Clinical trial NCT05674721
Conditions: Pain
Sponsor: HALEON
Start date: 2023-01-05; Completion date: 2023-03-21
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to support the submission of Advil PM Liqui-Gels Minis (ibuprofen/diphenhydramine hydrochloride 200 milligrams \[mg\]/25 mg) which is a size reduction of the currently marketed Advil PM Liqui-Gels, by determining if this product is bioequivalent to the reference product Advil PM Liqui-Gels (ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg) under fasting conditions.

Detailed description:
This is a single center, single dose, open-label, randomized, two-treatment, two-sequence, two-period crossover, bioequivalence study in healthy adult participants with at least a 7-day washout period. A sufficient number of participants will be screened to randomize approximately 44 to ensure at least 37 evaluable participants complete the entire study. Participants will be randomly assigned to one of 2 treatment sequences and receive a single dose of one of the treatments in each period following a crossover design.

Arms: arm 1: Participants will be randomly assigned as per cross-over design to receive a single dose of 2 Advil PM Liqui-Gels Minis capsules orally on day 1 of period 1 and will receive single dose of 2 Advil PM Liqui-Gels capsules orally on day 1 of period 2 with at least 7 days washout period. Participants will be instructed to consume the entire amount of ambient temperature water (approximately 240 milliliters \[mL\]) along their investigational product. arm 2: Participants will be randomly assigned as per cross-over design to receive a single dose of 2 Advil PM Liqui-Gels capsules orally on day 1 of period 1 and will receive single dose of 2 Advil PM Liqui-Gels Minis capsules orally on day 1 of period 2 with at least 7 days washout period. Participants will be instructed to consume the entire amount of ambient temperature water (approximately 240 mL) along their investigational product.
Interventions: intervention 1: Advil PM Liqui-Gels Minis intervention 2: Advil PM Liqui-Gels
Intervention descriptions: intervention 1: Ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg, Oral capsule which is a size reduction of the currently marketed reference product. intervention 2: Ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg, Oral capsule.

Protocol documents:
Prot_000.pdf: 
GSK Consumer Healthcare 
Clinical Study Report 
Study Protocol Number: 218677 
Property of GSK Consumer Healthcare Confidential 
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
Clinical Study Report Template v4.0 
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16.1.1 
Protocol and Protocol Amendments 
Table of contents 
16.1.1 
Protocol and Protocol Amendments ........................................................ 1 
Table of contents ................................................................................................................. 1 
Study Final Protocol Amendment 2 dated 30-NOV-2022 .................................................. 2 
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Clinical Study Report 
Study Protocol Number: 218677 
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Study Final Protocol Amendment 2 dated 30-NOV-2022 
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Clinical Protocol 
 
 
Protocol Number: 218677 
 
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CLINICAL PROTOCOL 218677 
 
A Randomized, Open label, Single Center, Single Dose, Two 
Treatment, Two Period, Two Sequence Crossover Bioequivalence 
Study of Advil PM Liqui-Gels Minis (ibuprofen/diphenhydramine 
hydrochloride 200 mg/25 mg) To Advil PM Liqui-Gels 
(ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg) in 
Healthy Adult Subjects Under Fasted Conditions 
 
Protocol Number: 
218677 
Compound/Product Name: 
Advil PM Liqui-Gels Minis 
United States (US) Investigational 
New Drug (IND) Number: 
 
Not applicable 
European Clinical Trials Database 
(EudraCT) Number: 
 
Not applicable 
Other Regulatory Agency Identified 
Number: 
 
Not applicable 
Phase: 
 
I 
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Protocol Number: 218677 
 
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Sponsor Information 
 
Sponsor Name & Legal 
Registered Address 
 
GlaxoSmithKline Consumer Healthcare 
(UK) Trading Limited 
980 Great West Road, 
Brentford, 
Middlesex, 
TW8 9GS, 
United Kingdom (UK) 
Sponsor Contact Details 
 
GlaxoSmithKline Consumer Healthcare 
(GSK CH) 
184 Liberty Corner Rd., Warren, NJ 07059 
United States of America (USA) 
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Protocol Number: 218677 
 
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Document History 
 
Document 
Version Summary of Changes  
Original protocol 
2.0 
Not applicable (N/A) 
Amendment 1 
3.0 
Added Acceptability to Table 3.1 Objectives and 
Endpoints 
 
Added the ease of swallowing to section 4.1 study 
design and schedule of activities  
 
Updated 
Table 
6.1 
with 
new 
Product 
Master 
Formulation Code (MFC) 
 
Updated section 8.2 with timing of acceptability 
assessment 
 
Updated section 9.4 with acceptability of “ease of 
swallowing”  
 
Updated section 12.3.4 with statistical methods for the 
ease of swallowing assessment 
 
Amendment 2 
 
Updated safety reporting sections 10.4.2, 10.6, 10.9.2 
and 10.11 
Deleted one duplicated PK timepoint in section 4.1 
Amendments incorporate all revisions to date, including amendments made at the request of 
country health authorities, institutional review boards/ethics committees (IRBs/ECs), etc.   
 
