Statistical Analysis Plan RH01649 Version Document Identifier Effective Date eldo_clinical_doc Reason For Issue

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1 STATISTICAL ANALYSIS PLAN FOR PROTOCOL RH01649 A Study to Assess Efficacy over Placebo and Speed of Onset of Pain Relief of New Panadol Extra as Compared to Ibuprofen in Episodic Tension Headache BIOSTATISTICS DEPARTMENT GLAXOSMITHKLINE CONSUMER HEALTHCARE 1500 Littleton Road Parsippany, NJ USA Prepared by: PPD Page 1 of 44

2 Table of Contents STATISTICAL ANALYSIS PLAN AMENDMENT INTRODUCTION Study Objectives Primary Objective Secondary Objective Study Design Sample Size Timing of Analysis Personnel DATA CONSIDERATIONS Analysis Populations and Data Sets Time Windows DEMOGRAPHICS AND BASELINE CHARACTERISTICS Subject Disposition Demographics Baseline Characteristics TREATMENT COMPLIANCE AND CONCOMITANT MEDICATIONS Treatment Compliance Rescue and Concomitant Medications CRITERIA FOR ASSESSMENT Missing Data Handling Primary Variable Secondary Variables HYPOTHESIS TESTING Primary Hypothesis Secondary Hypothesis STATISTICAL SUMMARIES AND ANALYSIS Efficacy Analysis Primary Efficacy Analyses Secondary Efficacy Analyses Exploratory Efficacy Analyses Safety Data Analysis STUDY SCHEDULE TOPLINE SUMMARY CHANGES TO PLANNED ANALYSES Page 2 of 44

3 11... REFERENCES DERIVED DATA Final Report Listings Final Report Tables Final Report Figures Templates for Some Tables/Figures...24 Page 3 of 44

4 Glossary AE ANCOVA BMI CI ETTH g hr kg m max mg min N nae PI PRN PRS SD sec SPID SPRID TOTPAR Adverse Event Analysis of Covariance Body mass index Confidence interval Episodic Tension Headache Gram(s) Hour(s) Kilogram(s) Metres Maximum Milligram (s) Minimum Number (count) Number of AEs Pain Intensity As needed Pain Relief Score standard deviation Second(s) Sum of Pain Intensity Differences Sum of Pain Relief and Pain Intensity Differences Total Pain Relief Page 4 of 44

5 Statistical Analysis Plan Amendment The analysis plan finalized on August 8, 2014 has been changed and is reflected in the current version. Rationale for Change: A decision was made to terminate enrollment into the trial after 165 (62%) subjects of the originally planned 265 had been randomized. This decision was based primarily on enrollment difficulties and expiring drug supplies. As a result of the lower enrollment, the expected power of the study to detect the original target treatment differences is reduced as follows: Comparison of Interest SPID 0-4hr between Panadol Extra and Placebo (primary endpoint) Target Treatment Difference Power with N=265 Power with N= points 84% 64% SPID 0-1hr between Panadol Extra and Ibuprofen (secondary endpoint) Time to First Perceptible Pain Relief between Panadol Extra and Ibuprofen (secondary endpoint) 0.19 point noninferiority margin 6 minute noninferiority margin 91% 73% 96% 83% Impact on SAP: The originally planned inferential statistics (p-values) will not be presented in the tables summarizing results. Treatment comparisons will now be based primarily on the respective confidence intervals. The full output from the models for analysis will be available in the study report as an appendix. As a result, the table shells associated with the results of efficacy analyses have been modified in this version of the SAP. Page 5 of 44

6 1. Introduction The purpose of this research study is to assess the efficacy over placebo and speed of a new fast-absorbing formula of paracetamol, which also contains caffeine, (new Panadol Extra) compared to ibuprofen in pain relief of Episodic Tension Headaches (ETTH). 1.1 Study Objectives Primary Objective To assess the efficacy of headache relief of new Panadol Extra over placebo as measured by Sum of Pain Intensity Difference during 4 hours post-dosing period (SPID 0-4hr ) Secondary Objective To prove non-inferiority of new Panadol Extra with ibuprofen for early phase headache relief (within 1 hour post-dose) between new Panadol Extra and ibuprofen as measured by SPID 0-1hr. To compare new Panadol Extra with ibuprofen for speed of onset of headache relief as measured by time to first perceptible pain relief (time when patients reach Pain Relief Score - PRS 1). To compare the time to reach meaningful (i.e., a definite ) headache relief between treatments as measured by the time to reach PRS 2. To compare treatments for proportion of pain free subjects (complete pain relief) at 2 hours post-dose between treatments. To compare treatments for headache relief as measured by PRS, SPID, TOTPAR (total pain relief), and SPRID (sum of pain relief and pain intensity difference) at different post-dose periods. To assess global assessment scores of headache relief to different treatments. To compare the rate and time to first dose of rescue medication among treatments. To compare treatments for proportion of subjects with complete headache relief (PRS = 4) at 1 hour post-dose. To assess the frequency of adverse events in all treatments. Page 6 of 44

