A.HEART) (MAPPINGS2:t_VITALS_X2_A.HEART) Sitting or standing after 3 minutes 12. Subject position (MAPPINGS1:t_VITALS_X2_A.VSPOSCD) (MAPPINGS2:t_VITALS_X2_A.VSPOSCD) [2] Sitting [3] Standing 13. Actual time Hr:Min (:-23:59) NReq / NReq / NReq (28-29) (MAPPINGS1:t_VITALS_X2_A.CDDVSACTTM) (MAPPINGS2:t_VITALS_X2_A.CDDVSACTDTTM) Req : Req 24-hour clock 14. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X2_A.SYSBP) (MAPPINGS2:t_VITALS_X2_A.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X2_A.DIABP) (MAPPINGS2:t_VITALS_X2_A.DIABP) 15. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X2_A.HEART) (MAPPINGS2:t_VITALS_X2_A.HEART) Form Design Note: Bench vitals (x2) clone A 9 Item Design Notes: Item No. Design Note itmvsbmi Item to be calculated as: Weight in kilograms divided by the square of height in meters 12. Item is optional. If one position is stipulated for protocol add specific text to Blood pressure. If more than one position is allowed, keep this item and remove the text from the BP item CDD: MAPPINGS1 Table: t_vitals_x20_a Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDVSACTTM DATE - DDMONYYYY HHMM HEIGHT NUMERIC - N3 WEIGHT FLOAT - F5.1 VSBMI STRING(255) SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 VSPOSCD STRING(1) CDD: MAPPINGS2 Table: t_vitals_x20_a Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDVSACTDTTM DATE - DDMONYYYY HHMM HEIGHT NUMERIC - N3 WEIGHT FLOAT - F5.1 VSBMI STRING(255) SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 VSPOSCD STRING(1)

346 ari111402_nwr_e : ELECTRONICALLY TRANSFERRED LAB DATA (Lab) Annotated Trial Design Page 10 of Haematology Date and time sample taken Hr:Min (:-23:59) 2. Clinical Chemistry Date and time sample taken Hr:Min (:-23:59) 3. Urinalysis Date and time sample taken Hr:Min (:-23:59) (MAPPINGS1:t_LABLINK_X1_A.rdcLABDTTM) (MAPPINGS2:t_LABLINK_X1_A.rdcLABDTTM) [- Date Req / Req / Req (28-29) (MAPPINGS1:t_LABLINK_X1_A.LBDTTM1) 99] (MAPPINGS2:t_LABLINK_X1_A.LBDTTM1) Req : Req 24-hour clock [ND] Not Done (MAPPINGS1:t_LABLINK_X1_A.rdcLABDTTM1) (MAPPINGS2:t_LABLINK_X1_A.rdcLABDTTM1) [- Same as the Haematology sample 98] [- Date Req / Req / Req (28-29) (MAPPINGS1:t_LABLINK_X1_A.LBDTTM1) 99] (MAPPINGS2:t_LABLINK_X1_A.LBDTTM1) Req : Req 24-hour clock [ND] Not Done (MAPPINGS1:t_LABLINK_X1_A.rdcLABDTTM) (MAPPINGS2:t_LABLINK_X1_A.rdcLABDTTM) [- Date Req / Req / Req (28-29) (MAPPINGS1:t_LABLINK_X1_A.LBDTTM1) 99] (MAPPINGS2:t_LABLINK_X1_A.LBDTTM1) Req : Req 24-hour clock [ND] Not Done Form Design Note: Bench Lablink form (x1) Clone A. Section Design Notes: Title Design Note sctlablink_x1_a_1 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 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. 2. Time is optional. Use this item for all other samples on the form 3. Time is optional. Use this item as the first item on this form. For additional tests, use the second item. CDD: MAPPINGS1 Table: t_lablink_x1_a Key Type: PATIENTTOITEM Column Name Column Data Type Design Note rdclabdttm STRING(3) LBDTTM1 DATE - DDMONYYYY HHMM rdclabdttm1 STRING(3) CDD: MAPPINGS2 Table: t_lablink_x1_a Key Type: PATIENTTOITEM Column Name Column Data Type Design Note rdclabdttm STRING(3) LBDTTM1 DATE - DDMONYYYY HHMM rdclabdttm1 STRING(3) 10

347 ari111402_nwr_e : ELIGIBILITY QUESTION (ELIG) Annotated Trial Design Page 11 of 51 ELIGIBILITY QUESTION 1. Did the subject meet all the entry criteria? (MAPPINGS1:t_ELIG.IEELIG) (MAPPINGS2:t_ELIG.IEELIG) [Y] Yes [N] No, please select all boxes corresponding to violations of any inclusion/exclusion criteria Inclusion Criteria (MAPPINGS1:t_ELIG.IECRTNUMI1) (MAPPINGS2:t_ELIG.IECRTNUMI1) [I01] Inclusion Criteria 1 (MAPPINGS1:t_ELIG.IECRTNUMI2) (MAPPINGS2:t_ELIG.IECRTNUMI2) [I02] Inclusion Criteria 2 (MAPPINGS1:t_ELIG.IECRTNUMI3) (MAPPINGS2:t_ELIG.IECRTNUMI3) [I03] Inclusion Criteria 3 (MAPPINGS1:t_ELIG.IECRTNUMI4) (MAPPINGS2:t_ELIG.IECRTNUMI4) [I04] Inclusion Criteria 4 (MAPPINGS1:t_ELIG.IECRTNUMI5) (MAPPINGS2:t_ELIG.IECRTNUMI5) [I05] Inclusion Criteria 5 (MAPPINGS1:t_ELIG.IECRTNUMI6) (MAPPINGS2:t_ELIG.IECRTNUMI6) [I06] Inclusion Criteria 6 (MAPPINGS1:t_ELIG.IECRTNUMI7) (MAPPINGS2:t_ELIG.IECRTNUMI7) [I07] Inclusion Criteria 7 Exclusion Criteria (MAPPINGS1:t_ELIG.IECRTNUME1) (MAPPINGS2:t_ELIG.IECRTNUME1) [E01] Exclusion Criteria 1 (MAPPINGS1:t_ELIG.IECRTNUME2) (MAPPINGS2:t_ELIG.IECRTNUME2) [E02] Exclusion Criteria 2 (MAPPINGS1:t_ELIG.IECRTNUME3) (MAPPINGS2:t_ELIG.IECRTNUME3) [E03] Exclusion Criteria 3 (MAPPINGS1:t_ELIG.IECRTNUME4) (MAPPINGS2:t_ELIG.IECRTNUME4) [E04] Exclusion Criteria 4 (MAPPINGS1:t_ELIG.IECRTNUME5) (MAPPINGS2:t_ELIG.IECRTNUME5) [E05] Exclusion Criteria 5 (MAPPINGS1:t_ELIG.IECRTNUME6) (MAPPINGS2:t_ELIG.IECRTNUME6) [E06] Exclusion Criteria 6 (MAPPINGS1:t_ELIG.IECRTNUME7) (MAPPINGS2:t_ELIG.IECRTNUME7) [E07] Exclusion Criteria 7 (MAPPINGS1:t_ELIG.IECRTNUME8) (MAPPINGS2:t_ELIG.IECRTNUME8) [E08] Exclusion Criteria 8 (MAPPINGS1:t_ELIG.IECRTNUME9) (MAPPINGS2:t_ELIG.IECRTNUME9) [E09] Exclusion Criteria 9 (MAPPINGS1:t_ELIG.IECRTNUME1) (MAPPINGS2:t_ELIG.IECRTNUME1) [E10] Exclusion Criteria 1 (MAPPINGS1:t_ELIG.IECRTNUME11) (MAPPINGS2:t_ELIG.IECRTNUME11) [E11] Exclusion Criteria 11 (MAPPINGS1:t_ELIG.IECRTNUME12) 11 Form Design Note: IDSL Version 2.A - 22 NOV 6 CDD: MAPPINGS1 Table: t_elig Key Type: PATIENTVISIT Column Name Column Data Type Design Note IEELIG STRING(1) IECRTNUMI1 STRING(255) IECRTNUMI2 STRING(255) IECRTNUMI3 STRING(255) IECRTNUMI4 STRING(255) IECRTNUMI5 STRING(255) IECRTNUMI6 STRING(255) IECRTNUMI7 STRING(255) IECRTNUME1 STRING(255) IECRTNUME2 STRING(255) IECRTNUME3 STRING(255) IECRTNUME4 STRING(255) IECRTNUME5 STRING(255) IECRTNUME6 STRING(255) IECRTNUME7 STRING(255) IECRTNUME8 STRING(255) IECRTNUME9 STRING(255) IECRTNUME1 STRING(255) IECRTNUME11 STRING(255) IECRTNUME12 STRING(255) IECRTNUME13 STRING(255) IECRTNUME14 STRING(255) IECRTNUME15 STRING(255) CDD: MAPPINGS2 Table: t_elig Key Type: PATIENTVISIT Column Name Column Data Type Design Note IEELIG STRING(1) IECRTNUMI1 STRING(255) IECRTNUMI2 STRING(255) IECRTNUMI3 STRING(255) IECRTNUMI4 STRING(255) IECRTNUMI5 STRING(255) IECRTNUMI6 STRING(255) IECRTNUMI7 STRING(255) IECRTNUME1 STRING(255) IECRTNUME2 STRING(255) IECRTNUME3 STRING(255) IECRTNUME4 STRING(255) IECRTNUME5 STRING(255) IECRTNUME6 STRING(255) IECRTNUME7 STRING(255) IECRTNUME8 STRING(255) IECRTNUME9 STRING(255) IECRTNUME1 STRING(255) (MAPPINGS2:t_ELIG.IECRTNUME12) [E12] Exclusion Criteria 12 (MAPPINGS1:t_ELIG.IECRTNUME13) (MAPPINGS2:t_ELIG.IECRTNUME13) [E13] Exclusion Criteria 13 (MAPPINGS1:t_ELIG.IECRTNUME14) (MAPPINGS2:t_ELIG.IECRTNUME14) [E14] Exclusion Criteria 14 (MAPPINGS1:t_ELIG.IECRTNUME15) (MAPPINGS2:t_ELIG.IECRTNUME15) [E15] Exclusion Criteria 15 IECRTNUME11 STRING(255) IECRTNUME12 STRING(255) IECRTNUME13 STRING(255)

348 Page 12 of 51 CONFIDENTIAL ZM2008/00081/00 Annotated Trial Design IECRTNUME14 STRING(255) IECRTNUME15 STRING(255) 12

349 ari111402_nwr_e : RANDOMISATION NUMBER (Rand) Annotated Trial Design Page 13 of 51 RANDOMISATION 1. Was the subject able to be randomised? (MAPPINGS1:t_RAND.rdcRandYN) (MAPPINGS2:t_RAND.rdcRandYN) [Y] Yes, provide: Randomisation number (MAPPINGS1:t_RAND.RANDNUM) xxxxxx (MAPPINGS2:t_RAND.RANDNUM) Date of randomisation Req / Req / Req (28-29) (MAPPINGS1:t_RAND.RANDDT) (MAPPINGS2:t_RAND.RANDDT) [N] No CDD: MAPPINGS1 Table: t_rand Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdcrandyn STRING(1) RANDNUM NUMERIC - N6 RANDDT DATE - DDMONYYYY CDD: MAPPINGS2 Table: t_rand Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdcrandyn STRING(1) RANDNUM NUMERIC - N6 RANDDT DATE - DDMONYYYY 13

350 ari111402_nwr_e : MEAL STATUS (Meal) Annotated Trial Design Page 14 of Did the subject eat breakfast prior to dosing? (MAPPINGS1:t_MEAL_1.FAST1) (MAPPINGS2:t_MEAL_1.FAST1) [Y] Yes [N] No CDD: MAPPINGS1 Table: t_meal_1 Key Type: PATIENTVISIT Column Name Column Data Type Design Note FAST1 STRING(1) CDD: MAPPINGS2 Table: t_meal_1 Key Type: PATIENTVISIT Column Name Column Data Type Design Note FAST1 STRING(1) 14

351 ari111402_nwr_e : INVESTIGATIONAL PRODUCT (Dose) Annotated Trial Design Page 15 of 51 INVESTIGATIONAL PRODUCT 1. Date/time of dose Req / Req / Req (28-29) (MAPPINGS1:t_EXPOSURE_SINGLE_A.EXSTDTTM) (MAPPINGS2:t_EXPOSURE_SINGLE_A.EXSTDTTM) Req : Req 24-hour clock Form Design Note: Bench IP form single dose Clone A CDD: MAPPINGS1 Table: t_exposure_single_a Key Type: PATIENTVISIT Column Name Column Data Type Design Note EXSTDTTM DATE - DDMONYYYY HHMM CDD: MAPPINGS2 Table: t_exposure_single_a Key Type: PATIENTVISIT Column Name Column Data Type Design Note EXSTDTTM DATE - DDMONYYYY HHMM 15

352 ari111402_nwr_e : TREATMENT CONFIRMATION (Trt Conf) Annotated Trial Design Page 16 of 51 TREATMENT CONFIRMATION 1. Did the subject receive the correct treatment (e.g., treatment which the subject was assigned to) during this dosing interval? (MAPPINGS1:t_EXPOSURE_TREATCONF.EXTRTCFM) (MAPPINGS2:t_EXPOSURE_TREATCONF.EXTRTCFM) [Y] Yes [N] No, record reason(s) A2 (MAPPINGS1:t_EXPOSURE_TREATCONF.EXTRTRS) (MAPPINGS2:t_EXPOSURE_TREATCONF.EXTRTRS) Form Design Note: This form is conditionally required when other IVRS system is used. This form is to be placed at every dosing interval. This page should not be placed at the log visit. CDD: MAPPINGS1 Table: t_exposure_treatconf Key Type: PATIENTVISIT Column Name Column Data Type Design Note EXTRTCFM STRING(1) EXTRTRS STRING(2) - A2 CDD: MAPPINGS2 Table: t_exposure_treatconf Key Type: PATIENTVISIT Column Name Column Data Type Design Note EXTRTCFM STRING(1) EXTRTRS STRING(2) - A2 16

353 ari111402_nwr_e : VITAL SIGNS (VS) Annotated Trial Design Page 17 of 51 DOSING DATE AND TIME 1. * Dosing date/time [read-only] Req / Req / Req (28-29) (MAPPINGS1:t_VITALS_X3_A.CDDDOSEDTTM) (MAPPINGS2:t_VITALS_X3_A.CDDDOSEDTTM) Req : Req 24-hour clock Supine 1 hour pre-dose 2. Actual date/time Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_VITALS_X3_A.VSACTDTTM) (MAPPINGS2:t_VITALS_X3_A.VSACTDTTM) Req : Req 24-hour clock 3. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X3_A.SYSBP) (MAPPINGS2:t_VITALS_X3_A.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X3_A.DIABP) (MAPPINGS2:t_VITALS_X3_A.DIABP) 4. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X3_A.HEART) (MAPPINGS2:t_VITALS_X3_A.HEART) Supine 2 hours post-dose 5. Actual date/time Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_VITALS_X3_A.VSACTDTTM) (MAPPINGS2:t_VITALS_X3_A.VSACTDTTM) Req : Req 24-hour clock 6. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X3_A.SYSBP) (MAPPINGS2:t_VITALS_X3_A.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X3_A.DIABP) (MAPPINGS2:t_VITALS_X3_A.DIABP) 7. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X3_A.HEART) (MAPPINGS2:t_VITALS_X3_A.HEART) Supine 4 hours post-dose 8. Actual date/time Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_VITALS_X3_A.VSACTDTTM) (MAPPINGS2:t_VITALS_X3_A.VSACTDTTM) Req : Req 24-hour clock 9. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X3_A.SYSBP) (MAPPINGS2:t_VITALS_X3_A.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X3_A.DIABP) (MAPPINGS2:t_VITALS_X3_A.DIABP) 1. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X3_A.HEART) (MAPPINGS2:t_VITALS_X3_A.HEART) * Item is not required Form Design Note: Bench vitals (x3) clone A CDD: MAPPINGS1 Table: t_vitals_x3_a Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 17 CDD: MAPPINGS2 Table: t_vitals_x3_a Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3