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Clinical Protocol 
 
 
Protocol Number: 218677 
 
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Table of Contents 
Sponsor Information ............................................................................................................ 2 
Document History ............................................................................................................... 3 
Principal Investigator Protocol Agreement Page ................................................................ 4 
Table of Contents ................................................................................................................ 5 
1 
PROTOCOL SUMMARY ................................................................................................ 11 
1.1 
Synopsis ................................................................................................................. 11 
1.2 
Schedule of Activities ............................................................................................ 14 
2 
INTRODUCTION ............................................................................................................. 17 
2.1 
Study Background and Rationale .......................................................................... 17 
2.2 
Benefit/Risk Assessment ....................................................................................... 17 
2.3 
Mechanism of Action/Indication ........................................................................... 17 
3 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 18 
4 
STUDY DESIGN .............................................................................................................. 19 
4.1 
Overall Design ....................................................................................................... 19 
4.2 
Scientific Rationale for Study Design ................................................................... 20 
4.3 
Justification for Dose ............................................................................................. 21 
4.4 
End of Study Definition ......................................................................................... 21 
5 
STUDY POPULATION .................................................................................................... 21 
5.1 
Type and Planned Number of Subjects ................................................................. 21 
5.2 
Inclusion Criteria ................................................................................................... 21 
5.3 
Exclusion Criteria .................................................................................................. 22 
5.4 
Randomization Criteria .......................................................................................... 25 
5.5 
Lifestyle Considerations ........................................................................................ 25 
5.5.1 
Meals and Dietary Restrictions ............................................................. 25 
5.5.2 
Alcohol, Caffeine and Tobacco ............................................................. 26 
5.5.3 
Activity .................................................................................................. 26 
5.5.4 
Contraception ........................................................................................ 26 
5.6 
Screen Failures ....................................................................................................... 27 
5.7 
Sponsor’s Qualified Medical Personnel ................................................................ 28 
5.8 
Rater/Clinical Assessor Qualifications .................................................................. 28 
6 
INVESTIGATIONAL/STUDY PRODUCTS ................................................................... 28 
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6.1 
Investigational/Study Product Supplies ................................................................. 28 
6.1.1 
Dosage Form and Packaging ................................................................. 32 
6.1.2 
Preparation and Dispensing ................................................................... 32 
6.2 
Administration ....................................................................................................... 33 
6.2.1 
Medication/Dosing Errors ..................................................................... 33 
6.2.2 
Overdose ............................................................................................... 34 
6.3 
Investigational/Study Product Storage .................................................................. 34 
6.4 
Investigational/Study Product Accountability ....................................................... 35 
6.4.1 
Destruction of Investigational/Study Product Supplies ........................ 35 
6.5 
Blinding and Allocation/Randomization ............................................................... 35 
6.6 
Breaking the Blind ................................................................................................. 36 
6.7 
Compliance ............................................................................................................ 36 
6.8 
Concomitant Medication/Treatment(s) .................................................................. 36 
7 
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ......................................................................... 36 
7.1 
Subject Discontinuation/Withdrawal ..................................................................... 36 
7.2 
Lost to Follow up ................................................................................................... 37 
8 
STUDY PROCEDURES ................................................................................................... 38 
8.1 
Screening ............................................................................................................... 38 
8.1.1 
Informed Consent .................................................................................. 38 
8.1.2 
Demographics ....................................................................................... 39 
8.1.3 
Inclusion/Exclusion Criteria.................................................................. 39 
8.1.4 
Medical History and Prior Medication/Treatment ................................ 39 
8.1.5 
Subject Eligibility.................................................................................. 39 
8.1.6 
Screening Procedures ............................................................................ 39 
8.2 
Study Periods ......................................................................................................... 40 
8.2.1 
Day -1 .................................................................................................... 41 
8.2.2 
Day 1 ..................................................................................................... 41 
8.2.3 
Day 2 ..................................................................................................... 42 
8.2.4 
Day 3 ..................................................................................................... 43 
8.2.5 
Washout Period ..................................................................................... 43 
8.2.6 
End of Study .......................................................................................... 43 
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Protocol Number: 218677 
 
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8.3 
Study Conclusion ................................................................................................... 44 
8.4 
Follow-up Visit ...................................................................................................... 44 
9 
STUDY ASSESSMENTS ................................................................................................. 44 
9.1 
Screening Assessments .......................................................................................... 45 
9.2 
Safety and Other Assessments ............................................................................... 45 
9.2.1 
Laboratory Tests .................................................................................... 45 
9.2.2 
Serology ................................................................................................ 46 
9.2.3 
Urine drug screen .................................................................................. 46 
9.2.4 
Alcohol test ........................................................................................... 46 
9.2.5 
Pregnancy Testing ................................................................................. 47 
9.2.6 
Physical Examinations .......................................................................... 47 
9.2.7 
Height and Weight ................................................................................ 47 
9.2.8 
Blood Pressure and Pulse Rate .............................................................. 48 
9.2.9 
Respiratory Rate .................................................................................... 48 
9.2.10 
Temperature .......................................................................................... 48 
9.2.11 
Electrocardiogram ................................................................................. 48 
9.2.12 
COVID-19 Test ..................................................................................... 49 
9.3 
Pharmacokinetics (PK) .......................................................................................... 49 
9.3.1 
Plasma for Analysis of Ibuprofen and Diphenhydramine ..................... 49 
9.3.2 
Shipment of Pharmacokinetic Samples ................................................. 50 
9.4 
Acceptability of “ease of swallowing” .................................................................. 50 
9.5 
Blood Volume ........................................................................................................ 50 
10 ADVERSE EVENT AND SERIOUS ADVERSE EVENTS ........................................... 51 
10.1 
Definition of an Adverse Event (AE) .................................................................... 51 
10.2 
Definition of a Serious Adverse Event (SAE) ....................................................... 52 
10.3 
Time Period and Frequency for Collecting AE and SAE Information .................. 53 
10.4 
Reporting Procedures ............................................................................................. 54 
10.4.1 
Reporting of an Adverse Event ............................................................. 55 
10.4.2 
Reporting of a Serious Adverse Event .................................................. 55 
10.5 
Evaluating Adverse Events .................................................................................... 56 
10.5.1 
Assessment of Intensity......................................................................... 56 
10.5.2 
Assessment of Causality ....................................................................... 56 
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10.6 
Follow-up of AEs and SAEs .................................................................................. 57 
10.7 
Withdrawal Due to an Adverse Event ................................................................... 58 
10.8 
Regulatory Reporting Requirements for SAEs ...................................................... 58 
10.9 
Pregnancy .............................................................................................................. 59 
10.9.1 
Time Period for Collecting Pregnancy Information .............................. 59 
10.9.2 
Action to be Taken if Pregnancy Occurs .............................................. 59 
10.10 Medical Device Incidents ...................................................................................... 59 
10.10.1 
Definition of an Incident ....................................................................... 59 
10.11 Reporting of Incidents and Malfunctions .............................................................. 60 
10.12 Follow-up of Medical Device Incidents ................................................................ 61 
10.13 Regulatory Reporting Requirements for Medical Device Incidents ...................... 61 
11 DATA MANAGEMENT .................................................................................................. 62 
11.1 
Case Report Form .................................................................................................. 62 
11.2 
Data Handling ........................................................................................................ 63 
11.2.1 
Data Queries .......................................................................................... 63 
11.3 
External Data ......................................................................................................... 63 
12 STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................. 64 
12.1 
Sample Size Determination ................................................................................... 64 
12.2 
Populations for Analysis ........................................................................................ 64 
12.3 
Statistical Analyses ................................................................................................ 65 
12.3.1 
Primary Analysis(es) ............................................................................. 65 
12.3.2 
Secondary Analysis(es) ......................................................................... 66 
12.3.3 
Safety Analysis(es) ................................................................................ 66 
12.3.4 
Ease of Swallowing ............................................................................... 67 
12.3.5 
Exclusion of Data from Analysis .......................................................... 67 
12.3.6 
Demographic and Baseline Characteristics ........................................... 67 
12.3.7 
Study Drug/Product Compliance and Use of Other Therapies ............. 67 
12.3.8 
Handling of Dropouts and Missing Data .............................................. 68 
12.3.9 
Interim Analysis .................................................................................... 68 
13 STUDY GOVERNANCE CONSIDERATIONS .............................................................. 68 
13.1 
Quality Control ...................................................................................................... 68 
13.2 
Quality Assurance .................................................................................................. 69 
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13.3 
Regulatory and Ethical Considerations ................................................................. 69 
13.3.1 
Institutional Review Board/ Ethics Committee ..................................... 69 
13.3.2 
Ethical Conduct of the Study ................................................................ 70 
13.3.3 
Subject Information and Consent .......................................................... 70 
13.3.4 
Subject Recruitment .............................................................................. 71 
13.3.5 
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP ............................................................................................... 71 
13.4 
Posting of Information on Publicly Available Clinical Trial Registers ................. 71 
13.5 
Provision of Study Results to Investigators ........................................................... 71 
13.6 
Records Retention .................................................................................................. 72 
13.7 
Conditions for Terminating the Study ................................................................... 73 
14 REFERENCES .................................................................................................................. 73 
15 APPENDICIES .................................................................................................................. 74 
15.1 
ABBREVIATIONS ............................................................................................... 74 
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Protocol Number: 218677 
 