7 1.2 Study Design This is a multi-center, randomized, 3-arm, parallel-group, double-blind, double-dummy, single-dose, placebo-controlled study in subjects with ETTH. Subjects who meet all the inclusion criteria and none of the exclusion criteria at Visit 1 will first enter an open-label Run-In Phase for four weeks. Subjects who experience at least one qualifying headache episode, not suspected of having chronic tension type headache, use the ediary successfully, and confirm receiving at least some headache pain relief (PRS>1) from their usual OTC analgesics within two hours of treatment for at least 50% of all qualifying headaches will be randomly-assigned to a blinded study treatment and will enter into a Treatment Phase for up to six weeks. Subjects will characterize all headache episodes during the Treatment Phase, treating the first three headache episodes that satisfy the protocol-defined selection criteria programmed into the ediary. Subjects who do not achieve adequate headache relief during either the Run-in Phase or Treatment Phase will be allowed to use Aspirin (1000mg) as needed (PRN) as a rescue medication but are requested to withhold rescue for at least the first two-hours postdosing. Additionally, subjects may use the rescue medication to treat any headache episodes that do not meet the protocol-defined criteria for treatment with blinded study medication. 1.3 Sample Size Sample size calculations were based on the primary endpoints using data from a previous tension headache study (A ), where the mean (SD) for SPID 0-4h of placebo was 8.21 (3.3). The effect size of new Panadol Extra was assumed to be at least 20% greater than that of placebo. Based on these assumptions, a sample size of 106 subjects in the new Panadol Extra arm and 53 subjects in the placebo arm (ratio 2: 1) would provide 80% power to show a significant improvement (P 0.05) in headache SPID 0-4h. The number of subjects in the ibuprofen arm was set to be the equal to that of new Panadol Extra, in order to keep the same ratio of active arms with placebo. This number will provide more than 90% power to show a significant difference between ibuprofen and placebo. Therefore, a total sample size of 265 evaluable subjects with a ratio of active arms vs. placebo of 2:1 is required. This sample size, also fulfills the requirements for non-inferiority comparisons of new Panadol Extra with ibuprofen for PRS at 1 hour (87 subjects per active arm) and time to first perceptible pain relief (73 subjects per active arm). Considering a dropout rate of about 10%, a total of 290 subjects need to be randomized in order to ensure that 265 subjects complete the study without any protocol deviation. Page 7 of 44

8 1.4 Timing of Analysis No interim analysis will be performed. 1.5 Personnel PHT corporation will design, develop, deploy and manage the ediary system for the study and will also provide project management, training, and support services. The Biostatistics and Data Management (BDM) Department of GlaxoSmithKline Consumer Healthcare will perform all statistical analysis and reporting of results from the study. 2. Data Considerations 2.1 Analysis Populations and Data Sets All subjects who are randomized into the study and who receive any double-blind study medication will be considered evaluable for the safety population. All safety tables and listings will be based on the safety population. Efficacy analysis will be conducted on the intention-to-treat (ITT) population. Qualifying headaches with at least one post-baseline pain intensity (PI) assessment will be considered evaluable. The ITT population will consist of all subjects who receive at least one dose of double-blind study medication and who have at least one evaluable headache. Subjects will be analyzed according to the treatments to which they were randomized. The ITT population will be the population of primary interest for the efficacy analyses. Protocol violations will be examined on the individual evaluable headache and subject level. If there are a sufficient number of major protocol violations (>10% of the evaluable headaches), a Per Protocol (PP) analysis will also be performed on the primary efficacy endpoint. A headache will be considered evaluable for PP analysis if it is an evaluable headache for which no major protocol violations have been identified. The PP population will include all subjects who receive a dose of double-blind study medication, have at least one PP-evaluable headache, and who have no major protocol violations. At a minimum, the following will be considered major protocol violations: Subjects not satisfying protocol inclusion/exclusion criteria that are deemed to affect treatment efficacy. Use of prohibited medication. Subjects who have been misrandomized. Page 8 of 44

9 Any other reasons likely to affect efficacy assessments (e.g., failure to comply with the study restrictions) will be determined during the blinded data review prior to database lock and documented appropriately. The Medical Affairs representative and biostatistician will make the final determinations regarding major protocol violations. 2.2 Time Windows The electronic diary will not allow entry of any assessment more than 5-minutes outside of the protocol-specified time intervals (10, 15, 20, 25, 30, 40, 50, 60, 90, 120, 180, 240 minutes post-treatment for each qualifying headache). For analyses based on the ITT population, nominal time intervals will be used regardless of when the assessment actually took place. 3. Demographics and Baseline Characteristics 3.1 Subject Disposition The subject disposition summary will include number of subjects screened, randomized, withdrawals (including reason), and the number of subjects in safety, ITT and PP populations. 3.2 Demographics Summary of demographic information will include age, gender, race, weight, height and BMI. Categorical measures (such as gender and race) will be summarized by the number and percentage of subjects in each category. Descriptive statistics for continuous measures (such as age) will include the mean, median, standard deviation and minimum/maximum. 3.3 Baseline Characteristics The distribution (number and percent of subjects) of the total number of headaches, the number of qualifying headache events during run-in, the time of dosing relative to the start of the headache, and the baseline severity of the run-in and treatment period qualifying headaches (mean, median, standard deviation, range) by treatment group will be provided for inspection. 4. Treatment Compliance and Concomitant Medications 4.1 Treatment Compliance Dosing times for each qualifying headache will be recorded in the ediary. Since each headache is dosed once, there is no compliance measure relating to the randomized treatment usage. Page 9 of 44

10 4.2 Rescue and Concomitant Medications Rescue medication use will be recorded in the ediary. Once rescue medication is used, the ediary will no longer allow subsequent headache assessments. Concomitant medications used during the study, including any prohibited medications, will be listed. 5. Criteria for Assessment Efficacy assessments will be based on all qualifying headaches during the treatment phase. A summary table of the distribution of the number of qualifying headache events during the treatment phase by treatment group will be provided for inspection. 5.1 Missing Data Handling Data will generally not be imputed except in the following situations: If the response to the question Do you have complete relief at this moment? asked at the 120-minute post-dosing timepoint is yes, then the PI will be imputed as 0=no headache and the PRS will be imputed as 4=complete relief for the 120, 180 and 240-minute timepoints. If a subject used rescue medication, the maximum of the last two PI scores prior to the rescue medication use will be imputed forward from the time of rescue use through 240 minutes. If a subject used rescue medication, a PRS of zero (i.e. no relief) will be imputed forward from the time of rescue use through 240 minutes. 5.2 Primary Variable The primary endpoint in assessing efficacy will be the per-subject average over all qualifying headaches of the sum of pain intensity difference (SPID) 0-4 hours. SPID 0-4h will be calculated as the weighted sum of headache pain intensity differences through 4 hours post-dose. o For each qualifying headache, pain intensity differences at each time point post dosing will be calculated as the difference between pain intensity at baseline (Time=0) and the pain intensity at each given time point. o Weighted pain differences will be calculated as the pain intensity difference multiplied by the time between assessments in fractions of an hour. o Only subjects with at least an actual or imputed (see section 5.1) 240-minute pain intensity assessment will have non-missing SPID 0-4h. Page 10 of 44