354 ari111402_nwr_e : ORTHOSTATIC VITAL SIGNS (ORTHO VS) Annotated Trial Design Page 18 of 51 ORTHOSTATIC VITAL SIGNS ARE TO BE TAKEN 6 HOURS POST DOSE DOSING DATE AND TIME 1. * Dosing date/time [read-only] Req / Req / Req (28-29) (MAPPINGS1:t_VITALS_X2_B.CDDDOSEDTTM) (MAPPINGS2:t_VITALS_X2_B.CDDDOSEDTTM) Req : Req 24-hour clock Supine (first measurement of three) 2. Actual time Hr:Min (:-23:59) Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X2_B.CDDVSACTTM) (MAPPINGS2:t_VITALS_X2_B.CDDVSACTTM) 3. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X2_B.SYSBP) (MAPPINGS2:t_VITALS_X2_B.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X2_B.DIABP) (MAPPINGS2:t_VITALS_X2_B.DIABP) 4. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X2_B.HEART) (MAPPINGS2:t_VITALS_X2_B.HEART) Supine (second measurement of three) 5. Actual time Hr:Min (:-23:59) Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X2_B.CDDVSACTTM) (MAPPINGS2:t_VITALS_X2_B.CDDVSACTTM) 6. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X2_B.SYSBP) (MAPPINGS2:t_VITALS_X2_B.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X2_B.DIABP) (MAPPINGS2:t_VITALS_X2_B.DIABP) 7. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X2_B.HEART) (MAPPINGS2:t_VITALS_X2_B.HEART) Supine (third measurement of three) 8. Actual time Hr:Min (:-23:59) Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X2_B.CDDVSACTTM) (MAPPINGS2:t_VITALS_X2_B.CDDVSACTTM) 9. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X2_B.SYSBP) (MAPPINGS2:t_VITALS_X2_B.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X2_B.DIABP) (MAPPINGS2:t_VITALS_X2_B.DIABP) 1. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X2_B.HEART) (MAPPINGS2:t_VITALS_X2_B.HEART) Sitting or standing after 3 minutes 11. Actual time Hr:Min (:-23:59) Req : Req 24-hour clock (MAPPINGS1:t_VITALS_X2_B.CDDVSACTTM) (MAPPINGS2:t_VITALS_X2_B.CDDVSACTTM) 12. Subject position (MAPPINGS1:t_VITALS_X2_B.VSPOSCD) (MAPPINGS2:t_VITALS_X2_B.VSPOSCD) [2] Sitting [3] Standing 13. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X2_B.SYSBP) (MAPPINGS2:t_VITALS_X2_B.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X2_B.DIABP) (MAPPINGS2:t_VITALS_X2_B.DIABP) 14. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X2_B.HEART) (MAPPINGS2:t_VITALS_X2_B.HEART) * Item is not required Form Design Note: Bench vitals (x2) clone B 18 Item Design Notes: Item No. Design Note 12. Item is optional. If one position is stipulated for protocol add specific text to Blood pressure. If more than one position is allowed, keep this item and remove the text from the BP item CDD: MAPPINGS1 Table: t_vitals_x20_b Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDVSACTTM DATE - HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 VSPOSCD STRING(1) CDD: MAPPINGS2 Table: t_vitals_x20_b Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDVSACTTM DATE - HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 VSPOSCD STRING(1)

355 ari111402_nwr_e : PHARMACOKINETICS BLOOD - GI (PK) Annotated Trial Design Page 19 of 51 DOSING DATE AND TIME 1. * Dosing date/time [read-only] Req / Req / Req (28-29) (MAPPINGS1:t_PK_X2_A.CDDDOSEDTTM) (MAPPINGS2:t_PK_X2_A.CDDDOSEDTTM) Req : Req 24-hour clock Pre-dose 2. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_A.CDDPKSTTM) (MAPPINGS2:t_PK_X2_A.CDDPKSTTM) 1 hour post-dose 3. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_A.CDDPKSTTM) (MAPPINGS2:t_PK_X2_A.CDDPKSTTM) 2 hours post-dose 4. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_A.CDDPKSTTM) (MAPPINGS2:t_PK_X2_A.CDDPKSTTM) 3 hours post-dose 5. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_A.CDDPKSTTM) (MAPPINGS2:t_PK_X2_A.CDDPKSTTM) 4 hours post-dose 6. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_A.CDDPKSTTM) (MAPPINGS2:t_PK_X2_A.CDDPKSTTM) 5 hours post-dose 7. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_A.CDDPKSTTM) (MAPPINGS2:t_PK_X2_A.CDDPKSTTM) 6 hours post-dose 8. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_A.CDDPKSTTM) (MAPPINGS2:t_PK_X2_A.CDDPKSTTM) 7 hours post-dose 9. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_A.CDDPKSTTM) (MAPPINGS2:t_PK_X2_A.CDDPKSTTM) 8 hours post-dose 1. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_A.CDDPKSTTM) (MAPPINGS2:t_PK_X2_A.CDDPKSTTM) 10 hours post-dose 11. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_A.CDDPKSTTM) (MAPPINGS2:t_PK_X2_A.CDDPKSTTM) 12 hours post-dose 12. Actual date/time Req / Req / Req (28-29) (MAPPINGS1:t_PK_X2_A.PKSTDTTM) (MAPPINGS2:t_PK_X2_A.PKSTDTTM) Req : Req 24-hour clock 16 hours post-dose 13. Actual date/time Req / Req / Req (28-29) (MAPPINGS1:t_PK_X2_A.PKSTDTTM) (MAPPINGS2:t_PK_X2_A.PKSTDTTM) Req : Req 24-hour clock * Item is not required Form Design Note: Bench PK (x2) clone A 19 CDD: MAPPINGS1 Table: t_pk_x20_a Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDPKSTTM DATE - HHMM PKSTDTTM DATE - DDMONYYYY HHMM CDD: MAPPINGS2 Table: t_pk_x20_a Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDPKSTTM DATE - HHMM PKSTDTTM DATE - DDMONYYYY HHMM

356 ari111402_nwr_e : VITAL SIGNS (VS) Annotated Trial Design Page 20 of 51 DOSING DATE AND TIME 1. * Dosing date/time [read-only] Req / Req / Req (28-29) (MAPPINGS1:t_VITALS_X1_B.CDDDOSEDTTM) (MAPPINGS2:t_VITALS_X1_B.CDDDOSEDTTM) Req : Req 24-hour clock Supine 1 hour pre-dose 2. Actual date/time Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_VITALS_X1_B.VSACTDTTM) (MAPPINGS2:t_VITALS_X1_B.VSACTDTTM) Req : Req 24-hour clock 3. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X1_B.SYSBP) (MAPPINGS2:t_VITALS_X1_B.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X1_B.DIABP) (MAPPINGS2:t_VITALS_X1_B.DIABP) 4. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X1_B.HEART) (MAPPINGS2:t_VITALS_X1_B.HEART) * Item is not required Form Design Note: Bench vitals (x1) clone B CDD: MAPPINGS1 Table: t_vitals_x1_b Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 CDD: MAPPINGS2 Table: t_vitals_x1_b Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 20

357 ari111402_nwr_e : PHARMACOKINETICS BLOOD - GI (PK) Annotated Trial Design Page 21 of 51 DOSING DATE AND TIME 1. * Dosing date/time [read-only] Req / Req / Req (28-29) (MAPPINGS1:t_PK_X1_A.CDDDOSEDTTM) (MAPPINGS2:t_PK_X1_A.CDDDOSEDTTM) Req : Req 24-hour clock Pre-dose 2. Actual date/time Req / Req / Req (28-29) (MAPPINGS1:t_PK_X1_A.PKSTDTTM) (MAPPINGS2:t_PK_X1_A.PKSTDTTM) Req : Req 24-hour clock * Item is not required Form Design Note: Bench PK (x1) clone A CDD: MAPPINGS1 Table: t_pk_x1_a Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM PKSTDTTM DATE - DDMONYYYY HHMM CDD: MAPPINGS2 Table: t_pk_x1_a Key Type: PATIENTVISIT Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM PKSTDTTM DATE - DDMONYYYY HHMM 21

358 ari111402_nwr_e : PHARMACOKINETICS BLOOD - GI (PK) Annotated Trial Design Page 22 of 51 DOSING DATE AND TIME 1. * Dosing date/time [read-only] Req / Req / Req (28-29) (MAPPINGS1:t_PK_X2_B.CDDDOSEDTTM) (MAPPINGS2:t_PK_X2_B.CDDDOSEDTTM) Req : Req 24-hour clock Pre-dose 2. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_B.CDDPKSTTM) (MAPPINGS2:t_PK_X2_B.CDDPKSTTM) 1 hour post-dose 3. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_B.CDDPKSTTM) (MAPPINGS2:t_PK_X2_B.CDDPKSTTM) 2 hours post-dose 4. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_B.CDDPKSTTM) (MAPPINGS2:t_PK_X2_B.CDDPKSTTM) 3 hours post-dose 5. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_B.CDDPKSTTM) (MAPPINGS2:t_PK_X2_B.CDDPKSTTM) 4 hours post-dose 6. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_B.CDDPKSTTM) (MAPPINGS2:t_PK_X2_B.CDDPKSTTM) 5 hours post-dose 7. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_B.CDDPKSTTM) (MAPPINGS2:t_PK_X2_B.CDDPKSTTM) 6 hours post-dose 8. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_B.CDDPKSTTM) (MAPPINGS2:t_PK_X2_B.CDDPKSTTM) 7 hours post-dose 9. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_B.CDDPKSTTM) (MAPPINGS2:t_PK_X2_B.CDDPKSTTM) 8 hours post-dose 1. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_B.CDDPKSTTM) (MAPPINGS2:t_PK_X2_B.CDDPKSTTM) 10 hours post-dose 11. Actual time Req : Req 24-hour clock (MAPPINGS1:t_PK_X2_B.CDDPKSTTM) (MAPPINGS2:t_PK_X2_B.CDDPKSTTM) 12 hours post-dose 12. Actual date/time Req / Req / Req (28-29) (MAPPINGS1:t_PK_X2_B.PKSTDTTM) (MAPPINGS2:t_PK_X2_B.PKSTDTTM) Req : Req 24-hour clock 16 hours post-dose 13. Actual date/time Req / Req / Req (28-29) (MAPPINGS1:t_PK_X2_B.PKSTDTTM) (MAPPINGS2:t_PK_X2_B.PKSTDTTM) Req : Req 24-hour clock 24 hours post-dose 14. Actual date/time Req / Req / Req (28-29) (MAPPINGS1:t_PK_X2_B.PKSTDTTM) (MAPPINGS2:t_PK_X2_B.PKSTDTTM) Req : Req 24-hour clock 36 hours post-dose 15. Actual date/time Req / Req / Req (28-29) (MAPPINGS1:t_PK_X2_B.PKSTDTTM) (MAPPINGS2:t_PK_X2_B.PKSTDTTM) Req : Req 24-hour clock hours post-dose (MAPPINGS1:t_PK_X2_B.PKSTDTTM) 16. Actual date/time Req / Req / Req (28-29) (MAPPINGS2:t_PK_X2_B.PKSTDTTM) Req : Req 24-hour clock 72 hours post-dose (MAPPINGS1:t_PK_X2_B.PKSTDTTM) 17. Actual date/time Req / Req / Req (28-29) (MAPPINGS2:t_PK_X2_B.PKSTDTTM) Req : Req 24-hour clock * Item is not required Form Design Note: Bench PK (x2) clone B CDD: MAPPINGS1 Table: t_pk_x20_b Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDPKSTTM DATE - HHMM PKSTDTTM DATE - DDMONYYYY HHMM CDD: MAPPINGS2 Table: t_pk_x20_b Key Type: PATIENTTOSECTION Column Name Column Data Type Design Note CDDDOSEDTTM DATE - DDMONYYYY HHMM CDDPKSTTM DATE - HHMM PKSTDTTM DATE - DDMONYYYY HHMM

359 ari111402_nwr_e : VITAL SIGNS (VS) Annotated Trial Design Page 23 of 51 SUPINE VITAL SIGNS 1. Actual date/time Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_VITALS_X1_C.VSACTDTTM) (MAPPINGS2:t_VITALS_X1_C.VSACTDTTM) Req : Req 24-hour clock 2. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_X1_C.SYSBP) (MAPPINGS2:t_VITALS_X1_C.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_X1_C.DIABP) (MAPPINGS2:t_VITALS_X1_C.DIABP) 3. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_X1_C.HEART) (MAPPINGS2:t_VITALS_X1_C.HEART) Form Design Note: Bench vitals (x1) clone C CDD: MAPPINGS1 Table: t_vitals_x1_c Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 CDD: MAPPINGS2 Table: t_vitals_x1_c Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 23

360 ari111402_nwr_e : 12-LEAD ECG (ECG) Annotated Trial Design Page 24 of 51 SUPINE 12-LEAD ECG 1. Date and Time of ECG Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_ECG_Z_FU.EGDTTM) (MAPPINGS2:t_ECG_Z_FU.EGDTTM) Req : Req 24-hour clock 2. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_ECG_Z_FU.EGHR) (MAPPINGS2:t_ECG_Z_FU.EGHR) 3. PR Interval xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_Z_FU.PR ) (MAPPINGS2:t_ECG_Z_FU.PR ) 4. QRS Duration xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_Z_FU.QRS ) (MAPPINGS2:t_ECG_Z_FU.QRS ) 5. Uncorrected QT Interval xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_Z_FU.QT ) (MAPPINGS2:t_ECG_Z_FU.QT ) 6. QTc Interval xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_Z_FU.QTC ) (MAPPINGS2:t_ECG_Z_FU.QTC ) 7. Result of the ECG (MAPPINGS1:t_ECG_Z_FU.EGINTPCD) (MAPPINGS2:t_ECG_Z_FU.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE [4] No result (not available) Form Design Note: Follow-up ECG CDD: MAPPINGS1 Table: t_ecg_z_fu Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR FLOAT - F6. QRS FLOAT - F6. QT FLOAT - F6. QTC FLOAT - F6. EGINTPCD STRING(1) CDD: MAPPINGS2 Table: t_ecg_z_fu Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR FLOAT - F6. QRS FLOAT - F6. QT FLOAT - F6. QTC FLOAT - F6. EGINTPCD STRING(1) 24

361 ari111402_nwr_e : VITAL SIGNS (VS) Annotated Trial Design Page 25 of 51 SUPINE VITAL SIGNS 1. Actual date/time Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_VITALS_Z_FU.VSACTDTTM) (MAPPINGS2:t_VITALS_Z_FU.VSACTDTTM) Req : Req 24-hour clock 2. Blood pressure xxx ( n >= ) / (MAPPINGS1:t_VITALS_Z_FU.SYSBP) (MAPPINGS2:t_VITALS_Z_FU.SYSBP) (systolic/diastolic) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_Z_FU.DIABP) (MAPPINGS2:t_VITALS_Z_FU.DIABP) 3. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_Z_FU.HEART) (MAPPINGS2:t_VITALS_Z_FU.HEART) Form Design Note: Follow-up vital signs CDD: MAPPINGS1 Table: t_vitals_z_fu Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 CDD: MAPPINGS2 Table: t_vitals_z_fu Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM SYSBP NUMERIC - N3 DIABP NUMERIC - N3 HEART NUMERIC - N3 25