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List of in text tables 
Table 1-1 
Schedule of Activities ........................................................................... 15 
Table 3-1 
Study Objectives and Endpoints ........................................................... 18 
Table 6-1 
Investigational/Study Product Supplies ................................................ 29 
Table 6-2 
Sundry Items ......................................................................................... 30 
Table 9-1 
Laboratory Tests .................................................................................... 45 
Table 9-2 
Blood Volume ....................................................................................... 51 
Table 15-1 
Abbreviations ........................................................................................ 74 
 
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Protocol Number: 218677 
 
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1 
PROTOCOL SUMMARY  
1.1 
Synopsis 
Short Title: 
A bioequivalence study of Advil PM Liqui-Gels Minis (ibuprofen/diphenhydramine 
hydrochloride 200 mg/25 mg) compared to the current marketed Advil PM Liqui-Gels 
(ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg) in healthy adult subjects under 
fasted conditions. 
Background and Rationale: 
This study will be conducted to support the submission of Advil PM Liqui-Gels Minis 
(ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg) which is a size reduction of the 
currently marketed Advil PM Liqui-Gels, by determining if this product is bioequivalent to the 
reference product Advil PM Liqui-Gels (ibuprofen/diphenhydramine hydrochloride 
200 mg/25 mg) under fasting conditions. Advil PM Liqui-Gels Minis was developed as a 
smaller capsule alternative to the currently marketed product.   
Bioequivalence studies are most sensitive to detect formulation differences (when such 
differences exist) after a single dose. The optimal design is therefore a randomized, open-label, 
2-treatment, 2-period, 2-sequence, single dose bioequivalence trial in fasted subjects. 
Objectives and Endpoints: 
Objective(s) 
Endpoint(s) 
Primary 
Demonstrate the bioequivalence of Advil PM 
Liqui-Gels Minis (Test) compared to Advil PM 
Liqui-Gels (Reference) 
For ibuprofen and diphenhydramine: 
x 
Cmax (The maximum observed post-
dose concentration; obtained without 
interpolation) 
x 
AUC0-t (The area under the plasma 
concentration versus time curve 
calculated from time 0 to the last 
measurable sampling time point, t, 
computed using the linear trapezoidal 
rule) 
x 
AUC0-inf (The area under the plasma 
concentration versus time curve 
calculated from time 0 to infinity AUC0-inf 
= AUC0-t &WȜz where C(t) is the 
concentration at the last measurable 
VDPSOLQJWLPHSRLQWDQGȜz is the 
terminal elimination rate constant) 
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Secondary 
Pharmacokinetics 
Assess the pharmacokinetic (PK) profile 
For ibuprofen and diphenhydramine: 
x 
Ȝz (The terminal elimination rate 
constant computed as the negative of 
the slope of the regression line of ln 
(C(t)) on time. The regression should 
generally involve at least 3 consecutive 
measurable concentrations that 
decrease over time excluding Cmax) 
x 
tmax (The time of the maximum observed 
post-dose concentration) 
x 
t1/2 (The elimination half-life computed 
as t1/2  OQȜz) 
x 
Vz/F (apparent volume of distribution, as 
FDOFXODWHGE\WKHGRVHDGPLQLVWHUHGȜz 
x AUC0-inf) 
x 
Cl/F (apparent total clearance, as 
calculated by the dose administered/ 
AUC0-inf) 
Acceptability 
Assess subject acceptability of each of the two 
products 
 