11 5.3 Secondary Variables SPID 0-1h, SPID 0-2h and SPID 0-3h where SPID is defined as above in section 5.2. o Subjects must have at least an actual or imputed (see section 5.1) 60-minute pain intensity difference to have a non-missing SPID 0-1h. Subjects must have at least an actual or imputed (see section 5.1) 120-minute pain intensity difference to have a non-missing SPID 0-2h. Subjects must have at least an actual or imputed (see section 5.1) 180-minute pain intensity difference to have a non-missing SPID 0-3h. Time to perceptible ( a little ) headache relief (minutes) Average time per subject over all qualifying headaches. o Perceptible relief will be defined as PRS 1. For each qualifying headache, the first time a subject reports PRS 1, they will be asked to provide the exact time at least a little relief was noted. For each subject, the average exact time overall qualifying headaches will be used in analysis. Proportion of pain free subjects at 2 hours post dose. o Pain free will be defined as a yes response to the question of Do you have complete relief right now? asked at the 120-minute timepoint. o If a subject is pain free at the 120-minute timepoint for the majority of their qualifying headaches, the subject will be considered to be pain free. If the subject has an equal number of qualifying headaches pain-free and not pain-free at the 120-minute timepoint, he/she will not be considered to be pain-free. o An additional secondary analysis of this variable will be a summary of the proportion of subjects pain-free at the 120-minute timepoint for at least one of their qualifying headaches. o An additional secondary analysis of this variable will be a summary of the proportion of subjects pain-free at the 120-minute timepoint for each of the qualifying headaches (first, second, third, etc.). Proportion of subjects with complete headache relief at 1 hour post dose. o Complete relief will be defined as PRS = 4 at the 1-hour timepoint. o If a subject has complete relief at the 1 hour timepoint for the majority of their qualifying headaches, the subject will be considered to have complete relief. If the subject has an equal number of qualifying headaches with and Page 11 of 44

12 without complete relief at the 1-hour timepoint, that subject will be classified as not having complete relief. o An additional secondary analysis of this variable will be a summary of the proportion of subjects with complete relief at the 1-hour timepoint for each of the qualifying headaches (first, second, third, etc.). Time to meaningful headache relief Mean time per subject over all qualifying headaches. o Meaningful relief will be defined as PRS 2. For each qualifying headache, the first timed interval assessment that a subject reported PRS 2 will be determined. For each subject, the mean time over all qualifying headaches will be the time used for analysis. Headache pain intensity differences from baseline (PID) at 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, 180 and 240 minutes for each subject averaged over all qualifying headaches. o Pain intensity is evaluated at baseline and each of the above timepoints post-baseline on a scale of 0 (no headache) to 3 (severe headache). A change from baseline will be calculated at each post-baseline timepoint as the difference in score from baseline. Headache pain relief scores (PRS) at 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, 180 and 240 minutes each endpoint for each subject averaged over all qualifying headaches. o Pain relief is evaluated at each of the above post-baseline timepoints on a scale of 0 (no relief) to 4 (complete relief). Total pain relief (TOTPAR) at 1, 2, 3 and 4 hours post dose each endpoint for each subject averaged over all qualifying headaches. o For each qualifying headache, TOTPAR is calculated as the sum of the products of pain relief scores (PRS) at each time point t and the time (in fraction of an hour) since the previous relief assessment (i.e. PRS (t) x [(time (t) time (t-1) )/60] ). o Subjects must have at least an actual or imputed 60-minute pain relief score to have a non-missing TOTPAR 0-1h. Subjects must have at least an actual or imputed 120-minute pain relief score to have a non-missing TOTPAR 0-2h. Subjects must have at least an actual or imputed 180-minute pain relief score to have a non-missing TOTPAR 0-3h. Subjects must have at least an Page 12 of 44

13 actual or imputed 240-minute pain relief score to have a non-missing TOTPAR 0-4h. Area under the time-response curve for change in headache pain intensity and headache pain relief (SPRID) at 1, 2, 3 and 4 hours, calculated as sum of TOTPAR and SPID, each endpoint for each subject averaged over all qualifying headaches. o Both TOTPAR and SPID scores must be non-missing to calculate the corresponding SPRID score. Global Evaluation of Response to Treatment averaged per subject over all qualifying headaches o Subjects rate the Global Evaluation of Response to Treatment 4-hours postbaseline of each qualifying headache on a scale of 0=very poor to 2=neutral to 4=very good. Rate of rescue medication o Proportion calculated as the number of subjects that took any rescue medication for any of their qualifying headaches over the total number of subjects for a given treatment group. o This endpoint will also be summarized as a proportion of the total number of rescue medications used divided by the total number of qualifying headaches for each treatment group. Time to rescue medication use Mean time per subject over all qualifying headaches. o Subjects who do not use rescue medication will be censored at 4 hours. 6. Hypothesis Testing In all hypotheses, the treatment difference being assessed will equal the estimate from the Panadol Extra treatment group minus the control treatment group (either placebo or ibuprofen). 6.1 Primary Hypothesis The following specific null hypotheses will be tested: H01: There is no difference in mean SPID 0-4h between new Panadol Extra and placebo. Page 13 of 44