362 ari111402_nwr_e : STUDY CONCLUSION (Conclusion) Annotated Trial Design Page 26 of 51 STUDY CONCLUSION 1. Date of subject completion or withdrawal Req / Req / Req (28-29) (MAPPINGS1:t_DS_CONCLUSION.DSSTDT) (MAPPINGS2:t_DS_CONCLUSION.DSSTDT) 2. Was the subject withdrawn from the study? (MAPPINGS1:t_DS_CONCLUSION.DSFAIL1) (MAPPINGS2:t_DS_CONCLUSION.DSFAIL1) [N] No [Y] (MAPPINGS1:t_DS_CONCLUSION.DSRSCD) (MAPPINGS2:t_DS_CONCLUSION.DSRSCD) Yes, complete primary reason for withdrawal [1] Adverse Event Record details on the Non-Serious Adverse Events or Serious Adverse Events forms as appropriate. Lack of efficacy [2] [3] Protocol deviation [4] Subject reached protocol defined stopping criteria [5] Study closed/terminated [6] Lost to Follow-up (MAPPINGS1:t_DS_CONCLUSION.DSRSSP) [7] Investigator discretion, specify (MAPPINGS2:t_DS_CONCLUSION.DSRSSP) Select this reason if none of the other primary reasons are appropriate. A2 [8] Withdrew consent * 3. Case book ready for signature [hidden] (MAPPINGS1:t_DS_CONCLUSION.chkReadyForSig) (MAPPINGS2:t_DS_CONCLUSION.chkReadyForSig) [Y] Yes Data owner should check the box when data cleaning is complete Office Use 1 [hidden] Office Use 2 [hidden] (MAPPINGS1:t_DS_CONCLUSION.COMPLETERADIO) (MAPPINGS2:t_DS_CONCLUSION.COMPLETERADIO) [N] No [Y] Yes (MAPPINGS1:t_DS_CONCLUSION.REASONRADIO) (MAPPINGS2:t_DS_CONCLUSION.REASONRADIO) [?] 1 [?] 2 [?] 3 [?] 4 [?] 5 [?] 6 [?] 7 [?] 8 [?] 9 * Item is not required Form Design Note: IDSL version 1.1A - 15 MAY 7 (modified for Phase 1 template) Section Design Notes: Title Design Note STUDY CONCLUSION Alignment of predefined sub-reasons will be rectified once ecrf Designer has replaced [?] by valid codes. Item Design Notes: Item No. Design Note 2. Pre-defined sub-reasons are optional. The following primary reasons are optional : Lack of efficacy, Subject reached protocol-defined stopping criteria, Investigator discretion. 26 CDD: MAPPINGS1 Table: t_ds_conclusion Key Type: PATIENTVISIT Column Name Column Data Type Design Note DSSTDT DATE - DDMONYYYY DSFAIL1 STRING(1) DSRSCD STRING(1) DSRSSP STRING(2) - A2 chkreadyforsig STRING(255) COMPLETERADIO STRING(1) REASONRADIO STRING(42) CDD: MAPPINGS2 Table: t_ds_conclusion Key Type: PATIENTVISIT Column Name Column Data Type Design Note DSSTDT DATE - DDMONYYYY DSFAIL1 STRING(1) DSRSCD STRING(1) DSRSSP STRING(2) - A2 chkreadyforsig STRING(255) COMPLETERADIO STRING(1) REASONRADIO STRING(42)

363 ari111402_nwr_e : PREGNANCY INFORMATION (Preg M) Annotated Trial Design Page 27 of 51 PREGNANCY INFORMATION 1. Did a female partner of the male subject become pregnant during the study? If Yes, complete the paper Pregnancy Notification form (MAPPINGS1:t_STATUS_PREG_M.PGFPYN) (MAPPINGS2:t_STATUS_PREG_M.PGFPYN) [N] No [Y] Yes [X] Not Applicable Check Not Applicable if female partner not of childbearing potential or no female partner Form Design Note: This is an optional form, but is conditional upon males in the trial. This form will be dynamically generated if the male is selected on the Demography form CDD: MAPPINGS1 Table: t_status_preg_m Key Type: PATIENTVISIT Column Name Column Data Type Design Note PGFPYN STRING(1) CDD: MAPPINGS2 Table: t_status_preg_m Key Type: PATIENTVISIT Column Name Column Data Type Design Note PGFPYN STRING(1) 27

364 ari111402_nwr_e : LOGS AND REPEATS (Logs/Rpts) Annotated Trial Design Page 28 of 51 Date below is the start of the study for this subject DATE OF VISIT/ASSESSMENT 1. Date of visit/assessment Req / Req / Req (28-29) (MAPPINGS1:t_STATUS_LOGS.DOV) (MAPPINGS2:t_STATUS_LOGS.DOV) ADVERSE EVENT/CONCOMITANT MEDICATION/REPEAT ASSESSMENT CHECK QUESTIONS 2. Did the subject experience any non-serious adverse events during the study? (MAPPINGS1:t_STATUS_LOGS.AEANY) (MAPPINGS2:t_STATUS_LOGS.AEANY) [Y] Yes [N] No (MAPPINGS1:t_STATUS_LOGS.SAEANY) 3. Did the subject experience any serious adverse events during the study? (MAPPINGS2:t_STATUS_LOGS.SAEANY) [Y] Yes [N] No (MAPPINGS1:t_STATUS_LOGS.CMANY) 4. Were any concomitant medications taken by the subject during the study? (MAPPINGS2:t_STATUS_LOGS.CMANY) [Y] Yes [N] No (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) 5. Were any repeat ECGs performed? (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) 6. Were any abnormal, clinically significant ECG measurements recorded for this subject during the study? (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) 7. Were any repeat vital signs recorded? (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) 8. Were any repeat orthostatic vital signs recorded? (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) 9. Were any repeat haematology, clinical chemistry, or urine samples taken? (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No (MAPPINGS1:t_STATUS_LOGS.rdcRptTrigger) 1. Were any repeat PK blood samples taken? (MAPPINGS2:t_STATUS_LOGS.rdcRptTrigger) [Y] Yes [N] No CDD: MAPPINGS1 Table: t_status_logs Key Type: PATIENTTOITEM Column Name Column Data Type Design Note DOV DATE - DDMONYYYY AEANY STRING(1) SAEANY STRING(1) CMANY STRING(1) rdcrpttrigger STRING(1) CDD: MAPPINGS2 Table: t_status_logs Key Type: PATIENTTOITEM Column Name Column Data Type Design Note DOV DATE - DDMONYYYY AEANY STRING(1) SAEANY STRING(1) CMANY STRING(1) rdcrpttrigger STRING(1) 28

365 ari111402_nwr_e : NON-SERIOUS ADVERSE EVENT (AE) - Repeating Form Annotated Trial Design Page 29 of 51 1 # Event Start Date and Time Outcome Frequency Maximum Intensity Action Taken Subject Withdrawn? Relationship NON-SERIOUS ADVERSE EVENT * 1. Sequence Number [hidden] A5 (MAPPINGS1:t_AE.AESEQ) (MAPPINGS2:t_AE.AESEQ) 2. Event Diagnosis Only (if knownotherwise Sign/Symptom A1 (MAPPINGS1:t_AE.AETERM) (MAPPINGS2:t_AE.AETERM) 3. * Modified term [hidden] A1 (AE_CODE:.LogsRpts.AE.sctAE..itmAELLTCD.AELLTCD) (AE_FAILED:.LogsRpts.AE.sctAE..itmAE_FAILED.calAE_FAILED) (AE_SYNONYM:.LogsRpts.AE.sctAE..itmAEMEDSYN.AEMEDSYN) (MAPPINGS1:t_AE.AEMODIFY) (MAPPINGS2:t_AE.AEMODIFY) MedDRA synonym [hidden] MedDRA lower level term code [hidden] Failed coding [hidden] 4. Start Date and Time Hr:Min (:-23:59) 5. Outcome / End Date and Time Hr:Min (:-23:59) (MAPPINGS1:t_AE.AEMEDSYN) (MAPPINGS2:t_AE.AEMEDSYN) (MAPPINGS1:t_AE.AELLTCD) (MAPPINGS2:t_AE.AELLTCD) (MAPPINGS1:t_AE.calAE_FAILED) (MAPPINGS2:t_AE.calAE_FAILED) Req / Req / Req (28-29) (MAPPINGS1:t_AE.AESTDTTM) (MAPPINGS2:t_AE.AESTDTTM) NReq : NReq 24-hour clock (MAPPINGS1:t_AE.AEOUTCD) (MAPPINGS2:t_AE.AEOUTCD) [1] Recovered/Resolved, provide End Date and Time Req / Req / Req (28-29) (MAPPINGS1:t_AE.AEENDTTM1) (MAPPINGS2:t_AE.AEENDTTM1) NReq : NReq 24-hour clock [2] Recovering/Resolving [3] Not recovered/not resolved [4] Recovered/Resolved with sequelae, provide End Date and Time Req / Req / Req (28-29) (MAPPINGS1:t_AE.AEENDTTM2) (MAPPINGS2:t_AE.AEENDTTM2) NReq : NReq 24-hour clock Frequency (MAPPINGS1:t_AE.AEFREQCD) (MAPPINGS2:t_AE.AEFREQCD) [1] Single Episode [2] Intermittent * 7. Maximum Intensity (MAPPINGS1:t_AE.AESEVCD) (MAPPINGS2:t_AE.AESEVCD) [1] Mild [2] Moderate [3] Severe Not applicable [X] * 8. Maximum Grade [hidden] (MAPPINGS1:t_AE.AETOXCD) (MAPPINGS2:t_AE.AETOXCD) [1] Grade 1 [2] Grade 2 [3] Grade 3 [4] Grade 4 [5] Grade 5 Not applicable [X] * 9. Maximum Grade or Intensity [hidden] (MAPPINGS1:t_AE.AETXHVCD) (MAPPINGS2:t_AE.AETXHVCD) [1] Mild or Grade 1 [2] Moderate or Grade 2 [3] Severe or Grade 3 [4] Grade 4 [5] Grade 5 Not applicable [X] (MAPPINGS1:t_AE.AEACTRCD) 1. Action Taken with Investigational Product(s) as a Result of the AE (MAPPINGS2:t_AE.AEACTRCD) [1] Investigational product(s) withdrawn [2] Dose reduced [3] Dose increased [4] Dose not changed [5] Dose interrupted Not applicable [X] (MAPPINGS1:t_AE.AEWD) 11. Did the subject withdraw from study as a result of this AE? (MAPPINGS2:t_AE.AEWD) [Y] Yes [N] No (MAPPINGS1:t_AE.AEREL) 12. Is there a reasonable possibility that the AE may have been caused by the investigational product? (MAPPINGS2:t_AE.AEREL) [Y] Yes [N] No (MAPPINGS1:t_AE.AEDURHR) (MAPPINGS1:t_AE.AEDURMIN) 13. * Duration of AE if < 24 hours [hidden] xx ( =< n <= 23 ) xx ( =< n <= 59 ) (MAPPINGS2:t_AE.AEDURHR) (MAPPINGS2:t_AE.AEDURMIN) Hr(s) Min(s) 14. * (MAPPINGS1:t_AE.AEONLDSH) (MAPPINGS1:t_AE.AEONLDSM) Time to Onset Since Last Dose [hidden] xx xx ( =< n <= 59 ) (MAPPINGS2:t_AE.AEONLDSH) (MAPPINGS2:t_AE.AEONLDSM) Hr(s) Min(s) * Item is not required Form Design Note: IDSL Version 3.1A - 16 NOV 25 Item Design Notes: Item No. Design Note 4. Start Time is optional 5. End Time is optional 6. This item is optional 7. Optional item: This item may be hidden if either the "Maximum Grade" or "Maximum Grade or Intensity" item has been used. Grade 5 is optional. 8. Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade or Intensity" item has been used Grade 5 is optional. 9. Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade" item has been used Grade 5 is optional. 13. If AE start and end time are used this item must be hidden. 14. This item is optional CDD: MAPPINGS1 Table: t_ae Key Type: PATIENTVISIT Column Name Column Data Type Design Note AESEQ STRING(5) - A5 AETERM STRING(1) - A1 AEMODIFY STRING(1) - A1 AEMEDSYN STRING(255) AELLTCD STRING(255) calae_failed STRING(255) AESTDTTM DATE - DDMONYYYY HHMM AEOUTCD STRING(1) AEENDTTM1 DATE - DDMONYYYY HHMM AEENDTTM2 DATE - DDMONYYYY HHMM AEFREQCD STRING(1) AESEVCD STRING(1) AETOXCD STRING(1) AETXHVCD STRING(1) AEACTRCD STRING(1) AEWD STRING(1)

366 AEREL STRING(1) Annotated Trial Design Page 30 of 51 AEDURHR NUMERIC - N2 AEDURMIN NUMERIC - N2 AEONLDSH NUMERIC - N2 AEONLDSM NUMERIC - N2 CDD: MAPPINGS2 Table: t_ae Key Type: PATIENTVISIT Column Name Column Data Type Design Note AESEQ STRING(5) - A5 AETERM STRING(1) - A1 AEMODIFY STRING(1) - A1 AEMEDSYN STRING(255) AELLTCD STRING(255) calae_failed STRING(255) AESTDTTM DATE - DDMONYYYY HHMM AEOUTCD STRING(1) AEENDTTM1 DATE - DDMONYYYY HHMM AEENDTTM2 DATE - DDMONYYYY HHMM AEFREQCD STRING(1) AESEVCD STRING(1) AETOXCD STRING(1) AETXHVCD STRING(1) AEACTRCD STRING(1) AEWD STRING(1) AEREL STRING(1) AEDURHR NUMERIC - N2 AEDURMIN NUMERIC - N2 AEONLDSH NUMERIC - N2 AEONLDSM NUMERIC - N2 30