Ease of swallowing (5-point ordinal scale) 
Safety 
Assess the safety profile 
x 
Monitoring and recording of adverse 
events (AEs)  
x 
Physical examination 
x 
Vital signs  
x 
Laboratory tests 
Study Design: 
This is a single center, single dose, open-label, randomized, two-treatment, two-sequence, 
two-period crossover, bioequivalence study in healthy adult subjects with at least a 7-day 
washout period.  
The study is intended to dose in more than one group; all groups will be dosed at the same 
clinical site and the same protocol requirements and procedures will be followed within each 
group. 
Blood will be sampled regularly at scheduled times for 48 hours following treatment. 
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Subjects will be randomly assigned to one of 2 treatment sequences and receive a single dose 
of one of the following treatments in each period following a crossover design:  
Treatment A: 2X Advil PM Liqui-Gels Minis; (ibuprofen/diphenhydramine hydrochloride 
200mg/25mg) (Test); 
Treatment B: 2X Advil PM Liqui-Gels; (ibuprofen/diphenhydramine hydrochloride 
200mg/25mg) (Reference). 
The study will consist of an ambulant screening day within 28 days prior to first product 
administration and two study periods. In each period, subjects will be confined from the day 
before dosing (Day -1) until 48 hours post-dosing (Day 3), during which time PK blood samples 
will be collected within one hour prior to dosing and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 
1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, 
and 48 hours following dosing (24, 36, and 48 hours for diphenhydramine only). Carry-over 
effects will be avoided by a washout interval of at least 7 days between investigational product 
administrations. 
According to data from studies
and 
, ibuprofen tmax 
is expected from 
hours after dosing. Diphenhydramine tmax is expected from 
hours after dosing. Ibuprofen half-life is expected to be up to 
hours and 
diphenhydramine half-life is expected to be up to 
 hours. 
Following an overnight fast of at least 10 hours, subjects will receive the investigational product 
in the fasted state. During each period, the investigational product will be administered by 
clinical staff and administered along with approximately 240 mL of ambient temperature water. 
Subjects will be instructed to consume the entire amount of water along with their 
investigational product. Immediately after dosing subjects will be asked to evaluate the ease of 
swallowing of each product.  
In order to standardize the conditions on PK sampling days, all subjects should refrain from 
lying down, eating, and drinking beverages other than water during the first 4 hours after dosing. 
Aside from time of product administration, water will be allowed ad libitum except within 
1 hour before and 1 hour after investigational product administration. 
For each subject the duration of study participation is 38 days of which up to 3 days confined 
in each period (total of up to 6 days confined). 
Study Products: 
 
Test Product 
Reference Product 
Product Name 
Advil PM Liqui-Gels Minis 
Advil PM Liqui-Gels 
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Dose/Application 
2X liquid filled capsules 
2X liquid filled capsules 
Route of Administration 
Oral 
Oral 
Type and Planned Number of Subjects: 
A sufficient number of male and female subjects will be screened to randomize approximately 
44 to ensure at least 37 evaluable subjects (refer to section 12.1) complete the entire study. An 
effort will be made to include similar proportions of males and females in the study. 
Statistical Methods: 
The PK analysis set will be used for the PK evaluations. It includes all subjects of the PK 
population who complete both treatment periods, and for which the relevant PK parameters (at 
least one AUC or Cmax) can be derived. Subjects with baseline concentration >5% of the 
individual Cmax for either period will be excluded from the PK analysis set. This analysis set 
will be used in summaries, the primary PK analysis, and the secondary PK analysis. 
The PK parameters that will be used in the primary analyses are AUC0-t, AUC0-inf, and Cmax. 
For ibuprofen and diphenhydramine separately, a linear mixed effects model will be fit to the 
log-transformed PK parameters (AUC0-t, AUC0-inf, and Cmax), as the dependent variable, and 
treatment, sequence, and period as fixed effects. Subject nested within sequence will be a 
random effect. The treatment least-squares means (LSMs), difference between treatment LSMs, 
and 90% confidence interval (CI) for the difference will be computed. The adjusted LSM and 
LSM difference with 90% CIs for the differences will be exponentiated to provide estimates of 
the adjusted treatment effects, ratio of adjusted geometric means (Test/Reference) and 90% CIs 
for the ratio. If all study subjects are not recruited from the same enrollment pool and the study 
doses in more than one group, the statistical model may be modified to reflect the multigroup 
nature of the study. Bioequivalence will be declared for a given parameter/analyte if the 90% 
2-sided CI for the ratio is between 80% and 125% for ibuprofen and diphenhydramine. 
One scale will be used to measure the acceptability of the easiness to swallow. Frequencies 
(number, percentage) will be tabulated. 
 
1.2 
Schedule of Activities 
The schedule of activities table provides an overview of the subject visits and study procedures.  
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The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, to conduct evaluations or assessments required to protect the well-being 
of the subject. 
Table 1-1 
Schedule of Activities 
 
Procedure/Assessment 
Screening 
Treatment Periods 1 and 2a 
End of Study* 
Study day 
-28 to -2 
-1 
1 
2 
3 
3 
Confinement 
 
x 
x 
x 
 
 
Discharge 
 
 
 
 
x 
 
Informed consent 
x 
 
 
 
 
 
Demography 
x 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
Physical examinationb 
x 
x 
 
 
 
x 
Height, weight, BMI 
x 
 
 
 
 
 
Vital signs (BP, PR, RR, OT) x 
xc 
xc 
xc 
xc 
x 
12-lead ECG 
x 
 
 
 
 
 
Laboratory tests 
x 
 
 
 
 
x 
COVID-19 testd 
x 
x 
 
 
x 
x 
Serology 
x 
 
 
 
 
 
Urine pregnancy teste 
x 
 
 
 
 
x 
Serum pregnancy teste 
 
x 
 
 
 
 
FSHf 
x 
 
 
 
 
 
Urine drug screen 
x 
x 
 
 
 
 
Urine cotinine test 
x 
x 
 
 
 
 
Alcohol breath test 
x 
x 
 
 
 
 
Inclusion/exclusion 
assessment 
x 
x 
xg 
 
 
 
Randomization 
 
 
xh 
 
 
 
Drug administration 
 
 
x 
 
 
 
Acceptability 
 
 
x 
 
 
 
PK blood samplingi 
 
 
x 
x 
x 
 
Concomitant treatments 
x 
x 
x 
x 
x 
x 
Adverse eventsj 
x 
x 
x 
x 
x 
x 
Study Conclusion 
 
 
 