14 6.2 Secondary Hypothesis The following secondary comparisons will be performed for SPID 0-4h : H02: There is no difference in mean SPID 0-4h between new Panadol Extra and ibuprofen; H03: There is no difference in mean SPID 0-4h between Ibuprofen and placebo. The following hypothesis will be tested to assess non-inferiority of new Panadol Extra with ibuprofen for SPID 0-1h : H04: The difference in mean SPID 0-1h between new Panadol Extra and ibuprofen is H14: The difference in mean SPID 0-1h between new Panadol Extra and ibuprofen is > Other secondary endpoints will include: The following hypothesis will be tested to assess non-inferiority of new Panadol Extra with ibuprofen for time to first perceptible headache relief (PRS 1): H05: The difference in mean time to reach first perceptible headache relief between new Panadol Extra and ibuprofen is 6 minutes. H15: The difference in mean time to reach first perceptible headache relief between new Panadol Extra and ibuprofen is > 6 minutes. If non-inferiority between new Panadol Extra and ibuprofen is established (H 0 is accepted) then a comparison for superiority between the two treatments will be performed. Other comparisons between treatments for time to first perceptible headache relief will include: new Panadol Extra vs. placebo and ibuprofen vs. placebo. The remaining secondary endpoints will be tested for differences between all 3 pairs of treatment groups: Proportion of pain free subjects at 2 hours post dose Proportion of subjects with complete headache relief at 1 hour post dose Time to meaningful headache relief Headache severity (PID) at 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, 180 and 240 minutes Headache relief (PRS) at 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, 180 and 240 minutes Total pain relief (TOTPAR) at 1, 2, 3 and 4 hours post dose Page 14 of 44

15 The Area under the time-response curve for change in headache intensity and headache relief (SPRID) at 1, 2, 3 and 4 hours Global Evaluation of Response to Treatment Proportion of subjects taking rescue medication 7. Statistical Summaries and Analysis All data recorded in the CRF will be listed. Descriptive statistics (sample size N, mean, median, standard deviation, minimum, and maximum) will be provided for demographics and baseline data. All efficacy data will be summarized and presented graphically where appropriate. All analyses will be carried out in SAS using version 9.2 or later. The relative significance of the results will be determined empirically. Ninety five percent confidence intervals will be provided for within- and between-treatment group point estimates. 7.1 Efficacy Analysis Primary Efficacy Analyses Analysis of covariance will be used to analyze SPID 0-4h. The model will include factors for treatment and site as fixed effects. Baseline assessment of pain intensity will be included in the model as a covariate. The baseline pain intensity will be averaged over all qualifying headaches. Treatment differences will be presented with 95% confidence intervals. SAS code for this analysis is as follows: PROC MIXED; CLASS TRT SITE; MODEL SPID0_4 = BASE TRT SITE; LSMEANS TRT/PDIFF CL; Since the number of subjects enrolled per site is expected to be low, sites may be pooled for the purposes of analysis or the site factor may be excluded from the analysis model altogether dependent on the final enrollment numbers Secondary Efficacy Analyses The ANCOVA model described above in section will be used for the analysis of SPID 0-1h, SPID 0-2h and SPID 0-3h, individual PIDs at each time point, individual PRS at each Page 15 of 44

16 time point, TOTPAR 0-1h, TOTPAR 0-2h, TOTPAR 0-3h and TOTPAR 0-4h, SPRID 0-1h, SPRID 0-2h, SPRID 0-3h, and SPRID 0-4h. Baseline assessment of pain intensity will be included in each model as a covariate. The baseline pain intensity will be averaged over all qualifying headaches. An ANOVA model with fixed effects for treatment and site will be used for the analysis of the Global Evaluation of Response to Treatment. Time to perceptible relief (PRS>=1) and time to meaningful relief (PRS>=2) will be analyzed using a Cox proportional hazards model accounting for effects due to treatment group and site and baseline assessment of pain intensity as a covariate. Subjects who use rescue medication prior to achieving the endpoint (PRS>=1 for perceptible relief and PRS>=2 for meaningful relief) and subjects who do not achieve time to perceptible relief/time to meaningful relief will have a censored time set to the duration of the study (240 minutes). Hazard ratios and their 95% confidence intervals will be used for treatment comparisons. Survival plots will be presented. SAS Code for these analyses is as follows (example given for time to perceptible relief and Panadol vs. placebo): PROC PHREG;* subset dataset to one pair of treatment groups for analysis*; CLASS TRT(REF= PLACEBO ) SITE; MODEL TTPR*PCENSOR(1) = TRT SITE BASE; HAZARDRATIO Panadol Extra vs. Placebo TRT / DIFF=REF CL=WALD; The proportion of pain-free subjects (i.e. subjects who answer yes to the question do you have complete relief right now? at 2-hours post-dosing), the rate of rescue medication use (i.e. subjects who report having taken rescue medication within 4 hours post-dosing), and the proportion of subjects with complete relief (PRS=4) at 1-hour post-dosing will be analyzed by a 2 x 2 chi-square test or exact test if the number of events are small (Yes/No categories between any two treatments: new Panadol Extra vs. placebo; ibuprofen vs. placebo and new Panadol Extra vs. ibuprofen). The time to rescue medication use will be summarized by means of descriptive statistics (N, mean, SD, median, min and max) Exploratory Efficacy Analyses The following exploratory analyses may also be performed: o Analyses of the continuous endpoints described above (SPID, TOTPAR, PID, PRS, SPRID) and the rate of rescue medication use may be repeated for the first, headache event separately. These results would be used to confirm the results of the average scores. Only descriptive statistics of the continuous endpoints may be displayed for the second and third headaches events. Page 16 of 44