367 ari111402_nwr_e : SERIOUS ADVERSE EVENTS (SAE) - Repeating Form Annotated Trial Design Page 31 of 51 # Initial Report Follow-Up Report Did SAE occur after initiation of study medication? 1 SERIOUS ADVERSE EVENT Serious? RELEVANT CONCOMITANT/TREATMENT MEDICATIONS RELEVANT MEDICAL CONDITIONS/RISK FACTORS Relevant Medical History / Risk Factors RELEVANT DIAGNOSTIC RESULTS Relevant diagnostic results If Investigational product(s) stopped, did the reported event(s) recur after further investigational product(s) were administered? General narrative comments If you wish to record a new SAE please determine if the new SAE is clinically or temporally related to an SAE previously entered on this form. If yes, record the details below using the 'Add Entry' button in this form. If not clinically or temporally related, create a new SAE form for this subject by clicking on the 'New' button at the top of the page. Do not record pre and post randomization events on the same form. TYPE OF REPORT 1. * Initial Report [read-only] (MAPPINGS1:t_AE_SER.chkSAE) (MAPPINGS2:t_AE_SER.chkSAE) [1] Initial * 2. Follow-Up Report [read-only] (MAPPINGS1:t_AE_SER.chkFU) (MAPPINGS2:t_AE_SER.chkFU) [2] Follow-Up RANDOMISATION 3. Did SAE occur after initiation of study medication? (MAPPINGS1:t_AE_SER.rdcSAERAND) (MAPPINGS2:t_AE_SER.rdcSAERAND) No [N] [Y] Yes SAE Sequence Number Event Modified MedDRA term synonym MedDRA Failed Start lower coding Date level term and code Time Outcome Maximum Maximum Maximum Action Subject Relationship Duration Time to Was Was the Intensity Grade Grade or Taken Withdrawn? of AE if Onset SAE event Intensity < 24 study serious? hours related? 4. [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] SERIOUS ADVERSE EVENT Entry * 4.a SAE Sequence Number [hidden] A5 (MAPPINGS1:t_AE_SER.AESEQ) (MAPPINGS2:t_AE_SER.AESEQ) 4.b Serious Adverse Event Diagnosis Only (if knownotherwise Sign/Symptom A1 (MAPPINGS1:t_AE_SER.AETERM) (MAPPINGS2:t_AE_SER.AETERM) 4.c * Modified term [hidden] A1 (AE_CODE1:.LogsRpts.AE_SER.sctSAE.itsSAE.itmAELLTCD.AELLTCD) (AE_FAILED1:.LogsRpts.AE_SER.sctSAE.itsSAE.itmAE_FAILED.calAE_FAILED) (AE_SYNONYM1:.LogsRpts.AE_SER.sctSAE.itsSAE.itmAEMEDSYN.AEMEDSYN) (MAPPINGS1:t_AE_SER.AEMODIFY) (MAPPINGS2:t_AE_SER.AEMODIFY) MedDRA synonym [hidden] MedDRA lower level term code [hidden] Failed coding [hidden] 4.d Start Date and Time Hr:Min (:-23:59) (MAPPINGS1:t_AE_SER.AEMEDSYN) (MAPPINGS2:t_AE_SER.AEMEDSYN) (MAPPINGS1:t_AE_SER.AELLTCD) (MAPPINGS2:t_AE_SER.AELLTCD) (MAPPINGS1:t_AE_SER.calAE_FAILED) (MAPPINGS2:t_AE_SER.calAE_FAILED) Req / Req / Req (28-29) (MAPPINGS1:t_AE_SER.AESTDTTM) (MAPPINGS2:t_AE_SER.AESTDTTM) NReq : NReq 24-hour clock 4.e Outcome / End Date and Time Hr:Min (:-23:59) (MAPPINGS1:t_AE_SER.AEOUTCD1) (MAPPINGS2:t_AE_SER.AEOUTCD1) [1] Recovered/Resolved, provide End Date and Time Req / Req / Req (28-29) (MAPPINGS1:t_AE_SER.AEENDTTM1) (MAPPINGS2:t_AE_SER.AEENDTTM1) NReq : NReq 24-hour clock [2] Recovering/Resolving [3] Not recovered/not resolved [4] Recovered/Resolved with sequelae, provide End Date and Time (MAPPINGS1:t_AE_SER.AEENDTTM2) Req / Req / Req (28-29) (MAPPINGS2:t_AE_SER.AEENDTTM2) NReq : NReq 24-hour clock 31 [5] Fatal, record Date and Time of Death Req / Req / Req (28-29) (MAPPINGS1:t_AE_SER.AEENDTTM3) (MAPPINGS2:t_AE_SER.AEENDTTM3) NReq : NReq 24-hour clock * 4.f Maximum Intensity (MAPPINGS1:t_AE_SER.AESEVCD) (MAPPINGS2:t_AE_SER.AESEVCD) [1] Mild [2] Moderate [3] Severe Not applicable [X] * 4.g Maximum Grade [hidden] (MAPPINGS1:t_AE_SER.AETOXCD) (MAPPINGS2:t_AE_SER.AETOXCD) [1] Grade 1 [2] Grade 2 [3] Grade 3 [4] Grade 4 [5] Grade 5 Not applicable [X] 4.h * Maximum Grade or Intensity [hidden] (MAPPINGS1:t_AE_SER.AETXHVCD) (MAPPINGS2:t_AE_SER.AETXHVCD) [1] Mild or Grade 1 [2] Moderate or Grade 2 [3] Severe or Grade 3 [4] Grade 4 [5] Grade 5 [X] Not applicable 4.i Action Taken with Investigational Product(s) as a Result of the AE (MAPPINGS1:t_AE_SER.AEACTRCD) (MAPPINGS2:t_AE_SER.AEACTRCD) [1] Investigational product(s) withdrawn [2] Dose reduced [3] Dose increased [4] Dose not changed [5] Dose interrupted [X] Not applicable 4.j Did the subject withdraw from study as a result of this AE? (MAPPINGS1:t_AE_SER.AEWD) (MAPPINGS2:t_AE_SER.AEWD) Yes [Y] [N] No 4.k Is there a reasonable possibility that the AE may have been (MAPPINGS1:t_AE_SER.AEREL) caused by the investigational product? (MAPPINGS2:t_AE_SER.AEREL) [Y] Yes [N] No xx ( =< n <= 23 ) (MAPPINGS1:t_AE_SER.AEDURHR) (MAPPINGS1:t_AE_SER.AEDURMIN) 4.l * Duration of AE if < 24 hours [hidden] xx ( =< n <= 59 ) (MAPPINGS2:t_AE_SER.AEDURHR) (MAPPINGS2:t_AE_SER.AEDURMIN) Hr(s) Min(s) * 4.m (MAPPINGS1:t_AE_SER.AEONLDSH) (MAPPINGS1:t_AE_SER.AEONLDSM) Time to Onset Since Last Dose [hidden] xx xx ( =< n <= 59 ) (MAPPINGS2:t_AE_SER.AEONLDSH) (MAPPINGS2:t_AE_SER.AEONLDSM) Hr(s) Min(s) 4.n Was SAE caused by activities related to study participation (e.g. procedures)? (MAPPINGS1:t_AE_SER.rdcAESREL) (MAPPINGS2:t_AE_SER.rdcAESREL) [Y] Yes [N] No 4.o * Was the event serious? [hidden] (MAPPINGS1:t_AE_SER.AESER) (MAPPINGS2:t_AE_SER.AESER) [Y] Yes [N] No SERIOUSNESS Specify the reason for considering this an SAE. Check all that apply. 5. Seriousness? (MAPPINGS1:t_AE_SER.AESERDTH) (MAPPINGS2:t_AE_SER.AESERDTH) Results in death [A] (MAPPINGS1:t_AE_SER.AESERLIF) (MAPPINGS2:t_AE_SER.AESERLIF) Is life-threatening [B] (MAPPINGS1:t_AE_SER.AESERHOS) (MAPPINGS2:t_AE_SER.AESERHOS) Requires hospitalisation or prolongation of existing hospitalisation [C] (MAPPINGS1:t_AE_SER.AESERDIS) (MAPPINGS2:t_AE_SER.AESERDIS) Results in disability/incapacity [D] (MAPPINGS1:t_AE_SER.AESERCON) (MAPPINGS2:t_AE_SER.AESERCON) Congenital anomaly/birth defect [E] (MAPPINGS1:t_AE_SER.AESEROTH) (MAPPINGS2:t_AE_SER.AESEROTH) [F] Other, specify within general narrative comment CM Sequence Number Drug Name Dose Unit Frequency Route Start Date (Trade Name preferred) 6. [hidden] Ongoing? Primary Drug Indication Type RELEVANT CONCOMITANT/TREATMENT MEDICATIONS Entry

368 Include details of any medication that may have contributed to the SAE or was used to treat the SAE. Annotated Trial Design Page 32 of 51 * 6.a CM Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAECMSEQ) (MAPPINGS2:t_AE_SER.txtSAECMSEQ) 6.b Drug Name (Trade Name preferred) A1 (MAPPINGS1:t_AE_SER.txtCMTERM) (MAPPINGS2:t_AE_SER.txtCMTERM) * 6.c Dose xxxxxxxxx. (MAPPINGS1:t_AE_SER.txtSAECMDOS) (MAPPINGS2:t_AE_SER.txtSAECMDOS) * 6.d Unit Pulldown List 1 (MAPPINGS1:t_AE_SER.pdcCMUNIT) (MAPPINGS2:t_AE_SER.pdcCMUNIT) 6.e * Frequency Pulldown List 2 (MAPPINGS1:t_AE_SER.pdcSAECMFRQ) (MAPPINGS2:t_AE_SER.pdcSAECMFRQ) * 6.f Route Pulldown List 3 (MAPPINGS1:t_AE_SER.pdcCMROUTCD) (MAPPINGS2:t_AE_SER.pdcCMROUTCD) 6.g * Start Date Req/Unk / Req/Unk / Req/Unk (197-29) (MAPPINGS1:t_AE_SER.dtmSAECMSTD) (MAPPINGS2:t_AE_SER.dtmSAECMSTD) * 6.h Ongoing? (MAPPINGS1:t_AE_SER.rdcSAECMONG) (MAPPINGS2:t_AE_SER.rdcSAECMONG) [Y] [N] Yes No, specify End Date Req/Unk / Req/Unk / Req/Unk (197-29) (MAPPINGS1:t_AE_SER.dtmSAECMEND) (MAPPINGS2:t_AE_SER.dtmSAECMEND) * 6.i Primary Indication A5 (MAPPINGS1:t_AE_SER.txtCMIND) (MAPPINGS2:t_AE_SER.txtCMIND) 6.j Drug Type Pulldown List 4 (MAPPINGS1:t_AE_SER.pdcCMDRGTYP) (MAPPINGS2:t_AE_SER.pdcCMDRGTYP) MHx Sequence Number Specific Condition Name Date of onset 7. [hidden] RELEVANT MEDICAL CONDITIONS/RISK FACTORS Entry Specify past or current medical disorders, allergies, surgeries, family or social history that may help explain the SAE * 7.a MHx Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtMHXSEQ) (MAPPINGS2:t_AE_SER.txtMHXSEQ) Continuing? 7.b Specific Condition Name A1 (MAPPINGS1:t_AE_SER.txtSAEMHTRM) (MAPPINGS2:t_AE_SER.txtSAEMHTRM) 7.c * Date of onset Req/Unk / Req/Unk / Req (197-29) (MAPPINGS1:t_AE_SER.dtmMHSTDTM) (MAPPINGS2:t_AE_SER.dtmMHSTDTM) * 7.d Continuing? (MAPPINGS1:t_AE_SER.rdcMHCONT) (MAPPINGS2:t_AE_SER.rdcMHCONT) [Y] Yes [N] No, specify date of last occurrence Req/Unk / Req/Unk / Req (197-29) (MAPPINGS1:t_AE_SER.dtmMHLSTOC) (MAPPINGS2:t_AE_SER.dtmMHLSTOC) [U] Unknown 8. * Relevant Medical History / Risk Factors not noted above A1 Lab Sequence Number Test Name Test Date Test Result Test Units Normal Normal Low High Range Range 9. [hidden] RELEVANT DIAGNOSTIC RESULTS Entry Provide details of any tests or procedures carried out to diagnose the SAE. 32 * 9.a Lab Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAELBSEQ) (MAPPINGS2:t_AE_SER.txtSAELBSEQ) 9.b Test Name Pulldown List 5 (MAPPINGS1:t_AE_SER.pdcLBTST) (MAPPINGS2:t_AE_SER.pdcLBTST) 9.c Test Date Req/Unk / Req/Unk / Req (28-29) (MAPPINGS1:t_AE_SER.dtmLABDTM) (MAPPINGS2:t_AE_SER.dtmLABDTM) 9.d Test Result A5 (MAPPINGS1:t_AE_SER.txtLABRES) (MAPPINGS2:t_AE_SER.txtLABRES) * 9.e Test Units A35 (MAPPINGS1:t_AE_SER.txtLABUNIT) (MAPPINGS2:t_AE_SER.txtLABUNIT) * 9.f Normal Low xxxxxxx. (MAPPINGS1:t_AE_SER.txtLABNLR) Range (MAPPINGS2:t_AE_SER.txtLABNLR) * 9.g Normal High Range xxxxxxx. (MAPPINGS1:t_AE_SER.txtLABNHR) (MAPPINGS2:t_AE_SER.txtLABNHR) * 1. Relevant diagnostic results not noted above A1 INVESTIGATIONAL PRODUCTS * 11. If Investigational product(s) stopped, did the reported event(s) recur after further investigational product(s) were administered? (MAPPINGS1:t_AE_SER.rdcSAEIP) (MAPPINGS2:t_AE_SER.rdcSAEIP) [N] No [Y] Yes [U] Unknown at this time [X] Not applicable GENERAL NARRATIVE COMMENTS Provide a brief narrative description of SAE, possible other causes of the event (e.g. lack of efficacy, withdrawal of investigational product, the disease under study or other medical conditions) and details of the treatment. 12. General narrative comments A1 NON CLINICAL * 13. Send incomplete SAE data to GSK Safety [hidden] (MAPPINGS1:t_AE_SER.chkSAESENDI) (MAPPINGS2:t_AE_SER.chkSAESENDI) [3] Incomplete SAE 14. * Receipt by GSK date [hidden] Req / Req / Req (28-29) (MAPPINGS1:t_AE_SER.dtmSAEDTM) (MAPPINGS2:t_AE_SER.dtmSAEDTM) Req : Req 24-hour clock * 15. Was the event serious? [hidden] (MAPPINGS1:t_AE_SER.AESE1) (MAPPINGS2:t_AE_SER.AESE1) [Y] Yes [N] No 16. * SAE Sequence Number [hidden] A5 (MAPPINGS1:t_AE_SER.AESE2) (MAPPINGS2:t_AE_SER.AESE2) * 17. Version Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAEVERSION) (MAPPINGS2:t_AE_SER.txtSAEVERSION) * 18. Case ID [hidden] A2 (MAPPINGS1:t_AE_SER.txtSAEID) (MAPPINGS2:t_AE_SER.txtSAEID) * 19. Randomisation Number [hidden] A255 (MAPPINGS1:t_AE_SER.txtSAERNDNO) (MAPPINGS2:t_AE_SER.txtSAERNDNO) * 2. OCEANS Code [hidden] A13 (MAPPINGS1:t_AE_SER.txtOCEANSCD) (MAPPINGS2:t_AE_SER.txtOCEANSCD) Flag [hidden] (MAPPINGS1:t_AE_SER.calSAE Flag) (MAPPINGS2:t_AE_SER.calSAE Flag) * Item is not required Form Design Note: Version 5.4A - 18 OCT 26 Item Design Notes: Item No. Design Note 4.d Start Time is optional 4.e End Time is optional A1 A1