 
 
x 
Abbreviations: BMI, BP, ECG, FSH, OT, PK, PR, RR 
Footnotes: 
*These assessments are also to be conducted for subjects who discontinue study drug. End of Study 
will occur before discharge, on study Day 3 of Period 2. 
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aThe washout period between each drug administration will be at least 7 days.  
bA full physical examination will be performed at screening and a brief physical examination will be 
performed on Day -1 in each treatment period and at End of Study. 
cBlood pressure (BP), pulse rate (PR), respiratory rate (RR), oral body temperature (OT): pre-treatment 
on Day 1 (within 1 hour before drug administration) of each treatment period. Oral body temperature 
(OT) on Day -1, Day 2 and Day 3 of each treatment period (Note: the oral body temperature obtained 
on Day 3 of Period 2 can be used as the oral body temperature required at End of Study). 
dBefore the first dosing two consecutive tests (locally approved tests [PCR or Antigen]) 
separated > 24 hours will be performed: one test at screening within 72 hours of admission and one 
test at check-in (Day-1). Before the second dosing two consecutive tests (locally approved tests [PCR 
or Antigen]) separated > 24 hours will be performed: one test during the washout period within 
72 hours of admission and one test at check-in (Day-1). If the first test is > 72 hours prior to unit 
admission, subjects should be advised to self -quarantine until entrance to the unit while awaiting final 
testing clearance. Subjects who report symptoms suggestive of COVID-19 while in the research unit 
should be isolated in the unit or at home and tested for COVID-19 infection using an approved 
molecular test. One test (locally approved tests [PCR or Antigen]) should be performed before 
releasing the subject from the unit in each period or at early discontinuation (Note: the COVID-19 test 
performed on Day 3 of Period 2 can be used as the test required at End of Study) 
efor all females of childbearing potential. 
fFSH done only in females who have been amenorrhoeic for at least 12 months. 
gAt the discretion of the investigator, subjects could continue the study if any deviation to the 
inclusion/exclusion criteria does not anticipate to alter study integrity. 
hRandomization conducted prior to the first dosing (Period 1). 
iPK blood samples will be collected within one hour prior to dosing and at 10, 15, 30, 45 minutes and 
1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 
24, 36, and 48 hours following dosing in each treatment period (24, 36, and 48 hours for 
diphenhydramine only). 
jAEs and therefore all serious adverse events (SAEs) will be collected immediately after a subject 
provides consent to participate in the study by the completion of the informed consent form. 
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2 
INTRODUCTION 
GSK Consumer Healthcare has developed a reduced filled softgel formulation containing 
ibuprofen 200 mg and diphenhydramine hydrochloride 25 mg as an analgesic sleep-aid 
combination product. 
2.1 
Study Background and Rationale 
This study will be conducted to support the submission of Advil PM Liqui-Gels Minis 
(ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg) which is a size reduction of the 
currently marketed Advil PM Liqui-Gels, by determining if this product is bioequivalent to the 
reference product Advil PM Liqui-Gels (ibuprofen/diphenhydramine hydrochloride 
200 mg/25 mg) under fasting conditions. Advil PM Liqui-Gels Minis was developed as a 
smaller capsule alternative to the currently marketed product.   
Bioequivalence studies are most sensitive to detect formulation differences (when such 
differences exist) after a single dose. The optimal design is therefore a randomized, open-label, 
2-treatment, 2-period, 2-sequence, single dose bioequivalence trial in fasted subjects. 
2.2 
Benefit/Risk Assessment  
Complete information for Advil PM Liqui-Gels may be found in the single reference safety 
document (SRSD), which for this study is the approved US Drug Facts Label for the reference 
product Advil PM Liqui-Gels. 
2.3 
Mechanism of Action/Indication 
To relieve occasional sleeplessness associated with pain at night, Advil PM Liqui-Gels Minis 
contains 2 active ingredients per liquid filled capsule: one pain reliever (200 mg ibuprofen) to 
treat pain and a sleep aid (diphenhydramine hydrochloride 25 mg), with a proposed dose of 
2 liquid filled capsules at bedtime to help pain sufferer gently fall and stay asleep. 
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) whose mechanism of action is 
thought to involve inhibition of both isoforms of enzyme cyclooxygenase (COX), which 
converts arachidonic acid to prostaglandin H2. Ibuprofen is a racemate; the molecule contains 
a single stereogenic carbon atom. The anti-inflammatory, antipyretic and analgesic properties 
of Ibuprofen are thought to be mainly due to inhibition of COX-2, through the (S)-enantiomer 
of Ibuprofen. The (R)-enantiomer is thought to be pharmacologically inactive. The 
(R)-enantiomer undergoes some degree of conversion to the (S)-enantiomer after absorption. 
Diphenhydramine hydrochloride is available globally in over-the-counter (OTC) allergy, cough, 
and cold medicines. It is an ethanolamine and first-generation H1 antagonist that acts as a 
reversible, competitive inhibitor of histamine binding to the H1 receptor. H1 antagonists, 
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especially ethanolamines, have significant antihistaminic and antimuscarinic activities and 
concurrent sedative properties. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
Table 3-1 
Study Objectives and Endpoints 
Objective(s) 
Endpoint(s) 
Primary 
Demonstrate the bioequivalence of Advil PM 
Liqui-Gels Minis (Test) compared to Advil PM 
Liqui-Gels (Reference) 
For ibuprofen and diphenhydramine: 
x 
Cmax (The maximum observed post-
dose concentration; obtained without 
interpolation) 
x 
AUC0-t (The area under the plasma 
concentration versus time curve 
calculated from time 0 to the last 
measurable sampling time point, t, 
computed using the linear trapezoidal 
rule) 
x 
AUC0-inf (The area under the plasma 
concentration versus time curve 
calculated from time 0 to infinity AUC0-
inf = AUC0-t &WȜz where C(t) is the 
concentration at the last measurable 
VDPSOLQJWLPHSRLQWDQGȜz is the 
terminal elimination rate constant) 
Secondary 
Pharmacokinetics 
Assess the PK profile 
For ibuprofen and diphenhydramine: 
x 
Ȝz (The terminal elimination rate 
constant computed as the negative of 
the slope of the regression line of ln 
(C(t)) on time. The regression should 
generally involve at least 3 consecutive 
measurable concentrations that 
decrease over time excluding Cmax) 
x 
tmax (The time of the maximum observed 
post-dose concentration) 
x 
t1/2 (The elimination half-life computed 
as t1/2  OQȜz) 
x 
Vz/F (apparent volume of distribution, as 
FDOFXODWHGE\WKHGRVHDGPLQLVWHUHGȜz 
x AUC0-inf) 
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x 
Cl/F (apparent total clearance, as 
calculated by the dose administered/ 
AUC0-inf) 
Acceptability 
Assess subject acceptability of each of the two 
products 
 
Ease of swallowing (5-point ordinal scale) 
 