17 o An additional analysis of the SPID 0-4h and TOTPAR 0-4h endpoints will be performed using an ANCOVA model including factors for treatment, site and gender as fixed effects along with the baseline pain severity intensity as covariate to explore the impact of gender on the results. o An additional analysis of the SPID 0-4h and TOTPAR 0-4h endpoints will be performed using an ANCOVA model including factors for treatment and site as fixed effects along with the number of headache episodes during the 3 months prior to screening as a covariate to explore the relationship between history and response. 7.2 Safety Data Analysis Only adverse events which have started during the treatment phase will be accounted for in AE tables (i.e. Treatment emergent adverse events ). Any events which start prior to the treatment phase will only be counted in the treatment emergent adverse event table if the severity of the event worsens during that phase. Safety data for all enrolled subjects will be listed. All subjects who are randomized and receive any study treatment will be included in the analysis of safety data (safety population). Treatment-emergent AEs (including severity/relationship to study treatment) will be summarized by treatment group for the safety population using N and %. Non-treatment emergent AEs will be listed. AEs will be considered to be related to study medication if their relationship to study medication is classified as highly probable or probable or possible. AEs will be considered to be unrelated to study medication if their relationship to study medication is classified as unlikely or not related. Summary tables for the treatment emergent adverse events will be provided by treatment group according to body system and preferred term and reported by treatment group. Similar summary tables will be provided in addition for treatment related adverse events. In addition a summary of the severity of adverse events and also the incidence, severity and relationship of treatment emergent adverse events will be produced. Page 17 of 44

18 8. Study Schedule Procedures Site Visit 1 Screening Telephon e Contact 1 15 (±2) days from Visit 1* Site Visit 2 30 (±2) days from Visit 1 Telephon e Contact 2 12 (±2) days from Visit 2* Telephon e Contact 3 24 (±2) days from Visit 2* Telephon e Contact 4 36 (±2) days from Visit 2* Site Visit 3 42 (±3) Days from Visit 2** Informed Consent Administration X Demography & Medical (including Headache) X History Inclusion/Exclusion Criteria Assessment X Adverse Events Assessment X X X Concomitant Medications Assessment X X X Physical Examination X Neurological Examination X Urine Drug Screen X Urine Pregnancy Test (All Females) X X ediary and Paper Diary Training X X ediary Assignment and Dispensation X X Paper Diary Dispensation X X Usual OTC Analgesic Dispensation X Rescue Medication Dispensation X Remote ediary, Paper Diary, & Medication Review X X X X On-site ediary and Paper Diary Review X X Usual OTC Analgesic Collection X Subject Continued Eligibility Assessment X Randomization X Study Medication Dispensation X Paper Diary Collection X X Study Medication and Rescue Medication Collection X * Appropriate site personnel to call subject if no qualifying headache has been treated in 7 consecutive days during the Run-in Phase or 12 consecutive days during the Treatment Phase ** Visit may occur earlier if 3 qualifying headaches have been treated before Day 42 Page 18 of 44

19 9. Topline Summary No topline summary is planned for this study. 10. Changes to Planned Analyses The criteria for efficacy presented in Section of the protocol states that the efficacy of Panadol Extra would be proved by a significant difference over placebo at p 0.05 for SPID 0-4hr. It further states that the non-inferiority of Panadol Extra with ibuprofen for SPID 0-1hr would be established if the upper limit of the 95% confidence interval for the difference between the treatment groups was 0.19 and for time to reach first perceptible pain relief would be established if the upper limit of the 95% confidence interval for the difference between the two treatment groups was 6 minutes. This SAP changes the assessment of efficacy for the primary endpoint of SPID 0-4hr to be primarily based on an assessment of the confidence interval for the difference between Panadol Extra and placebo. Also, while the non-inferiority of Panadol Extra to ibuprofen in the key secondary endpoints of SPID 0-1hr and time to first perceptible relief will continue to be evaluated based on the confidence intervals around the difference between treatment groups, consideration of any loss in precision due to sample size will be made viz. the a priori stated margins. 11. References A Study to Assess the Efficacy of Paracetamol Taken in Combination with Caffeine for the Treatment of Episodic Tension Headache. GSKCH Clinical Study A Hills M, Armitage P. The two period cross-over clinical trial. Br J Clin Pharmac 1979; 8: Hollander M, Wolfe DA. Nonparametric statistical methods. New York: Wiley, 1999: Page 19 of 44

20 12. Derived Data The following tables present the derived population and efficacy variables. PROFILE dataset derived variables: The PROFILE dataset should include all of the standard variables including flags for the three analysis populations (safety: all randomized subjects treated with double-blind product, ITT: all randomized subjects treated with double-blind product who have at least one assessment for a qualifying headache, and Per-Protocol: ITT subjects with no major protocol violations). EFFIC dataset derived variables: The EFFIC dataset should have all the standard variables (including TRT and TRT_T) and the following additional variables (for each qualifying headache): Derived Variable Name HEADNUM Definition of Variable Qualifying Headache Number How Determined Extracted from the HQUAL raw logpad dataset along with an assigned number to represent the average over all qualifying headaches (HEADNUM=400) Valid Values or Range of Values 1 ASTIME Assessment Time Actual assessment times post-baseline extracted from HQUAL raw logpad dataset (10 ASTIME 240) along with assigned times for each of the composite SPID scores (SPID 0-1 hour ASTIME=310, SPID 0-2 hour ASTIME=320, SPID 0-3 hour ASTIME=330, and SPID 0-4 hour ASTIME=340) 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, 180, 240, 310, 320, 330, 340 PAIN Headache severity Severity score as recorded in logpad from HQUAL dataset 0-3 RELIEF Headache relief Relief score as recorded in logpad from HQUAL dataset 0-4 COMPLETE Complete Headache Only at ASTIME=120, response to was complete relief achieved from HQUAL Yes/no Page 20 of 44