369 4.f Optional item: Annotated Trial Design Page 33 of 51 This item may be hidden if either the "Maximum Grade" or "Maximum Grade or Intensity" item has been used. Grade 5 is optional. 4.g Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade or Intensity" item has been used Grade 5 is optional. 4.h Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Grade" item has been used Grade 5 is optional. 4.l If AE start and end time are used this item must be hidden. 4.m This item is optional 5. Optional Criterion G is an optional criterion and may be removed 13. This item is optional 33 Pulldown List 1: RefName Display Text Value Design Note estrsaeunitactu Actuation ACTU estrsaeunitamp Ampoule AMP estrsaeunitapp Application AP estrsaeunitbot Bottle BT estrsaeunitcap Capsule CAP estrsaeunitcc Cubic centimeter CC estrsaeunitgtt Drops 31 estrsaeunitgm Gram 2 estrsaeunitiu International units 25 estrsaeunitiukg International units per kilogram 28 estrsaeunitiuml International units per millilitre IUML estrsaeunitl Litre 11 estrsaeunitlpm Litre per minute LM estrsaeunitloz Lozenge LOZ estrsaeunitmu Megaunits (million units) MEGU estrsaeunitmcg Microgram (MCG) 4 estrsaeunitug Microgram (UG) 4 estrsaeunitmcgkg Microgram/kilogram 8 estrsaeunitmcgkgmin Microgram/kilogram per minute MCG/KG/MIN estrsaeunitmcgmin Micrograms per minute MCG/MIN estrsaeunitmcl Microlitre 13 estrsaeunitmeq Milliequivalent 29 estrsaeunitmeq24hr Milliequivalent per 24 hours MEQ24 estrsaeunitmg Milligram 3 estrsaeunitmgper Milligrams percent MGPER estrsaeunitmghr Milligram per hour MGH estrsaeunitmgkg Milligram/kilogram 7 estrsaeunitmgkghr Milligram/kilogram per hour MGKH estrsaeunitmgkgmin Milligram/kilogram per minute MGKM estrsaeunitmgm2 Milligram/metre squared 9 estrsaeunitmgml Milligram/millilitre MGML estrsaeunitml Millilitre 12 estrsaeunitmlhr Millilitre per hour MLH estrsaeunitmlmin Millilitre per minute MLM estrsaeunitmmol Millimole 23 estrsaeunitmiu Million international units 27 estrsaeunitmac Minimum alveolar concentration MAC estrsaeunitneb Nebule NEB estrsaeunitpatch Patch PAT estrsaeunitper Percent 3 estrsaeunitpuff Puff PUFF estrsaeunitsach Sachet SAC estrsaeunitsp Spray SPR estrsaeunitsupp Suppository SUP estrsaeunittbsp Tablespoon TBS estrsaeunittab Tablet TAB estrsaeunittsp Teaspoon TSP estrsaeunitunit Units UNT estrsaeunitunk Unknown U estrsaeunitvial Vial VIA Pulldown List 2: RefName Display Text Value Design Note estrsaefreq2xwk 2 times per week 2W estrsaefreq3xwk 3 times per week 3W estrsaefreq4xwk 4 times per week 4W estrsaefreq5xd 5 times per day 5D estrsaefreq5xwk 5 times per week 5W estrsaefreqac AC AC estrsaefreqbid BID 2D estrsaefreqcinf Continuous infusion CO estrsaefreqq2wk Every 2 weeks FO estrsaefreqq3wk Every 3 weeks Q3WK estrsaefreqq3m Every 3 months Q3M estrsaefreqqod Every other day AD estrsaefreqhs At Bedtime 1N estrsaefreqqm Once a month MO estrsaefreqqwk Once a week WE estrsaefreqqd Once daily 1D estrsaefreqone Once only 1S estrsaefreqpc PC PC estrsaefreqprn PRN PRN estrsaefreqq2h Q2H 12D estrsaefreqq3d Q3D Q3D estrsaefreqq4d Q4D Q4D estrsaefreqq4h Q4H 6D estrsaefreqq6h Q6H 4D estrsaefreqq8h Q8H 3D estrsaefreqq12h Q12H 2D estrsaefreqqam QAM 1M estrsaefreqqh QH 24D estrsaefreqqid QID 4D estrsaefreqqpm QPM 1N estrsaefreqtid TID 3D estrsaefrequnk Unknown U Pulldown List 3: RefName Display Text Value Design Note estrsaerouteou Both eyes 47 estrsaerouteep Epidural 8 estrsaeroutegtt Gastrostomy tube GT estrsaerouteih Inhalation 55 estrsaerouteinj Injection INJ estrsaerouteia Intra-arterial 13

370 estrsaerouteib Intra-bursa IBU Annotated Trial Design Page 34 of 51 estrsaerouteil Intralesional 26 estrsaerouteim Intramuscular 3 estrsaeroutein Intranasal 45 estrsaerouteio Intraocular 31 estrsaerouteios Intraosteal IOS estrsaerouteip Intraperitoneal 33 estrsaerouteit Intrathecal 37 estrsaerouteiu Intrauterine 15 estrsaerouteiv Intravenous 42 estrsaeroutens Nasal 45 estrsaeroutepo Oral 48 estrsaeroutepr Rectal 54 estrsaeroutesc Subcutaneous 58 estrsaeroutesl Sublingual 6 estrsaeroutetp Topical 61 estrsaeroutetd Transdermal 62 estrsaerouteunk Unknown 65 estrsaeroutevg Vaginal 67 Pulldown List 4: RefName Display Text Value Design Note estrdrugtype1 Concomitant 2 estrdrugtype2 Treatment T estrdrugtype3 Cause of SAE 1 34 Pulldown List 5: RefName Display Text Value Design Note estrsaelbtst1 Activated partial Activated thromboplastin time partial thromboplastin time estrsaelbtst2 Albumin Albumin estrsaelbtst3 Alkaline phosphatase Alkaline phosphatase estrsaelbtst4 Amylase Amylase estrsaelbtst5 Basophils Basophils estrsaelbtst6 Bicarbonate Bicarbonate estrsaelbtst7 Bilirubin Bilirubin estrsaelbtst8 Bilirubin direct Bilirubin direct estrsaelbtst9 Bilirubin total Bilirubin total estrsaelbtst1 Blood myoglobin Blood myoglobin estrsaelbtst11 Blood ph Blood ph estrsaelbtst12 Blood pressure Blood pressure estrsaelbtst13 Blood urea nitrogen Blood urea nitrogen estrsaelbtst14 Body temperature Body temperature estrsaelbtst15 Calcium Calcium estrsaelbtst16 CD4 lymphocytes CD4 lymphocytes estrsaelbtst17 CD8 lymphocytes CD8 lymphocytes estrsaelbtst18 Chloride Chloride estrsaelbtst19 Cholesterol total Cholesterol total estrsaelbtst2 C-reactive protein C-reactive protein estrsaelbtst21 Creatine Creatine estrsaelbtst22 Creatine phosphokinase Creatine phosphokinase estrsaelbtst23 Creatine phosphokinase MB Creatine phosphokinase MB estrsaelbtst24 Creatinine Creatinine estrsaelbtst25 Creatinine clearance Creatinine clearance estrsaelbtst26 Diastolic blood pressure Diastolic blood pressure estrsaelbtst27 Eosinophils Eosinophils estrsaelbtst28 Erythrocyte sedimentation rate Erythrocyte sedimentation rate estrsaelbtst29 Fasting blood glucose Fasting blood glucose estrsaelbtst3 FEV 1 FEV 1 estrsaelbtst31 Gamma-glutamyltransferase Gamma-glutamyltransferase estrsaelbtst32 Glutamic-oxaloacetic transferase Glutamic-oxaloacetic transferase estrsaelbtst33 Glutamic-pyruvate transaminase Glutamic-pyruvate transaminase estrsaelbtst34 HbA1c HbA1c estrsaelbtst35 HBV-DNA decreased HBV-DNA decreased estrsaelbtst36 HBV-DNA increased HBV-DNA increased estrsaelbtst37 Heart rate Heart rate estrsaelbtst38 Hematocrit Hematocrit estrsaelbtst39 Hemoglobin Hemoglobin estrsaelbtst4 High density lipoprotein High density lipoprotein estrsaelbtst41 HIV viral load HIV viral load estrsaelbtst42 INR INR estrsaelbtst43 Lactic dehydrogenase Lactic dehydrogenase estrsaelbtst44 Lipase Lipase estrsaelbtst45 Low density lipoprotein Low density lipoprotein estrsaelbtst46 Lymphocytes Lymphocytes estrsaelbtst47 Magnesium Magnesium estrsaelbtst48 Mean cell hemoglobin concentration Mean cell hemoglobin concentration estrsaelbtst49 Mean corpuscular hemoglobin Mean corpuscular hemoglobin estrsaelbtst5 Mean corpuscular volume Mean corpuscular volume estrsaelbtst51 Monocytes Monocytes estrsaelbtst52 Neutrophils Neutrophils estrsaelbtst53 Oxygen saturation Oxygen saturation estrsaelbtst54 pco2 pco2 estrsaelbtst55 ph ph estrsaelbtst56 Phosphate Phosphate estrsaelbtst57 Platelet count Platelet count estrsaelbtst58 po2 po2 estrsaelbtst59 Potassium Potassium estrsaelbtst6 Protein total Protein total estrsaelbtst61 Prothrombin time Prothrombin time estrsaelbtst62 Red blood cell count Red blood cell count estrsaelbtst63 Respiratory rate Respiratory rate estrsaelbtst64 Reticulocyte count Reticulocyte count estrsaelbtst65 Serum glucose Serum glucose estrsaelbtst66 Serum uric acid Serum uric acid estrsaelbtst67 Sodium Sodium estrsaelbtst68 Systolic blood pressure Systolic blood pressure estrsaelbtst69 Thrombin time Thrombin time estrsaelbtst7 Total lung capacity Total lung capacity estrsaelbtst71 Triglycerides Triglycerides estrsaelbtst72 Troponin Troponin estrsaelbtst73 Troponin I Troponin I estrsaelbtst74 Troponin T Troponin T estrsaelbtst75 Urine myoglobin Urine myoglobin estrsaelbtst76 Urine ph Urine ph estrsaelbtst77 Vital capacity Vital capacity estrsaelbtst78 White blood cell count White blood cell count CDD: MAPPINGS1 Table: t_ae_ser Key Type: PATIENTVISIT Column Name Column Data Type Design Note

371 chksae STRING(255) Annotated Trial Design Page 35 of chkfu STRING(255) rdcsaerand STRING(1) AESEQ STRING(5) - A5 AETERM STRING(1) - A1 AEMODIFY STRING(1) - A1 AEMEDSYN STRING(255) AELLTCD STRING(255) calae_failed STRING(255) AESTDTTM DATE - DDMONYYYY HHMM AEOUTCD1 STRING(1) AEENDTTM1 DATE - DDMONYYYY HHMM AEENDTTM2 DATE - DDMONYYYY HHMM AEENDTTM3 DATE - DDMONYYYY HHMM AESEVCD STRING(1) AETOXCD STRING(1) AETXHVCD STRING(1) AEACTRCD STRING(1) AEWD STRING(1) AEREL STRING(1) AEDURHR NUMERIC - N2 AEDURMIN NUMERIC - N2 AEONLDSH NUMERIC - N2 AEONLDSM NUMERIC - N2 rdcaesrel STRING(1) AESER STRING(1) AESERDTH STRING(255) AESERLIF STRING(255) AESERHOS STRING(255) AESERDIS STRING(255) AESERCON STRING(255) AESEROTH STRING(255) txtsaecmseq STRING(4) - A4 txtcmterm STRING(1) - A1 txtsaecmdos FLOAT - F1. pdccmunit STRING(255) - ACTU, AMP, AP, BT, CAP, CC, 31, 2, 25, 28, IUML, 11, LM, LOZ, MEGU, 4, 4, 8, MCG/KG/MIN, MCG/MIN, 13, 29, MEQ24, 3, MGPER, MGH, 7, MGKH, MGKM, 9, MGML, 12, MLH, MLM, 23, 27, MAC, NEB, PAT, 3, PUFF, SAC, SPR, SUP, TBS, TAB, TSP, UNT, U, VIA pdcsaecmfrq STRING(255) - 2W, 3W, 4W, 5D, 5W, AC, 2D, CO, FO, Q3WK, Q3M, AD, 1N, MO, WE, 1D, 1S, PC, PRN, 12D, Q3D, Q4D, 6D, 4D, 3D, 2D, 1M, 24D, 4D, 1N, 3D, U pdccmroutcd STRING(255) - 47, 8, GT, 55, INJ, 13, IBU, 26, 3, 45, 31, IOS, 33, 37, 15, 42, 45, 48, 54, 58, 6, 61, 62, 65, 67 dtmsaecmstd DATE - DDMONYYYY rdcsaecmong STRING(1) dtmsaecmend DATE - DDMONYYYY txtcmind STRING(5) - A5 pdccmdrgtyp STRING(255) - 2, T, 1 txtmhxseq STRING(4) - A4 txtsaemhtrm STRING(1) - A1 dtmmhstdtm DATE - DDMONYYYY rdcmhcont STRING(1) dtmmhlstoc DATE - DDMONYYYY txtsaelbseq STRING(4) - A4 pdclbtst STRING(255) - Activated partial thromboplastin time, Albumin, Alkaline phosphatase, Amylase, Basophils, Bicarbonate, Bilirubin, Bilirubin direct, Bilirubin total, Blood myoglobin, Blood ph, Blood pressure, Blood urea nitrogen, Body temperature, Calcium, CD4 lymphocytes, CD8 lymphocytes, Chloride, Cholesterol total, C-reactive protein, Creatine, Creatine phosphokinase, Creatine phosphokinase MB, Creatinine, Creatinine clearance, Diastolic blood pressure, Eosinophils, Erythrocyte sedimentation rate, Fasting blood glucose, FEV 1, Gamma-glutamyltransferase, Glutamic-oxaloacetic transferase, Glutamic-pyruvate transaminase, HbA1c, HBV-DNA decreased, HBV-DNA increased, Heart rate, Hematocrit, Hemoglobin, High density lipoprotein, HIV viral load, INR, Lactic dehydrogenase, Lipase, Low density lipoprotein, Lymphocytes, Magnesium, Mean cell hemoglobin concentration, Mean corpuscular hemoglobin, Mean corpuscular volume, Monocytes, Neutrophils, Oxygen saturation, pco2, ph, Phosphate, Platelet count, po2, Potassium, Protein total, Prothrombin time, Red blood cell count, Respiratory rate, Reticulocyte count, Serum glucose, Serum uric acid, Sodium, Systolic blood pressure, Thrombin time, Total lung capacity, Triglycerides, Troponin, Troponin I, Troponin T, Urine myoglobin, Urine ph, Vital capacity, White blood cell count dtmlabdtm DATE - DDMONYYYY txtlabres STRING(5) - A5 txtlabunit STRING(35) - A35 txtlabnlr FLOAT - F8. txtlabnhr FLOAT - F8. rdcsaeip STRING(1) chksaesendi STRING(255) dtmsaedtm DATE - DDMONYYYY HHMM AESE1 STRING(1) AESE2 STRING(5) - A5 txtsaeversion STRING(4) - A4 txtsaeid STRING(2) - A2 txtsaerndno STRING(255) - A255 txtoceanscd STRING(13) - A13 calsae flag STRING(255) CDD: MAPPINGS2 Table: t_ae_ser Key Type: PATIENTVISIT Column Name Column Data Type Design Note chksae STRING(255) chkfu STRING(255) rdcsaerand STRING(1) AESEQ STRING(5) - A5 AETERM STRING(1) - A1 AEMODIFY STRING(1) - A1 AEMEDSYN STRING(255) AELLTCD STRING(255) calae_failed STRING(255) AESTDTTM DATE - DDMONYYYY HHMM AEOUTCD1 STRING(1) AEENDTTM1 DATE - DDMONYYYY HHMM AEENDTTM2 DATE - DDMONYYYY HHMM AEENDTTM3 DATE - DDMONYYYY HHMM AESEVCD STRING(1) AETOXCD STRING(1) AETXHVCD STRING(1) AEACTRCD STRING(1) AEWD STRING(1) AEREL STRING(1) AEDURHR NUMERIC - N2 AEDURMIN NUMERIC - N2 AEONLDSH NUMERIC - N2 AEONLDSM NUMERIC - N2 rdcaesrel STRING(1) AESER STRING(1) AESERDTH STRING(255) AESERLIF STRING(255) AESERHOS STRING(255) AESERDIS STRING(255) AESERCON STRING(255) AESEROTH STRING(255) txtsaecmseq STRING(4) - A4 txtcmterm STRING(1) - A1 txtsaecmdos FLOAT - F1. pdccmunit STRING(255) - ACTU, AMP, AP, BT, CAP, CC, 31, 2, 25, 28, IUML, 11, LM, LOZ, MEGU, 4, 4, 8, MCG/KG/MIN, MCG/MIN, 13, 29, MEQ24, 3, MGPER, MGH, 7, MGKH, MGKM, 9, MGML, 12, MLH, MLM, 23, 27, MAC, NEB, PAT, 3, PUFF, SAC, SPR, SUP, TBS, TAB, TSP, UNT, U, VIA pdcsaecmfrq STRING(255) - 2W, 3W, 4W, 5D, 5W, AC, 2D, CO, FO, Q3WK, Q3M, AD, 1N, MO, WE, 1D, 1S, PC, PRN, 12D, Q3D, Q4D, 6D, 4D, 3D, 2D, 1M, 24D, 4D, 1N, 3D, U pdccmroutcd STRING(255) - 47, 8, GT, 55, INJ, 13, IBU, 26, 3, 45, 31, IOS, 33, 37, 15, 42, 45, 48, 54, 58, 6, 61, 62, 65, 67 dtmsaecmstd DATE - DDMONYYYY