Safety 
Assess the safety profile 
x 
Monitoring and recording of AEs  
x 
Physical examination 
x 
Vital signs  
x 
Laboratory tests 
This study will be considered successful if bioequivalence is demonstrated between Advil PM 
Liqui-Gels Minis (Test) compared to Advil PM Liqui-Gels (Reference). 
4 
STUDY DESIGN  
4.1 
Overall Design 
This is a single center, single dose, open-label, randomized, two-treatment, two-sequence, 
two-period crossover, bioequivalence study in healthy adult subjects with at least a 7-day 
washout period.  
The study is intended to dose in more than one group; all groups will be dosed at the same 
clinical site and the same protocol requirements and procedures will be followed within each 
group. 
Blood will be sampled regularly at scheduled times for 48 hours following treatment. 
A sufficient number of male and female subjects will be screened to randomize approximately 
44 to ensure at least 37 evaluable subjects (refer to section 12.1) complete the entire study. An 
effort will be made to include similar proportions of males and females in the study. 
Subjects will be randomly assigned to one of 2 treatment sequences and receive a single dose 
of one of the following treatments in each period following a crossover design:  
Treatment A: 2X Advil PM Liqui-Gels Minis; (ibuprofen/diphenhydramine hydrochloride 
200mg/25mg) (Test); 
Treatment B: 
2X 
Advil 
PM 
Liqui-Gels;(ibuprofen/diphenhydramine 
hydrochloride 
200mg/25mg) (Reference). 
The study will consist of an ambulant screening day within 28 days prior to first product 
administration and two study periods. In each period, subjects will be confined from the day 
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before dosing (Day -1) until 48 hours post-dosing (Day 3), during which time PK blood samples 
will be collected within one hour prior to dosing and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 
1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, 
and 48 hours following dosing (24, 36, and 48 hours for diphenhydramine only). Carry-over 
effects will be avoided by a wash-out interval of at least 7 days between investigational product 
administrations. 
According to data from studies
and 
, ibuprofen tmax 
is expected from
 hours after dosing. Diphenhydramine tmax is expected from 
 
hours after dosing. Ibuprofen half-life is expected to be up to 
 hours and 
diphenhydramine half-life is expected to be up to 
 hours. 
Following an overnight fast of at least 10 hours, subjects will receive the investigational product 
in the fasted state. During each period, the investigational product will be administered by 
clinical staff and administered along with approximately 240 mL of ambient temperature water. 
Subjects will be instructed to consume the entire amount of water along with their 
investigational product. Immediately after dosing subjects will be asked to evaluate the ease of 
swallowing of each product. 
In order to standardize the conditions on PK sampling days, all subjects should refrain from 
lying down, eating, and drinking beverages other than water during the first 4 hours after dosing. 
Aside from time of product administration, water will be allowed ad libitum except within 
1 hour before and 1 hour after investigational product administration. 
Figure A- study design 
 