21 Derived Variable Name Definition of Variable Relief raw logpad dataset How Determined Valid Values or Range of Values TTFPR Time to First Perceptible Pain Relief At the earliest ASTIME where RELIEF 1, an actual time (hr:min) relative to the start of the headache expressed in minutes; value=. if RELIEF is never 1 Missing or >0 TTMPR Time to Meaningful Pain Relief The earliest ASTIME where RELIEF 2; value=. if RELIEF is never 1 Missing 10 or GLOBAL Global Evaluation of Response to Treatment At ASTIME=240 or at the earliest ASTIME where RELIEF=4 0-4 TTRM Time to Rescue Medication Earliest non-missing RCTIME (from RCMED logpad dataset) minus HQUALTM (from HQUAL logpad dataset) expressed in minutes; value=. if no rescue med use for the given headache event Missing or 1 to 240 minutes BPAIN DPAIN Baseline Headache Severity Difference in Headache Severity PAIN at ASTIME=0 0-3 PAIN minus BPAIN -3 to 1 (minimum baseline score=2) SPID Sum of Pain Intensity Differences Sum from ASTIME=10 to current ASTIME(=i) of {DPAINi times [ASTIME=i ASTIME=(i-1) ] } numeric TOTPAR Total Pain Relief Sum from ASTIME=10 to current ASTIME(=i) of {RELIEFi times [ASTIME=i ASTIME=(i-1) ] } numeric Page 21 of 44

22 Derived Variable Name SPRID Definition of Variable Sum of Pain and Relief Differences How Determined Sum of SPID and TOTAR Valid Values or Range of Values numeric The EFFIC dataset should have one row for each subject, each qualifying headache and each post-baseline (ASTIME=0) assessment time. Therefore if no assessments are missing, a subject could have as many as 16 rows per qualifying headache for as many as 3 headaches (maximum per protocol). An additional 16 rows are to be included in this dataset for the average over all qualifying headaches (HEADNUM=400). Where HEADNUM=400, the value of PAIN, RELIEF, COMPLETE, BPAIN, DPAIN, GLOBAL, SPID, TOTPAR, SPRID, TTFPR, TTMPR and TTRM are to be the averages over all qualifying headaches. Therefore, each subject in the EFFIC dataset can have a maximum of 64 observations. In addition to the above efficacy-specific variables, it should have merged by subject all of the variables from the PROFILE dataset and the basic demographic variables from the DEMOG dataset of age, gender, and race. Page 22 of 44

23 METHODS OF PRESENTATION 12.1 Final Report Listings The following standard listings will appear in Section 2 of the final clinical study report: Demography and Baseline Characteristics Subject Disposition Protocol Deviations Demographics & Baseline Characteristics Vital Signs Comments Listing Safety Adverse Events Physical Exam Abnormalities Laboratory Abnormalities and Positives Medical History Concomitant Medications 12.2 Final Report Tables The following tables will appear in Section 9 of the final clinical study report: Disposition and Demography and Baseline Characteristics (Section 9.1) (All standard format) Disposition of Subjects Demographics Baseline Characteristics Efficacy Analysis (Section 9.2) SPID Change from Baseline in Headache Intensity over Time TOTPAR Pain Relief Scores over Time Time to Perceptible ( a little ) Headache Relief Time to Meaningful Relief SPRID Complete Relief at 1 and 2 hours Post-Dosing Rate and Time to Rescue Medication Use Global Evaluation of Response to Treatment Safety Analysis (Section 9.3) (All standard format) Treatment emergent adverse events Treatment emergent treatment related adverse events Page 23 of 44

24 9.3.3 Treatment Emergent Adverse Events by Severity Treatment Emergent Treatment Related Adverse Events by Severity 12.3 Final Report Figures The following figures will appear in Section 9 of the final clinical study report: Efficacy Analysis (Section 9.2) Headache Intensity over Time Pain Relief over Time Time to Perceptible Relief Time to Meaningful Relief 12.4 Templates for Some Tables/Figures The following are template examples showing how the non-standard tables/figures in Section 9 will appear. Page 24 of 44

25 Page 25 of 44 Document Name Table Baseline Characteristics ITT Population Treatment Group Panadol Extra IBUPROFEN PLACEBO Total (n=xxx) Age at Onset of Condition (Yrs) N xx xx Xx Xx Mean xx.x xx.x xx.x xx.x S.D. x.xx x.xx x.xx x.xx Median xx xx Xx Xx Minimum xx xx Xx Xx Maximum xx xx xx Xx Severity of historical Headaches Mild xx (xx.x%) xx (xx.x%) XX (XX.X%) Xx (xx.x%) Moderate xx (xx.x%) xx (xx.x%) Xx (xx.x%) Xx (xx.x%) Severe xx (xx.x%) xx (xx.x%) Xx (xx.x%) Xx (xx.x%) Duration of Historical Headaches (if untreated) N xx xx Xx Xx Mean xx.x xx.x xx.x xx.x S.D. x.xx x.xx x.xx x.xx Median xx xx Xx Xx Minimum xx xx Xx Xx Maximum xx xx xx Xx Number of Historical Headaches (in 3 months prior to run-in) N xx xx Xx Xx Mean xx.x xx.x xx.x xx.x S.D. x.xx x.xx x.xx x.xx Median xx xx Xx Xx Minimum xx xx Xx Xx Maximum xx xx xx Xx