372 rdcsaecmong STRING(1) Annotated Trial Design Page 36 of 51 dtmsaecmend DATE - DDMONYYYY txtcmind STRING(5) - A5 pdccmdrgtyp STRING(255) - 2, T, 1 txtmhxseq STRING(4) - A4 txtsaemhtrm STRING(1) - A1 dtmmhstdtm DATE - DDMONYYYY rdcmhcont STRING(1) dtmmhlstoc DATE - DDMONYYYY txtsaelbseq STRING(4) - A4 pdclbtst STRING(255) - Activated partial thromboplastin time, Albumin, Alkaline phosphatase, Amylase, Basophils, Bicarbonate, Bilirubin, Bilirubin direct, Bilirubin total, Blood myoglobin, Blood ph, Blood pressure, Blood urea nitrogen, Body temperature, Calcium, CD4 lymphocytes, CD8 lymphocytes, Chloride, Cholesterol total, C-reactive protein, Creatine, Creatine phosphokinase, Creatine phosphokinase MB, Creatinine, Creatinine clearance, Diastolic blood pressure, Eosinophils, Erythrocyte sedimentation rate, Fasting blood glucose, FEV 1, Gamma-glutamyltransferase, Glutamic-oxaloacetic transferase, Glutamic-pyruvate transaminase, HbA1c, HBV-DNA decreased, HBV-DNA increased, Heart rate, Hematocrit, Hemoglobin, High density lipoprotein, HIV viral load, INR, Lactic dehydrogenase, Lipase, Low density lipoprotein, Lymphocytes, Magnesium, Mean cell hemoglobin concentration, Mean corpuscular hemoglobin, Mean corpuscular volume, Monocytes, Neutrophils, Oxygen saturation, pco2, ph, Phosphate, Platelet count, po2, Potassium, Protein total, Prothrombin time, Red blood cell count, Respiratory rate, Reticulocyte count, Serum glucose, Serum uric acid, Sodium, Systolic blood pressure, Thrombin time, Total lung capacity, Triglycerides, Troponin, Troponin I, Troponin T, Urine myoglobin, Urine ph, Vital capacity, White blood cell count dtmlabdtm DATE - DDMONYYYY txtlabres STRING(5) - A5 txtlabunit STRING(35) - A35 txtlabnlr FLOAT - F8. txtlabnhr FLOAT - F8. rdcsaeip STRING(1) chksaesendi STRING(255) dtmsaedtm DATE - DDMONYYYY HHMM AESE1 STRING(1) AESE2 STRING(5) - A5 txtsaeversion STRING(4) - A4 txtsaeid STRING(2) - A2 txtsaerndno STRING(255) - A255 txtoceanscd STRING(13) - A13 calsae flag STRING(255) 36

373 ari111402_nwr_e : CONCOMITANT MEDICATIONS (Con Meds) - Repeating Form Annotated Trial Design Page 37 of 51 # Sequence Number Drug Name Unit Dose Units Frequency Route Reason for Medication Start Date and Time Taken Prior to Study? Ongoing? (Trade Name preferred) 1 CONCOMITANT MEDICATIONS Sequence Number 1. Drug Name (Trade Name preferred) (MAPPINGS1:t_CONMEDS.CMSEQ) (MAPPINGS2:t_CONMEDS.CMSEQ) A1 (MAPPINGS1:t_CONMEDS.CMTERM) (MAPPINGS2:t_CONMEDS.CMTERM) 2. * Modified reported term [hidden] A1 (CM_CODE:.LogsRpts.CONMEDS.sctCM..itmCMDRGCOL.CMDRGCOL) (CM_FAILED:.LogsRpts.CONMEDS.sctCM..itmCM_FAILED.calCM_FAILED) (CM_SYNONYM:.LogsRpts.CONMEDS.sctCM..itmCMDRGSYN.CMDRGSYN) (MAPPINGS1:t_CONMEDS.CMMODIFY) (MAPPINGS2:t_CONMEDS.CMMODIFY) GSK Drug synonym [hidden] GSK Drug Collection code [hidden] Failed coding [hidden] (MAPPINGS1:t_CONMEDS.CMDRGSYN) (MAPPINGS2:t_CONMEDS.CMDRGSYN) (MAPPINGS1:t_CONMEDS.CMDRGCOL) (MAPPINGS2:t_CONMEDS.CMDRGCOL) (MAPPINGS1:t_CONMEDS.calCM_FAILED) (MAPPINGS2:t_CONMEDS.calCM_FAILED) 3. Unit Dose A1 (MAPPINGS1:t_CONMEDS.CMUDOS) (MAPPINGS2:t_CONMEDS.CMUDOS) 4. Units Pulldown List 1 (MAPPINGS1:t_CONMEDS.CMUNIT) (MAPPINGS2:t_CONMEDS.CMUNIT) 5. Frequency Pulldown List 2 (MAPPINGS1:t_CONMEDS.CMFREQ) (MAPPINGS2:t_CONMEDS.CMFREQ) 6. Route Pulldown List 3 (MAPPINGS1:t_CONMEDS.CMROUTCD) (MAPPINGS2:t_CONMEDS.CMROUTCD) 7. Reason for Medication A7 (MAPPINGS1:t_CONMEDS.CMREAS) (MAPPINGS2:t_CONMEDS.CMREAS) 8. Start Date and Time Hr:Min (:-23:59) Req/Unk / Req/Unk / Req/Unk (19-29) (MAPPINGS1:t_CONMEDS.CMSTDTTM) (MAPPINGS2:t_CONMEDS.CMSTDTTM) NReq : NReq 24-hour clock 9. Taken Prior to Study? (MAPPINGS1:t_CONMEDS.CMPRIOR) (MAPPINGS2:t_CONMEDS.CMPRIOR) [Y] Yes [N] No 1. Ongoing? Hr:Min (:-23:59) (MAPPINGS1:t_CONMEDS.CMONGO) (MAPPINGS2:t_CONMEDS.CMONGO) [Y] Yes [N] No, specify End Date and Time Req/Unk / Req/Unk / Req/Unk (28-29) (MAPPINGS1:t_CONMEDS.CMENDTTM) (MAPPINGS2:t_CONMEDS.CMENDTTM) NReq : NReq 24-hour clock * Item is not required Item Design Notes: Item No. Design Note 3. This item is conditional 37 Pulldown List 1: RefName Display Text Value Design Note mestrunitactu Actuation ACTU mestrunitamp Ampoule AMP mestrunitapp Application APP mestrunitauc Area under curve AUC mestrunitbot Bottle BOT mestrunitcap Capsule CAP mestrunitcc Cubic centimeter CC mestrunitcup Cup CUP mestrunitgakgm Gamma per kilogram per minute GA/KG/MIN mestrunitgm Gram G mestrunitgtt Drops GTT mestrunithiuml 1International units/ml 1IU/ML mestrunitinh Inhalation INH mestrunitiu International units IU mestrunitiukg International units per kilogram IU/KG mestrunitiukgh International units per kilogram per IU/KG/HR hour mestrunitiuml International units per millilitre IU/ML mestrunitl Litre L mestrunitloz Lozenge LOZ mestrunitlpm Litre per minute L/MIN mestrunitmac Minimum alveolar concentration MAC mestrunitmbq Mega becquerels (MBq) MBQ mestrunitmcg Microgram (MCG) MCG mestrunitmcgh Micrograms per hour MCG/HR mestrunitmcgkg Microgram/kilogram MCG/KG mestrunitmcgkgmin Microgram/kilogram per minute MCG/KG/MIN mestrunitmcgmin Micrograms per minute MCG/MIN mestrunitmcgml Micrograms per millitre MCG/ML mestrunitmcl Microlitre MCL mestrunitmeq Milliequivalent MEQ mestrunitmeq24hr Milliequivalent per 24 hours MEQ/24HR mestrunitmg Milligram MG mestrunitmgd Milligram per day MG/DAY mestrunitmghr Milligram per hour MG/HR mestrunitmgkg Milligram/kilogram MG/KG mestrunitmgkghr Milligram/kilogram per hour MG/KG/HR mestrunitmgkgmin Milligram/kilogram per minute MG/KG/MIN mestrunitmgm2 Milligram/metre squared MG/M2 mestrunitmgml Milligram/millilitre MG/ML mestrunitmgper Milligrams percent MG% mestrunitmiu Million international units MIU mestrunitml Millilitre ML mestrunitmlhr Millilitre per hour ML/HR mestrunitmlmin Millilitre per minute ML/MIN mestrunitmmol Millimole MMOL mestrunitmu Megaunits (million units) MU mestrunitneb Nebule NEB mestrunitoz Ounce OZ mestrunitpatch Patch PATCH mestrunitper Percent % mestrunitpuff Puff PUFF mestrunitsach Sachet SACH mestrunitsp Spray SPR mestrunitsupp Suppository SUPP mestrunittab Tablet TAB mestrunittbsp Tablespoon TBLSP mestrunittsp Teaspoon TSP mestrunitug Microgram (UG) UG mestrunituhr Units per hour U/HR mestrunitukgm Units per kilogram per minute U/KG/MIN

374 mestrunitumn Units per minute U/MIN Annotated Trial Design Page 38 of 51 mestrunitunit Units U mestrunitunk Unknown UNK mestrunitvial Vial VIAL 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 mestrfreqhs HS HS mestrfreqod Once daily OD mestrfreqone Once only ONE mestrfreqpc PC PC mestrfreqprn PRN PRN mestrfreqq12h Q12H Q12H mestrfreqq2h Q2H Q2H mestrfreqq2wk Every Q2WK 2 weeks mestrfreqq3d Q3D Q3D mestrfreqq3m Every 3 months Q3M mestrfreqq3wk Every 3 weeks Q3WK mestrfreqq4d Q4D Q4D mestrfreqq4h Q4H Q4H mestrfreqq6h Q6H Q6H mestrfreqq8h Q8H Q8H mestrfreqqam QAM QAM mestrfreqqh QH QH mestrfreqqid QID QID mestrfreqqm Once a month QM mestrfreqqod Every other day QOD mestrfreqqpm QPM QPM mestrfreqqwk Once a week QWK mestrfreqtid TID TID mestrfrequnk Unknown UNK 38 Pulldown List 3: RefName Display Text Value Design Note mestrrouteep Epidural EP mestrroutegtt Gastrostomy tube GTT mestrrouteia Intra-arterial IA mestrrouteiart Intra-articular IART mestrrouteib Intra-bursa IB mestrrouteid Intradermal ID mestrrouteih Inhalation IH mestrrouteil Intralesional ILES mestrrouteim Intramuscular IM mestrroutein Intranasal IN mestrrouteinj Injection INJ mestrrouteio Intraocular IO mestrrouteios Intraosteal IOS mestrrouteip Intraperitoneal IP mestrrouteit Intrathecal IT mestrrouteiu Intrauterine IU mestrrouteiv Intravenous IV mestrrouteng Nasogastric NG mestrroutens Nasal NS mestrrouteod Right OD eye mestrrouteop Ophthalmic OP mestrrouteos Left eye OS mestrrouteot Otic OT mestrrouteoth Other OTH mestrrouteou Both eyes OU mestrroutepo Oral PO mestrroutepr Rectal PR mestrroutesc Subcutaneous SC mestrroutesl Sublingual SL mestrroutetd Transdermal TD mestrroutetp Topical TP mestrrouteunk Unknown UNK mestrroutevg Vaginal VG CDD: MAPPINGS1 Table: t_conmeds Key Type: PATIENTVISIT Column Name Column Data Type Design Note CMSEQ STRING(255) CMTERM STRING(1) - A1 CMMODIFY STRING(1) - A1 CMDRGSYN STRING(255) CMDRGCOL STRING(255) calcm_failed STRING(255) CMUDOS STRING(1) - A1 CMUNIT STRING(255) - ACTU, AMP, APP, AUC, BOT, CAP, CC, CUP, GA/KG/MIN, G, GTT, 1IU/ML, INH, IU, IU/KG, IU/KG/HR, IU/ML, L, LOZ, L/MIN, MAC, MBQ, MCG, MCG/HR, MCG/KG, MCG/KG/MIN, MCG/MIN, MCG/ML, MCL, MEQ, MEQ/24HR, MG, MG/DAY, MG/HR, MG/KG, MG/KG/HR, MG/KG/MIN, MG/M2, MG/ML, MG%, MIU, ML, ML/HR, ML/MIN, MMOL, MU, NEB, OZ, PATCH, %, PUFF, SACH, SPR, SUPP, TAB, TBLSP, TSP, UG, U/HR, U/KG/MIN, U/MIN, U, UNK, VIAL CMFREQ STRING(255) - 2XWK, 3XWK, 4XWK, 5XD, 5XWK, AC, BID, CINF, HS, OD, ONE, PC, PRN, Q12H, Q2H, Q2WK, Q3D, Q3M, Q3WK, Q4D, Q4H, Q6H, Q8H, QAM, QH, QID, QM, QOD, QPM, QWK, TID, UNK CMROUTCD STRING(255) - EP, GTT, IA, IART, IB, ID, IH, ILES, IM, IN, INJ, IO, IOS, IP, IT, IU, IV, NG, NS, OD, OP, OS, OT, OTH, OU, PO, PR, SC, SL, TD, TP, UNK, VG CMREAS STRING(7) - A7 CMSTDTTM DATE - DDMONYYYY HHMM CMPRIOR STRING(1) CMONGO STRING(1) CMENDTTM DATE - DDMONYYYY HHMM CDD: MAPPINGS2 Table: t_conmeds Key Type: PATIENTVISIT Column Name Column Data Type Design Note CMSEQ STRING(255) CMTERM STRING(1) - A1 CMMODIFY STRING(1) - A1 CMDRGSYN STRING(255) CMDRGCOL STRING(255) calcm_failed STRING(255) CMUDOS STRING(1) - A1 CMUNIT STRING(255) - ACTU, AMP, APP, AUC, BOT, CAP, CC, CUP, GA/KG/MIN, G, GTT, 1IU/ML, INH, IU, IU/KG, IU/KG/HR, IU/ML, L, LOZ, L/MIN, MAC, MBQ, MCG, MCG/HR, MCG/KG, MCG/KG/MIN, MCG/MIN, MCG/ML, MCL, MEQ, MEQ/24HR, MG, MG/DAY, MG/HR, MG/KG, MG/KG/HR, MG/KG/MIN, MG/M2, MG/ML, MG%, MIU, ML, ML/HR, ML/MIN, MMOL, MU, NEB, OZ, PATCH, %, PUFF, SACH, SPR, SUPP, TAB, TBLSP, TSP, UG, U/HR, U/KG/MIN, U/MIN, U, UNK, VIAL CMFREQ STRING(255) - 2XWK, 3XWK, 4XWK, 5XD, 5XWK, AC, BID, CINF, HS, OD, ONE, PC, PRN, Q12H, Q2H, Q2WK, Q3D, Q3M, Q3WK, Q4D, Q4H, Q6H, Q8H, QAM, QH, QID, QM, QOD, QPM, QWK, TID, UNK CMROUTCD STRING(255) - EP, GTT, IA, IART, IB, ID, IH, ILES, IM, IN, INJ, IO, IOS, IP, IT, IU, IV, NG, NS, OD, OP, OS, OT, OTH, OU, PO, PR, SC, SL, TD, TP, UNK, VG CMREAS STRING(7) - A7 CMSTDTTM DATE - DDMONYYYY HHMM CMPRIOR STRING(1)