Screening 
Periods 1 and 2a 
End of study 
Day -28 to -2 
Day -1 to 3 
Day 3 of Period 2 
aWashout period of at least 7 days between each dosing 
For each subject the duration of study participation is 38 days of which up to 3 days confined 
in each period (total of up to 6 days confined). 
4.2 
Scientific Rationale for Study Design 
This will be an open label study. Blinding is not considered essential as study measurements 
(plasma ibuprofen and diphenhydramine concentrations) are biological.  
A crossover design, using the same subjects to test each product, will be used to reduce 
variability. 
The blood sampling times have been chosen based on the information available particularly on 
ibuprofen and diphenhydramine absorption, as well as their elimination. 
Non-smokers have been chosen as the population for this study to reduce variability. 
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The following guidance have been followed for designing the study: 
x Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General 
Considerations (FDA 2014) 
x Bioavailability Studies Submitted in NDAs or INDs — General Considerations (FDA 
2019) 
4.3 
Justification for Dose 
This is a study to assess the bioequivalence of the test product to a commercial reference product. 
4.4 
End of Study Definition 
A subject is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities. 
The end of this study is defined as the date of the last visit of the last subject in the study. 
5 
STUDY POPULATION 
5.1 
Type and Planned Number of Subjects 
A sufficient number of male and female subjects will be screened to randomize approximately 
44 to ensure at least 37 evaluable subjects (refer to section 12.1) complete the entire study. An 
effort will be made to include similar proportions of males and females in the study. 
An enrolled subject is one who has agreed to participate in the clinical study following 
completion of the informed consent process directly and successfully met eligibility criteria to 
proceed beyond the screening visit as applicable for the protocol design.  
This study can fulfill its objectives only if appropriate subjects are enrolled. The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether a subject is suitable for this protocol. 
Subject eligibility to participate in the clinical study should be reviewed and documented by an 
appropriate member of the investigator’s study team before subjects are included in the study. 
5.2 
Inclusion Criteria 
An individual must meet all the following inclusion criteria to be eligible to be included into 
the study: 
1. Evidence of a personally signed and dated informed consent document indicating that the 
subject has been informed of all pertinent aspects of the study before any assessment is 
performed. 
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2. Male or female subject who, at the time of screening, is between the ages of 18 and 
55 years, inclusive.  
3. Subject who is willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures. 
4. Healthy subject, which is defined as in general good physical health, as judged by the 
investigator and no clinically relevant abnormalities identified by a detailed medical 
history, full physical examination, including blood pressure and pulse rate measurement, 
12-lead ECG or clinical laboratory tests.  
5. Body Mass Index (BMI) of 18.5 to 30.0 kg/m2DQGDWRWDOERG\ZHLJKWNJIRUPDOHV
DQGNJIRUIHPDOHV 
6. Female subject of childbearing potential and at risk for pregnancy must agree to use a 
highly effective method of contraception throughout the study and for at least 30 days 
after the last dose of assigned treatment. Female subject who is not of childbearing 
potential must meet requirements in section 5.5.4. 
7. Subject with two negative tests (one at screening within 72 hours of admission and one 
one at check in Day-1 in Period 1) for active COVID-19, separated by > 24 hours. 
5.3 
Exclusion Criteria 
An individual who meets any of the following exclusion criteria will be excluded from the study: 
1. Subject who is an investigational site staff member directly involved in the conduct of the 
study and his/her family members, site staff member otherwise supervised by the 
Investigator, or subject who is a GSK employee directly involved in the conduct of the 
study. 
2. Participation in other studies involving investigational drug(s) within 30 days prior to 
study entry and/or during study participation. 
3. Acute or chronic medical or psychiatric condition or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study. 
4. Pregnant female subject as confirmed by a positive pregnancy test or intending to become 
pregnant over the duration of the study. 
5. Breastfeeding female subject. 
6. Known or suspected intolerance or hypersensitivity to the study materials (or closely 
related compounds) or any of their stated ingredients (D&C red no. 33, FD&C blue no. 1, 
gelatin, medium-chain triglycerides, pharmaceutical ink, polyethylene glycol, potassium 
hydroxide, purified water, sorbitol sorbitan solution). 
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7. Any history of asthma, urticaria, or other significant allergic diathesis or allergic reaction 
to any other pain reliever/fever reducer. Subject with uncomplicated seasonal allergic 
rhinitis can be accepted if expected allergy season is clearly outside enrollment/treatment 
period.  
8. Diagnosis of long QT syndrome or QTcF > 450 msec for males and > 470 msec for 
females at screening. 
9. Clinically significant vital sign abnormalities (systolic blood pressure lower than 90 or 
over 140 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or pulse rate 
less than 50 or over 100 bpm). 
10. Unwilling or unable to comply with the Lifestyle Considerations described in this 
protocol. 
11. Use of any medication (including OTC medications and herbal remedies) within 2 weeks 
or within less than 10 times the elimination half-life of the respective drug (whichever is 
longer) before first scheduled study drug administration, or is anticipated to require any 
concomitant medication during that period or at any time throughout the study. Allowed 
treatments are: 
x systemic contraceptives and hormone replacement therapy, as long as female subject 
is on stable treatment for at least 3 months before first scheduled study drug 
administration and continues treatment throughout the study; 
x occasional use of acetaminophen (up to 2 g daily). 
12. Evidence or history of clinically significant laboratory abnormality, hematological, renal, 
endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease 
within the last 5 years that may increase the risk associated with study participation. 
13. Clinically relevant chronic or acute infectious illnesses or febrile infections within two 
weeks prior to start of the study. 
14. Any surgical or medical condition which may significantly alter the absorption, 
distribution, metabolism or excretion of any drug substance but not limited to any of the 
following: 
x History of major gastrointestinal tract surgery such as gastrectomy, 
gastroenterostomy, bowel resection, gastric bypass, gastric stapling or gastric banding 
(note: this is not applicable for minor abdominal surgery without significant tissue 
resection, e.g., appendectomy and herniorrhaphy); 
x History of inflammatory bowel disease or gastrointestinal bleeding including peptic 
ulcers; 
x History or current evidence of renal disease or impaired renal function at screening as 
indicated by abnormal levels of serum creatinine (> 1.43 mg/dL) or BUN 
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 35 mg/dL) or the presence of clinically significant abnormal urinary constituents 
(e.g. albuminuria);  
x History or current evidence of ongoing hepatic disease or impaired hepatic function at 
screening. A candidate will be excluded if more than one of the following lab value 
deviDWLRQVDUHIRXQG$678/1$/78/1**78/1
$/3 1.2 ULN), 3) total bilirubin (> 2.00 mg/dL) or creatine kinase 8/1$
single deviation from the above values is acceptable and will not exclude the 
candidate, unless specifically advised by the investigator; 
x Evidence of urinary obstruction (e.g. due to benign prostate hyperplasia) or difficulty 
in voiding at screening; 
x Diagnosis of angle-closure (narrow angle) glaucoma; 
x History or clinical evidence at screening of pancreatic injury or pancreatitis. 
15. Subject with signs and symptoms suggestive of COVID-19 (i.e. fever, cough, etc.)* within 
14 days of inpatient admission. *as defined by WHO or local guidance 
16. Subject with known COVID-19 positive contacts in the past 14 days. 
17. Any vaccination, including COVID-19 vaccine, within 14 days prior to the first dose. 
18. History of drug abuse within 1 year prior to screening or recreational use of soft drugs 
(such as marijuana) within 1 month or hard drugs (such as cocaine, phencyclidine [PCP], 
crack, opioid derivatives including heroin, and amphetamine derivatives) within 3 months 
prior to screening. 
19. History of alcohol abuse within 1 year prior to screening or regular use of alcohol within 
6 months prior to screening that exceeds 10 units for women or 15 units for men of 
alcohol per week (1 unit = 340 mL of beer 5%, 140 mL of wine 12%, or 45 mL of distilled 
alcohol 40%). 
20. Positive urine drug screen or alcohol breath test at screening. 
21. Subject reported regular consumption of beverages or food containing xanthine 
derivatives or xanthine-related compounds (e.g., coffee, tea, caffeine-containing sodas and 