26 Page 26 of 44 Document Name Table (Continued) Baseline Characteristics ITT Population Treatment Group Panadol Extra IBUPROFEN PLACEBO Total (n=xxx) Total Number of Run-In Headache Episodes 1 Xx (xx%) Xx (xx%) Xx (xx%) Xxx (xx%) 2 xx (xx.x%) xx (xx.x%) XX (XX.X%) Xx (xx.x%) >=3 xx (xx.x%) xx (xx.x%) Xx (xx.x%) Xx (xx.x%) Number of Run-In Qualifying Headache Episodes 1 Xx (xx%) Xx (xx%) Xx (xx%) Xxx (xx%) 2 xx (xx.x%) xx (xx.x%) XX (XX.X%) Xx (xx.x%) >=3 xx (xx.x%) xx (xx.x%) Xx (xx.x%) Xx (xx.x%) Average Baseline pain severity of All Qualifying Run-In Events (a) N xx xx Xx Xx Mean xx.x xx.x xx.x xx.x S.D. x.xx x.xx x.xx x.xx Median xx xx Xx Xx a Average calculated over all qualifying events for each subject

27 Page 27 of 44 Document Name Table (Continued) Baseline Characteristics ITT Population Treatment Group Panadol Extra IBUPROFEN PLACEBO Total (n=xxx) a Average calculated over all qualifying events for each subject Number of Treatment Phase Qualifying Headache Episodes 1 xx (xx.x%) xx (xx.x%) XX (XX.X%) Xx (xx.x%) 2 xx (xx.x%) xx (xx.x%) Xx (xx.x%) Xx (xx.x%) 3 xx (xx.x%) xx (xx.x%) Xx (xx.x%) Xx (xx.x%) Baseline pain severity of First Qualifying Treatment Phase Event MODERATE xx (xx.x%) xx (xx.x%) XX (XX.X%) Xx (xx.x%) SEVERE xx (xx.x%) xx (xx.x%) Xx (xx.x%) Xx (xx.x%) Average Baseline pain severity of All Qualifying Treatment Phase Events (a) N xx xx Xx Xx Mean xx.x xx.x xx.x xx.x S.D. x.xx x.xx x.xx x.xx Median xx xx Xx Xx Average Time from Symptom Start to Time of Dosing for All Qualifying Treatment Phase Events (min) (a) N xx xx Xx Xx Mean xx.x xx.x xx.x xx.x S.D. x.xx x.xx x.xx x.xx Median xx xx Xx Xx

28 Page 28 of 44 Document Name Table SPID ITT Population SPID 0-1hr SPID 0-2hr SPID 0-3hr SPID 0-4hr RAPC N XX XX XX XX MEAN X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX IBUPROFEN N XX XX XX XX MEAN X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX PLACEBO N XX XX XX XX MEAN X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX TREATMENT COMPARISONS RAPC vs. IBU TRT DIFF[2] X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX RAPC vs. PBO TRT DIFF[2] X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX IBU vs. PBO TRT DIFF[2] x.xx X.XX X.XX X.XX 95% CI x.xx, x.xx X.XX,X.XX X.XX,X.XX X.XX,X.XX SPID=Sum of Pain Intensity Differences over the specified interval [1]: Adjusted means and confidence limits for treatment differences from ANCOVA model with fixed factors for treatment, site and baseline intensity covariate.

29 Page 29 of 44 Document Name [2] Difference between the first named treatment group and the second named treatment group such that a negative result favors the first treatment. Note: If rescue med used, the maximum of the last two values before rescue use are imputed forward from the time of use through 240 minutes.

30 Page 30 of 44 Document Name Table Change from Baseline in Headache Pain Intensity over Time ITT Population 10 mins 15 mins 20 mins 25 mins 30 mins 40 mins 50 mins RAPC N XX XX XX XX XX XX XX MEAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX X.XX X.XX X.XX IBUPROFEN N XX XX XX XX XX XX XX MEAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX X.XX X.XX X.XX PLACEBO N XX XX XX XX XX XX XX MEAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX X.XX X.XX X.XX TREATMENT COMPARISONS RAPC vs. IBU TRT DIFF[2] X.XX X.XX X.XX X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX RAPC vs. PBO TRT DIFF[2] X.XX X.XX X.XX X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX IBU vs. PBO TRT Diff[2] X.XX X.XX X.XX X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX [1]: Adjusted means and confidence limits for treatment differences from ANCOVA model with fixed factors for treatment, site and baseline intensity covariate.

31 Page 31 of 44 Document Name [2] Difference between the first named treatment group and the second named treatment group such that a negative result favors the first treatment. Note: If rescue med used, the maximum of the last two values before rescue use are imputed forward from the time of use through 240 minutes. PROGRAMMING NOTE: This table needs to continue on 2 more pages with columns for the remaining timepoints evaluated (60, 90, 120, 180, 240).

32 Page 32 of 44 Document Name Table TOTPAR ITT Population TOTPAR 0-1hr TOTPAR 0-2hr TOTPAR 0-3hr TOTPAR 0-4hr RAPC N XX XX XX XX MEAN X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX IBUPROFEN N XX XX XX XX MEAN X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX PLACEBO N XX XX XX XX MEAN X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX TREATMENT COMPARISONS RAPC vs. IBU TRT DIFF[2] X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX RAPC vs. PBO TRT DIFF[2] X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX IBU vs. PBO TRT DIFF[2] X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX TOTPAR=Total of Pain Relief scores over the specified time interval [1]: Adjusted means and confidence limits for treatment differences from ANCOVA model with fixed factors for treatment, site and baseline intensity covariate.

33 Page 33 of 44 Document Name [2] Difference between the first named treatment group and the second named treatment group such that a positive result favors the first treatment. Note: If rescue med used, the maximum of the last two values before rescue use are imputed forward from the time of use through 240 minutes.