375 Page 39 of 51 CONFIDENTIAL ZM2008/00081/00 Annotated Trial Design CMONGO STRING(1) CMENDTTM DATE - DDMONYYYY HHMM 39

376 ari111402_nwr_e : 12-LEAD ECG (ECG Rpt) - Repeating Form Annotated Trial Design Page 40 of 51 1 # Date HR PR QRS QT QTC Result SUPINE 12-LEAD ECG 1. Date and Time of ECG Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_ECG_RPT.EGDTTM) (MAPPINGS2:t_ECG_RPT.EGDTTM) Req : Req 24-hour clock 2. Heart rate xxx ( n >= ) beats/min (MAPPINGS1:t_ECG_RPT.EGHR) (MAPPINGS2:t_ECG_RPT.EGHR) 3. PR Interval xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_RPT.PR ) (MAPPINGS2:t_ECG_RPT.PR ) 4. QRS Duration xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_RPT.QRS ) (MAPPINGS2:t_ECG_RPT.QRS ) 5. Uncorrected QT Interval xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_RPT.QT ) (MAPPINGS2:t_ECG_RPT.QT ) 6. QTc Interval xxxxx. ( n >=.) msec (MAPPINGS1:t_ECG_RPT.QTC ) (MAPPINGS2:t_ECG_RPT.QTC ) 7. Result of the ECG (MAPPINGS1:t_ECG_RPT.EGINTPCD) (MAPPINGS2:t_ECG_RPT.EGINTPCD) [1] Normal [2] Abnormal - Not clinically significant [3] Abnormal - Clinically significant (complete the ECG abnormality form for all clinically significant abnormalities, and additionally complete the AE form if the abnormality meets the protocol definition for an AE [4] No result (not available) Form Design Note: Repeat ECG CDD: MAPPINGS1 Table: t_ecg_rpt Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR FLOAT - F6. QRS FLOAT - F6. QT FLOAT - F6. QTC FLOAT - F6. EGINTPCD STRING(1) CDD: MAPPINGS2 Table: t_ecg_rpt Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM EGHR NUMERIC - N3 PR FLOAT - F6. QRS FLOAT - F6. QT FLOAT - F6. QTC FLOAT - F6. EGINTPCD STRING(1) 40

377 ari111402_nwr_e : ECG ABNORMALITIES (ECG Abn) - Repeating Form Annotated Trial Design Page 41 of 51 1 # Date Result 12-LEAD ECG ABNORMALITIES 1. Date and Time of ECG Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_ECG_ABNORM.EGDTTM) (MAPPINGS2:t_ECG_ABNORM.EGDTTM) Req : Req 24-hour clock Record clinically significant abnormalities (check all that apply A. Rhythm (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_AAA) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_AAA) [A1] Sinus bradycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_BBB) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_BBB) [A21] Sinus bradycardia (heart rate 4-5beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_CCC) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_CCC) [A22] Sinus bradycardia (heart rate 3-39 beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_DDD) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_DDD) [A23] Sinus bradycardia (heart rate <3beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_EEE) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_EEE) [A3] Sinus pause (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_FFF) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_FFF) [A2] Sinus tachycardia (heart rate > 1beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_GGG) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_GGG) [A4] Ectopic supraventricular beats (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_HHH) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_HHH) [A20] Ectopic supraventricular rhythm (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_III) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_III) [A17] Wandering atrial pacemaker (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_JJJ) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_JJJ) [A26] Multifocal atrial tachycardia (wandering atrial pacemaker w/rate >1beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_KKK) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_KKK) [A6] Supraventricular tachycardia (heart rate>1beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_LLL) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_LLL) [A7] Atrial flutter (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_MMM) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_MMM) [A8] Atrial fibrillation (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_NNN) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_NNN) [A5] Junctional rhythm (heart rate<=1beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_OOO) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_OOO) [A25] Junctional rhythm (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_PPP) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_PPP) [A24] Junctional tachycardia (heart rate>1beats/min) (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_QQQ) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_QQQ) [A9] Ectopic ventricular beats (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_RRR) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_RRR) [A12] Ventricular couplets (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_SSS) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_SSS) [A13] Bigeminy (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_TTT) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_TTT) [A28] Trigeminy (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_UUU) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_UUU) [A14] Electrical alternans (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_VVV) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_VVV) [A29] R on T phenomenon (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_WWW) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_WWW) [A18] Ventricular fibrillation (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_XXX) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_XXX) [A19] Idioventricular rhythm (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_YYY) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_YYY) [A10] Sustained ventricular tachycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM1_ZZZ) (MAPPINGS2:t_ECG_ABNORM.RHYTHM1_ZZZ) [A11] Non-sustained ventricular tachycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_GGG) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_GGG) [A32] Wide QRS tachycardia (diagnosis unknown) (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_AAA) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_AAA) [A27] Ventricular tachycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_BBB) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_BBB) [A30] Monomorphic ventricular tachycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_CCC) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_CCC) [A15] Torsades de Pointes (Polymorphic ventricular tachycardia with prolonged QT) (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_DDD) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_DDD) [A31] Polymorphic (sustained and non-sustained) ventricular tachycardia (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_EEE) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_EEE) [A16] Artificial Pacemaker (MAPPINGS1:t_ECG_ABNORM.RHYTHM2_FFF) (MAPPINGS2:t_ECG_ABNORM.RHYTHM2_FFF) [A99] Other abnormal rhythm, enter comment (MAPPINGS1:t_ECG_ABNORM.EGFOTHA) (MAPPINGS2:t_ECG_ABNORM.EGFOTHA) A2 B. P-Wave Morphology (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_AAA) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_AAA) [B1] Left atrial abnormality (P mitrale) (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_BBB) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_BBB) [B2] Right atrial abnormality (P pulmonale) (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_CCC) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_CCC) [B3] Right ventricular hypertrophy (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_DDD) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_DDD) [B5] Intraatrial conduction delay (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_EEE) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_EEE) [D14] Increased voltage consistent with left ventricular hypertrophy (MAPPINGS1:t_ECG_ABNORM.MORPHOLOGY_FFF) (MAPPINGS2:t_ECG_ABNORM.MORPHOLOGY_FFF) [B99] Other morphology, enter comment (MAPPINGS1:t_ECG_ABNORM.EGFOTHB) (MAPPINGS2:t_ECG_ABNORM.EGFOTHB) A2 C. Conduction (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_AAA) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_AAA) [C1] First degree AV block (PR interval > 2msec) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_TTT) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_TTT) [C20] Short PR interval (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_BBB) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_BBB) [C2] Second degree AV block (Mobitz type 1) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_CCC) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_CCC) [C3] Second degree AV block (Mobitz type 2) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_DDD) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_DDD) [C16] 2:1 AV block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_EEE) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_EEE) [C4] Third degree AV block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_FFF)

378 (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_FFF) Annotated Trial Design Page 42 of 51 [C5] Left axis deviation (QRS axis more negative than -3degrees) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_GGG) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_GGG) [C6] Right axis deviation (QRS axis more positive than +11degrees) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_HHH) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_HHH) [C7] Incomplete right bundle branch block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_III) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_III) [C13] Incomplete left bundle branch block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_JJJ) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_JJJ) [C8] Right bundle branch block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_KKK) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_KKK) [C14] Left anterior hemiblock (synonymous to left anterior fascicular block) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_LLL) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_LLL) [C15] Left posterior hemiblock (synonymous to left posterior fascicular block) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_MMM) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_MMM) [C9] Left bundle branch block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_NNN) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_NNN) [C17] Bifascicular block (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_OOO) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_OOO) [C10] Non-specific intraventricular conduction delay (QRS > 12msec) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_PPP) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_PPP) [C11] Accessory pathway (Wolff-Parkinson White, Lown-Ganong-Levine) (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_UUU) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_UUU) [C19] Prolonged QT interval (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_QQQ) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_QQQ) [C12] QT/QTc prolongation > 5msec (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_RRR) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_RRR) [C18] AV dissociation (MAPPINGS1:t_ECG_ABNORM.CONDUCTION_SSS) (MAPPINGS2:t_ECG_ABNORM.CONDUCTION_SSS) [C99] Other conduction, enter comment A2 (MAPPINGS1:t_ECG_ABNORM.EGFOTHC) (MAPPINGS2:t_ECG_ABNORM.EGFOTHC) D. Myocardial Infarction (MAPPINGS1:t_ECG_ABNORM.MI_AAA) (MAPPINGS2:t_ECG_ABNORM.MI_AAA) [D1] Myocardial infarction, old (MAPPINGS1:t_ECG_ABNORM.MI_BBB) (MAPPINGS2:t_ECG_ABNORM.MI_BBB) [D2] Myocardial infarction, anterior (MAPPINGS1:t_ECG_ABNORM.MI_CCC) (MAPPINGS2:t_ECG_ABNORM.MI_CCC) [D3] Myocardial infarction, lateral (MAPPINGS1:t_ECG_ABNORM.MI_DDD) (MAPPINGS2:t_ECG_ABNORM.MI_DDD) [D4] Myocardial infarction, posterior (MAPPINGS1:t_ECG_ABNORM.MI_EEE) (MAPPINGS2:t_ECG_ABNORM.MI_EEE) [D5] Myocardial infarction, inferior (MAPPINGS1:t_ECG_ABNORM.MI_FFF) (MAPPINGS2:t_ECG_ABNORM.MI_FFF) [D6] Myocardial infarction, septal (MAPPINGS1:t_ECG_ABNORM.MI_GGG) 42 CDD: MAPPINGS1 Table: t_ecg_abnorm Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM RHYTHM1_AAA STRING(255) RHYTHM1_BBB STRING(255) RHYTHM1_CCC STRING(255) RHYTHM1_DDD STRING(255) RHYTHM1_EEE STRING(255) RHYTHM1_FFF STRING(255) RHYTHM1_GGG STRING(255) RHYTHM1_HHH STRING(255) RHYTHM1_III STRING(255) RHYTHM1_JJJ STRING(255) RHYTHM1_KKK STRING(255) (MAPPINGS2:t_ECG_ABNORM.MI_GGG) [D20] Myocardial infarction, Non Q-wave (MAPPINGS1:t_ECG_ABNORM.MI_HHH) (MAPPINGS2:t_ECG_ABNORM.MI_HHH) [D98] Other myocardial infarction, enter comment (MAPPINGS1:t_ECG_ABNORM.EGFOTHD) (MAPPINGS2:t_ECG_ABNORM.EGFOTHD) A2 E. Depolarisation/Repolarisation (QRS-T) (MAPPINGS1:t_ECG_ABNORM.DEPO_AAA) (MAPPINGS2:t_ECG_ABNORM.DEPO_AAA) [D7] Non-specific ST-T changes (MAPPINGS1:t_ECG_ABNORM.DEPO_BBB) (MAPPINGS2:t_ECG_ABNORM.DEPO_BBB) [D19] J point elevation (MAPPINGS1:t_ECG_ABNORM.DEPO_CCC) (MAPPINGS2:t_ECG_ABNORM.DEPO_CCC) [D8] ST elevation (MAPPINGS1:t_ECG_ABNORM.DEPO_DDD) (MAPPINGS2:t_ECG_ABNORM.DEPO_DDD) [D21] ST-elevation - pericarditis (MAPPINGS1:t_ECG_ABNORM.DEPO_EEE) (MAPPINGS2:t_ECG_ABNORM.DEPO_EEE) [D9] ST depression (MAPPINGS1:t_ECG_ABNORM.DEPO_FFF) (MAPPINGS2:t_ECG_ABNORM.DEPO_FFF) [D10] U waves abnormal (MAPPINGS1:t_ECG_ABNORM.DEPO_GGG) (MAPPINGS2:t_ECG_ABNORM.DEPO_GGG) [D11] T wave inversion (MAPPINGS1:t_ECG_ABNORM.DEPO_HHH) (MAPPINGS2:t_ECG_ABNORM.DEPO_HHH) [D12] T wave peaked (MAPPINGS1:t_ECG_ABNORM.DEPO_III) (MAPPINGS2:t_ECG_ABNORM.DEPO_III) [D15] T waves flat (MAPPINGS1:t_ECG_ABNORM.DEPO_JJJ) (MAPPINGS2:t_ECG_ABNORM.DEPO_JJJ) [D16] T waves biphasic (MAPPINGS1:t_ECG_ABNORM.DEPO_KKK) (MAPPINGS2:t_ECG_ABNORM.DEPO_KKK) [D18] Notched T-waves (MAPPINGS1:t_ECG_ABNORM.DEPO_LLL) (MAPPINGS2:t_ECG_ABNORM.DEPO_LLL) [D13] Low QRS voltage (MAPPINGS1:t_ECG_ABNORM.DEPO_MMM) (MAPPINGS2:t_ECG_ABNORM.DEPO_MMM) [D17] T-wave flattening/inversion (MAPPINGS1:t_ECG_ABNORM.DEPO_NNN) (MAPPINGS2:t_ECG_ABNORM.DEPO_NNN) [D99] Other depolarisation/repolarisation, enter comment (MAPPINGS1:t_ECG_ABNORM.EGFOTHE) (MAPPINGS2:t_ECG_ABNORM.EGFOTHE) A2 Other abnormalities (MAPPINGS1:t_ECG_ABNORM.OTHER_AAA) (MAPPINGS2:t_ECG_ABNORM.OTHER_AAA) [E99] Enter comment (MAPPINGS1:t_ECG_ABNORM.EGFOTHO) (MAPPINGS2:t_ECG_ABNORM.EGFOTHO) A2 RHYTHM1_LLL STRING(255) RHYTHM1_MMM STRING(255) RHYTHM1_NNN STRING(255)

379 RHYTHM1_OOO STRING(255) Annotated Trial Design Page 43 of RHYTHM1_PPP STRING(255) RHYTHM1_QQQ STRING(255) RHYTHM1_RRR STRING(255) RHYTHM1_SSS STRING(255) RHYTHM1_TTT STRING(255) RHYTHM1_UUU STRING(255) RHYTHM1_VVV STRING(255) RHYTHM1_WWW STRING(255) RHYTHM1_XXX STRING(255) RHYTHM1_YYY STRING(255) RHYTHM1_ZZZ STRING(255) RHYTHM2_GGG STRING(255) RHYTHM2_AAA STRING(255) RHYTHM2_BBB STRING(255) RHYTHM2_CCC STRING(255) RHYTHM2_DDD STRING(255) RHYTHM2_EEE STRING(255) RHYTHM2_FFF STRING(255) EGFOTHA STRING(2) - A2 MORPHOLOGY_AAA STRING(255) MORPHOLOGY_BBB STRING(255) MORPHOLOGY_CCC STRING(255) MORPHOLOGY_DDD STRING(255) MORPHOLOGY_EEE STRING(255) MORPHOLOGY_FFF STRING(255) EGFOTHB STRING(2) - A2 CONDUCTION_AAA STRING(255) CONDUCTION_TTT STRING(255) CONDUCTION_BBB STRING(255) CONDUCTION_CCC STRING(255) CONDUCTION_DDD STRING(255) CONDUCTION_EEE STRING(255) CONDUCTION_FFF STRING(255) CONDUCTION_GGG STRING(255) CONDUCTION_HHH STRING(255) CONDUCTION_III STRING(255) CONDUCTION_JJJ STRING(255) CONDUCTION_KKK STRING(255) CONDUCTION_LLL STRING(255) CONDUCTION_MMM STRING(255) CONDUCTION_NNN STRING(255) CONDUCTION_OOO STRING(255) CONDUCTION_PPP STRING(255) CONDUCTION_UUU STRING(255) CONDUCTION_QQQ STRING(255) CONDUCTION_RRR STRING(255) CONDUCTION_SSS STRING(255) EGFOTHC STRING(2) - A2 MI_AAA STRING(255) MI_BBB STRING(255) MI_CCC STRING(255) MI_DDD STRING(255) MI_EEE STRING(255) MI_FFF STRING(255) MI_GGG STRING(255) MI_HHH STRING(255) EGFOTHD STRING(2) - A2 DEPO_AAA STRING(255) DEPO_BBB STRING(255) DEPO_CCC STRING(255) DEPO_DDD STRING(255) DEPO_EEE STRING(255) DEPO_FFF STRING(255) DEPO_GGG STRING(255) DEPO_HHH STRING(255) DEPO_III STRING(255) DEPO_JJJ STRING(255) DEPO_KKK STRING(255) DEPO_LLL STRING(255) DEPO_MMM STRING(255) DEPO_NNN STRING(255) EGFOTHE STRING(2) - A2 OTHER_AAA STRING(255) EGFOTHO STRING(2) - A2 CDD: MAPPINGS2 Table: t_ecg_abnorm Key Type: PATIENTVISIT Column Name Column Data Type Design Note EGDTTM DATE - DDMONYYYY HHMM RHYTHM1_AAA STRING(255) RHYTHM1_BBB STRING(255) RHYTHM1_CCC STRING(255) RHYTHM1_DDD STRING(255) RHYTHM1_EEE STRING(255) RHYTHM1_FFF STRING(255) RHYTHM1_GGG STRING(255) RHYTHM1_HHH STRING(255) RHYTHM1_III STRING(255) RHYTHM1_JJJ STRING(255) RHYTHM1_KKK STRING(255) RHYTHM1_LLL STRING(255) RHYTHM1_MMM STRING(255) RHYTHM1_NNN STRING(255) RHYTHM1_OOO STRING(255) RHYTHM1_PPP STRING(255) RHYTHM1_QQQ STRING(255) RHYTHM1_RRR STRING(255) RHYTHM1_SSS STRING(255) RHYTHM1_TTT STRING(255) RHYTHM1_UUU STRING(255) RHYTHM1_VVV STRING(255) RHYTHM1_WWW STRING(255) RHYTHM1_XXX STRING(255) RHYTHM1_YYY STRING(255) RHYTHM1_ZZZ STRING(255) RHYTHM2_GGG STRING(255) RHYTHM2_AAA STRING(255) RHYTHM2_BBB STRING(255) RHYTHM2_CCC STRING(255)

380 RHYTHM2_DDD STRING(255) Annotated Trial Design Page 44 of RHYTHM2_EEE STRING(255) RHYTHM2_FFF STRING(255) EGFOTHA STRING(2) - A2 MORPHOLOGY_AAA STRING(255) MORPHOLOGY_BBB STRING(255) MORPHOLOGY_CCC STRING(255) MORPHOLOGY_DDD STRING(255) MORPHOLOGY_EEE STRING(255) MORPHOLOGY_FFF STRING(255) EGFOTHB STRING(2) - A2 CONDUCTION_AAA STRING(255) CONDUCTION_TTT STRING(255) CONDUCTION_BBB STRING(255) CONDUCTION_CCC STRING(255) CONDUCTION_DDD STRING(255) CONDUCTION_EEE STRING(255) CONDUCTION_FFF STRING(255) CONDUCTION_GGG STRING(255) CONDUCTION_HHH STRING(255) CONDUCTION_III STRING(255) CONDUCTION_JJJ STRING(255) CONDUCTION_KKK STRING(255) CONDUCTION_LLL STRING(255) CONDUCTION_MMM STRING(255) CONDUCTION_NNN STRING(255) CONDUCTION_OOO STRING(255) CONDUCTION_PPP STRING(255) CONDUCTION_UUU STRING(255) CONDUCTION_QQQ STRING(255) CONDUCTION_RRR STRING(255) CONDUCTION_SSS STRING(255) EGFOTHC STRING(2) - A2 MI_AAA STRING(255) MI_BBB STRING(255) MI_CCC STRING(255) MI_DDD STRING(255) MI_EEE STRING(255) MI_FFF STRING(255) MI_GGG STRING(255) MI_HHH STRING(255) EGFOTHD STRING(2) - A2 DEPO_AAA STRING(255) DEPO_BBB STRING(255) DEPO_CCC STRING(255) DEPO_DDD STRING(255) DEPO_EEE STRING(255) DEPO_FFF STRING(255) DEPO_GGG STRING(255) DEPO_HHH STRING(255) DEPO_III STRING(255) DEPO_JJJ STRING(255) DEPO_KKK STRING(255) DEPO_LLL STRING(255) DEPO_MMM STRING(255) DEPO_NNN STRING(255) EGFOTHE STRING(2) - A2 OTHER_AAA STRING(255) EGFOTHO STRING(2) - A2

381 ari111402_nwr_e : VITAL SIGNS (VS Rpt) - Repeating Form Annotated Trial Design Page 45 of 51 1 # Actual BP HR SUPINE VITAL SIGNS 1. Actual date/time Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_VITALS_RPT.VSACTDTTM) (MAPPINGS2:t_VITALS_RPT.VSACTDTTM) Req : Req 24-hour clock 2. Blood pressure (MAPPINGS1:t_VITALS_RPT.rdcBPRpt) (MAPPINGS2:t_VITALS_RPT.rdcBPRpt) [Y] xxx ( n >= ) / (MAPPINGS1:t_VITALS_RPT.SYSBP) (MAPPINGS2:t_VITALS_RPT.SYSBP) xxx ( n >= ) mmhg (MAPPINGS1:t_VITALS_RPT.DIABP) (MAPPINGS2:t_VITALS_RPT.DIABP) (systolic/diastolic) [ND] Not Done 3. Heart rate (MAPPINGS1:t_VITALS_RPT.rdcHEART) (MAPPINGS2:t_VITALS_RPT.rdcHEART) [Y] xxx ( n >= ) beats/min (MAPPINGS1:t_VITALS_RPT.HEART) (MAPPINGS2:t_VITALS_RPT.HEART) [ND] Not Done Form Design Note: Repeat vital signs CDD: MAPPINGS1 Table: t_vitals_rpt Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM rdcbprpt STRING(2) SYSBP NUMERIC - N3 DIABP NUMERIC - N3 rdcheart STRING(2) HEART NUMERIC - N3 CDD: MAPPINGS2 Table: t_vitals_rpt Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM rdcbprpt STRING(2) SYSBP NUMERIC - N3 DIABP NUMERIC - N3 rdcheart STRING(2) HEART NUMERIC - N3 45

382 ari111402_nwr_e : ORTHO VITAL SIGNS (Ortho Rpt) - Repeating Form Annotated Trial Design Page 46 of 51 1 # Actual BP HR Subj Pos VITAL SIGNS 1. Actual date/time Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_ORTHO_VS_RPT.VSACTDTTM) (MAPPINGS2:t_ORTHO_VS_RPT.VSACTDTTM) Req : Req 24-hour clock 2. Blood pressure (MAPPINGS1:t_ORTHO_VS_RPT.rdcBPRpt) (MAPPINGS2:t_ORTHO_VS_RPT.rdcBPRpt) [ND] Not Done [Y] xxx ( n >= ) / (MAPPINGS1:t_ORTHO_VS_RPT.SYSBP) (MAPPINGS2:t_ORTHO_VS_RPT.SYSBP) xxx ( n >= ) mmhg (MAPPINGS1:t_ORTHO_VS_RPT.DIABP) (MAPPINGS2:t_ORTHO_VS_RPT.DIABP) (systolic/diastolic) 3. Heart rate (MAPPINGS1:t_ORTHO_VS_RPT.rdcHEART) (MAPPINGS2:t_ORTHO_VS_RPT.rdcHEART) [ND] Not Done [Y] xxx ( n >= ) beats/min (MAPPINGS1:t_ORTHO_VS_RPT.HEART) (MAPPINGS2:t_ORTHO_VS_RPT.HEART) 4. Subject position (MAPPINGS1:t_ORTHO_VS_RPT.VSPOSCD) (MAPPINGS2:t_ORTHO_VS_RPT.VSPOSCD) [1] Supine [2] Sitting [3] Standing Form Design Note: Repeat orthostatic vital signs Item Design Notes: Item No. Design Note 4. Item is optional. If one position is stipulated for protocol add specific text to Blood pressure. If more than one position is allowed, keep this item and remove the text from the BP item CDD: MAPPINGS1 Table: t_ortho_vs_rpt Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM rdcbprpt STRING(2) SYSBP NUMERIC - N3 DIABP NUMERIC - N3 rdcheart STRING(2) HEART NUMERIC - N3 VSPOSCD STRING(1) 46 CDD: MAPPINGS2 Table: t_ortho_vs_rpt Key Type: PATIENTVISIT Column Name Column Data Type Design Note VSACTDTTM DATE - DDMONYYYY HHMM rdcbprpt STRING(2) SYSBP NUMERIC - N3 DIABP NUMERIC - N3 rdcheart STRING(2) HEART NUMERIC - N3 VSPOSCD STRING(1)

383 ari111402_nwr_e : ELECTRONICALLY TRANSFERRED LAB DATA (Lab Rpt) - Repeating Form Annotated Trial Design Page 47 of 51 1 # Laboratory Test Type Date ELECTRONICALLY TRANSFERRED LAB DATA Record each repeat lab in a separate record 1. Laboratory Test Type (MAPPINGS1:t_LABLINK_RPT.rdcLBType) (MAPPINGS2:t_LABLINK_RPT.rdcLBType) [H] Haematology [C] Clinical Chemistry [U] Urinalysis 2. Date and time sample taken Hr:Min (:-23:59) Req / Req / Req (28-29) (MAPPINGS1:t_LABLINK_RPT.LBDTTM) (MAPPINGS2:t_LABLINK_RPT.LBDTTM) Req : Req 24-hour clock Form Design Note: Repeat Lablink Item Design Notes: Item No. Design Note 1. Study team can add additional test types if needed for their protocol CDD: MAPPINGS1 Table: t_lablink_rpt Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdclbtype STRING(1) LBDTTM DATE - DDMONYYYY HHMM CDD: MAPPINGS2 Table: t_lablink_rpt Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdclbtype STRING(1) LBDTTM DATE - DDMONYYYY HHMM 47

384 ari111402_nwr_e : REPEAT PHARMACOKINETICS BLOOD - GI (PK Rpt) - Repeating Form Annotated Trial Design Page 48 of 51 1 # Actual date/time Sample Identifier/Sample Number REPEAT PHARMACOKINETICS BLOOD 1. Actual date/time Req / Req / Req (28-29) (MAPPINGS1:t_PK_RPT.PKSTDTTM) (MAPPINGS2:t_PK_RPT.PKSTDTTM) Req : Req 24-hour clock 2. Sample Identifier/Sample Number A3 (MAPPINGS1:t_PK_RPT.PKSMPID) (MAPPINGS2:t_PK_RPT.PKSMPID) Form Design Note: Repeat PK CDD: MAPPINGS1 Table: t_pk_rpt Key Type: PATIENTVISIT Column Name Column Data Type Design Note PKSTDTTM DATE - DDMONYYYY HHMM PKSMPID STRING(3) - A3 CDD: MAPPINGS2 Table: t_pk_rpt Key Type: PATIENTVISIT Column Name Column Data Type Design Note PKSTDTTM DATE - DDMONYYYY HHMM PKSMPID STRING(3) - A3 48

385 ari111402_nwr_e : VISIT REPORTS (VRP) Annotated Trial Design Page 49 of 51 VISIT REPORTS * 1. This section is not implemented for your study (MAPPINGS1:t_VISITREPORT.NOTAVAIL_CC) (MAPPINGS2:t_VISITREPORT.NOTAVAIL_CC) * Item is not required CDD: MAPPINGS1 Table: t_visitreport Key Type: PATIENTVISIT Column Name Column Data Type Design Note NOTAVAIL_CC STRING(255) CDD: MAPPINGS2 Table: t_visitreport Key Type: PATIENTVISIT Column Name Column Data Type Design Note NOTAVAIL_CC STRING(255) 49

386 ari111402_nwr_e : Reg Docs (REG) Annotated Trial Design Page 50 of 51 Reg Docs 1. This section is not implemented for your study (MAPPINGS1:t_REGDOCS.NOTAVAIL_CC) (MAPPINGS2:t_REGDOCS.NOTAVAIL_CC) CDD: MAPPINGS1 Table: t_regdocs Key Type: PATIENTVISIT Column Name Column Data Type Design Note NOTAVAIL_CC STRING(255) CDD: MAPPINGS2 Table: t_regdocs Key Type: PATIENTVISIT Column Name Column Data Type Design Note NOTAVAIL_CC STRING(255) 50

387 CRB Electronic Signature Affidavit Annotated Trial Design Page 51 of 51 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 11.1of 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 user name and 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 11.1of 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 user name and password and clicking the button marked Submit below. 51

388 LIST OF INVESTIGATORS AND IECS/IRBS FOR PharmD Investigator Investigator/ Site no. Hospital/ Institution and Address MD and IEC/IRB Committee Chair and Name of Committee Phone: Fax: (fax) Chair: JD 1 1

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

390 CONFIDENTIAL ZM2008/00081/00 1

391 CONFIDENTIAL ZM2008/00081/00 2

392 CONFIDENTIAL ZM2008/00081/00 3

393 CONFIDENTIAL ZM2008/00081/00 4

394 CONFIDENTIAL ZM2008/00081/00 5

395 CONFIDENTIAL ZM2008/00081/00 6

396 CONFIDENTIAL ZM2008/00081/00 7

397 CONFIDENTIAL ZM2008/00081/00 8

398 CONFIDENTIAL ZM2008/00081/00 9

399 CONFIDENTIAL ZM2008/00081/00 10

400 CONFIDENTIAL ZM2008/00081/00 11