34 Page 34 of 44 Document Name Table Pain Relief scores over Time ITT Population 10 mins 15 mins 20 mins 25 mins 30 mins 40 mins 50 mins RAPC N XX XX XX XX XX XX XX MEAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX X.XX X.XX X.XX IBUPROFEN N XX XX XX XX XX XX XX MEAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX X.XX X.XX X.XX PLACEBO N XX XX XX XX XX XX XX MEAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX SD X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX X.XXX MINIMUM X.X X.X X.X X.X X.X X.X X.X MAXIMUM X.X X.X X.X X.X X.X X.X X.X MEDIAN X.XX X.XX X.XX X.XX X.XX X.XX X.XX ADJ MEAN[1] X.XX X.XX X.XX X.XX X.XX X.XX X.XX TREATMENT COMPARISONS RAPC vs. IBU TRT DIFF[2] X.XX X.XX X.XX X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX RAPC vs. PBO TRT DIFF[2] X.XX X.XX X.XX X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX IBU vs. PBO TRT DIFF[2] X.XX X.XX X.XX X.XX X.XX X.XX X.XX 95% CI X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX X.XX,X.XX [1]: Adjusted means and confidence limits for treatment differences from ANCOVA model with fixed factors for treatment, site and baseline intensity covariate. [2] Difference between the first named treatment group and the second named treatment group such that a positive result favors the first treatment.

35 Page 35 of 44 Document Name Note: If rescue med used, the maximum of the last two values before rescue use are imputed forward from the time of use through 240 minutes. PROGRAMMING NOTE: This table needs to continue on 2 more pages with columns for the remaining timepoints evaluated (60, 90, 120, 180, 240). This table shell is also to be used for SPRID scores with an appropriate change in title (Table 9.2.7).

36 Page 36 of 44 Document Name Table Time to perceptible ( a little ) headache relief (Mins) ITT Population Treatment Group Panadol Extra (n=xx) IBUPROFEN (n=xx) Placebo (n=xx) Summary N 1 xx xx xx CENSORED 2 xx xx xx MEAN xx.xx xx.xx xx.xx SD x.xx x.xx x.xx MIN xx xx Xx MAX xx xx Xx MEDIAN xx xx xx TREATMENT COMPARISONS Hazard Ratio 95% CI Pana vs. PBO X.XX (x.xx, x.xx) Pana vs. IBU X.XX (x.xx, x.xx) IBU vs. PBO X.XX (x.xx, x.xx) 1 N is the number of subjects reporting a little headache relief during the time of pain assessment Hazard ratio and confidence interval are based on Cox regression model with factors of treatment group, site and baseline intensity covariate for each pairwise comparison. Subjects who used Rescue medication prior to perceptible relief and subjects with no perceptible relief are censored at 4 hours. PROGRAMMER S NOTE: Use this shell for Time to Meaningful Relief (Table 9.2.6) with appropriate title and footnote change.

37 Page 37 of 44 Document Name Table Complete Relief at 1 and 2 hours Post-Dosing Treatment Panadol Extra IBUPROFEN PLACEBO Number with Complete Relief at 1 hour Number with Complete Relief at 2 hours XX (XX.X%) XX (XX.X%) XX (XX.X%) XX (XX.X%) XX (XX.X%) XX (XX.X%) Complete Relief at 1 hour defined as PRS=4 Complete Relief at 2 hours defined as subjects responding yes to Do you have complete relief at this moment? Subjects who used Rescue medication prior to the time point (1 or 2 hours) are assigned no relief/not resolved.

38 Page 38 of 44 Document Name Rate of Rescue Medication Use: Table Rate and Time to rescue medication Treatment Panadol Extra IBUPROFEN PLACEBO Number of Subjects Using Rescue Medication Total No. Rescue Medications Used/Total Number of Headaches XX (XX.X%) XX (XX.X%) XX (XX.X%) Xxx/xxx Xxx/xxx Xxx/xxx Time to Rescue Medication Use: Panadol Extra Treatment IBUPROFEN PLACEBO Summary N XX XX XX Statistics MEAN X.XX X.XX X.XX (min) SD X.XXX X.XXX X.XXX MIN X.X X.X X.X MAX X.X X.X X.X MEDIAN X.XX X.XX X.XX

39 Page 39 of 44 Document Name Table Global Evaluation of Response to Treatment Score Panadol Extra Treatment IBUPROFEN PLACEBO 0 (very poor) XX (XX.X%) XX (XX.X%) XX (XX.X%) 1 (poor) XX (XX.X%) XX (XX.X%) XX (XX.X%) 2 (neutral) XX (XX.X%) XX (XX.X%) XX (XX.X%) 3 (good) XX (XX.X%) XX (XX.X%) XX (XX.X%) 4 (very good) XX (XX.X%) XX (XX.X%) XX (XX.X%) Summary N XX XX XX Statistics (min) MEAN X.XX X.XX X.XX SD X.XXX X.XXX X.XXX MIN X.X X.X X.X MAX X.X X.X X.X MEDIAN X.XX X.XX X.XX Adj. Mean [1] Comparison Panadol Extra v Placebo Panadol Extra v Ibuprofen Ibuprofen v Placebo Treatment Difference [2] 95% Confidence Interval [1]: Adjusted means and confidence limits for treatment differences from ANOVA model with fixed factors for treatment and site. [2] Difference between the first named treatment group and the second named treatment group such that a positive result favors the first treatment.

40 Page 40 of 44 Document Name Table Time to Perceptible Relief Treatment Panadol Extra IBUPROFEN PLACEBO Summary N XX XX XX Statistics MEAN X.XX X.XX X.XX (min) SD X.XXX X.XXX X.XXX MIN X.X X.X X.X MAX X.X X.X X.X MEDIAN X.XX X.XX X.XX Comparison Hazard Ratio 95% Confidence Interval Panadol Extra v Placebo Panadol Extra v Ibuprofen Ibuprofen v Placebo