chocolate), equivalent to PJ[DQWKLQHSHUGD\ 
22. Current smoker, defined as the use of tobacco or nicotine products during the 3 months 
prior to screening until admission to the unit or a positive urine cotinine test at screening. 
23. Subject reports consumption of any drug metabolizing enzyme (e.g. CYP3A4 or other 
cytochrome P450 enzymes) inducing or inhibiting aliments, beverages or food 
supplements (e.g. broccoli, Brussels sprouts, grapefruit, grapefruit juice, star fruit, 
St. John’s Wort etc.) within 2 weeks prior to admission to the unit. 
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24. Positive results in any of the serology tests for HIV antigen and antibody, HCV-Ab, 
HBsAg and HBc-Ab (IgG + IgM). 
25. Performance of strenuous physical exercise (body building, high performance sports) from 
2 weeks prior to admission and throughout the entire study. 
26. Allergy to skin disinfecting agents, tape, or latex rubber, whenever appropriate 
substitutions cannot be applied or in the Investigator’s opinion may pose a risk to the 
subject. 
27. Any condition not identified in the protocol that in the opinion of the investigator would 
confound the evaluation and interpretation of the study data or may put the subject at risk. 
28. Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of 
whole blood within 8 weeks prior to dosing. 
29. Hemoglobin value < 12.0 g/dL for males and < 11.5 g/dL for females. 
30. Subject who has previously been enrolled in this study.  
5.4 
Randomization Criteria 
Subjects will be randomized into the study provided they have satisfied all subject selection 
criteria.  
5.5 
Lifestyle Considerations 
5.5.1 
Meals and Dietary Restrictions 
x Subjects must abstain from all food and drink (except water) at least 4 hours prior to 
any safety laboratory evaluations and 10 hours prior to the collection of the pre-dose 
PK sample. Water is permitted until 1 hour prior to investigational product 
administration.  
x Water may be consumed without restriction beginning 1 hour after dosing. 
x Non-caffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices – see 
below) may be consumed with meals and the evening snack. 
x Lunch will be provided approximately 4 hours after dosing. 
x Dinner will be provided approximately 10 hours after dosing. 
x An evening snack may be permitted approximately 2 hours after the evening meal. 
x Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus fruits 
(e.g. Seville oranges, pomelo, papaya, pineapple, dragon fruit, kiwi fruit, mango, 
passion fruit, pomegranate, rambutan, star fruit or products that contain these fruits) 
from 2 weeks prior to admission to the unit until collection of the final PK blood 
sample. 
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x Subjects will not be allowed to eat food containing poppy seeds from 24 hours prior 
to admission of each period. 
x Meals intake during the study will be standardized. 
5.5.2 
Alcohol, Caffeine and Tobacco 
x Subjects will abstain from alcohol for 48 hours prior to admission to the clinical site 
and continue abstaining from alcohol until collection of the final PK sample of each 
study period. Subjects may undergo an alcohol breath test at screening, at admission 
of each period, and at the discretion of the investigator. 
x Subjects will abstain from food or beverages containing xanthine derivatives or 
xanthine-related compounds (coffee, black/green tea, chocolate) or energy drinks for 
48 hours prior to the start of dosing until collection of the final PK sample of each 
study period.  
x Subjects will abstain from the use of tobacco- or nicotine-containing products 
including nicotine patches and other delivery devices such as electronic cigarettes or 
vaporizers) from screening and throughout the study.  
5.5.3 
Activity 
x Subjects will not be permitted to assume a fully recumbent position for 4 hours 
following dosing. 
x Subjects will abstain from strenuous exercise (e.g., heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests and throughout the entire study. Walking at a normal pace will be 
permitted. 
5.5.4 
Contraception 
Female subjects of non-childbearing potential must meet at least one of the following criteria: 
x Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or physiological 
cause; and have a serum follicle-VWLPXODWLQJKRUPRQH)6+OHYHO mIU/mL; 
x Have undergone a documented (including self-reported) hysterectomy and/or 
bilateral oophorectomy. 
All other female subjects (including females with tubal ligations) will be considered to be of 
childbearing potential. 
All female subjects who are of childbearing potential and are sexually active and at risk for 
pregnancy must agree to use a highly effective method of contraception consistently and 
correctly for the duration of the active study period and for 30 days after the last dose of 
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investigational product. The investigator or his or her designee, in consultation with the subject, 
will confirm that the subject has selected an appropriate method of contraception for the 
individual subject from the permitted list of contraception methods (see below) and instruct the 
subject in its consistent and correct use. Subjects need to affirm that they meet the criteria for 
the correct use of at least 1 of the selected methods of contraception. The investigator or his or 
her designee will discuss with the subject the need to use highly effective contraception 
consistently and correctly according to the schedule of activities and document such 
conversation in the subject’s chart. In addition, the investigator or his or her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (i.e., perfect use) and 
include the following: 
1. Established use of oral, inserted, injected, transdermal, or implanted hormonal methods of 
contraception is allowed provided the subject plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an adequate 
period of time to ensure effectiveness as deemed appropriate by the investigator; 
2. Intrauterine contraceptive device (IUD); 
3. Male condom or female condom used WITH a spermicide (i.e., foam, gel, film, cream, or 
suppository); 
4. Male partner sterilization with absence of sperm in the post-vasectomy ejaculate (self-
reported); 
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed [self-reported] in accordance with the device’s 
label); 
5.6 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized. To ensure transparent reporting of screen failure subjects, a 
minimal set of screen failure information will include demography, screen failure details (e.g. 
withdrawal of consent), eligibility criteria, any protocol deviations and any AEs or incidents as 
applicable.  
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be re-screened. 
Subjects who have successfully completed the screening procedures but were not selected for a 
given group (e.g., reserve subjects) may be invited to another screening session for participation 
in a subsequent group. 
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5.7 
Sponsor’s Qualified Medical Personnel 
Contact information for the sponsor's appropriately qualified medical personnel for the study is 
documented in the Study Contact List located in the electronic investigator study master file. 
The contact number is only to be used by investigational staff seeking advice on medical 
questions or problems in the event that the established communication pathways between the 
investigational site and the study team are not available. 
The contact number is not intended for direct use by study subjects. To facilitate access to 
appropriately qualified medical personnel on study-related medical questions or problems, 
subjects will be provided with a contact card. The contact card will provide, as a minimum, 
protocol identifiers, the subject’s study identification number, contact information for the 
investigational site, and contact details in the event that the investigational site cannot be 
reached to provide advice on a medical question or problem identified by a healthcare 
professional other than the investigator. 
5.8 
Rater/Clinical Assessor Qualifications  
No rater/clinical assessor qualifications are required for this study. 
6 
INVESTIGATIONAL/STUDY PRODUCTS 
For the purposes of this study, per International Conference on Harmonization (ICH) guidelines, 
and GSK policy, study intervention is defined as any investigational intervention(s), marketed 
product(s), placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol. 
This includes a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use.  
6.1 
Investigational/Study Product Supplies 
The selection of the Reference product (the currently marketed and commercially available 
Advil PM Liqui-Gels), will be based on assay content to ensure that this product does not differ 
by more than 5% from that of the batch used as Test product (Advil PM Liqui-Gels Minis). 
The following study products (including retention samples) will be supplied by the Clinical 
Supplies Department, GSK CH: 
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Table 6-1 
Investigational/Study Product Supplies 
 
Test Product 
Reference Product 
Product Name 
Advil PM Liqui-Gels Minis 
Advil PM Liqui-Gels 
Pack Design 
Bottles 
Bottles 
Dispensing Details 
Two liquid filled capsules once  
Two liquid filled capsules once 
Product Master Formulation 
Code (MFC) 
Commercial Product 
Dose/Application 
2X liquid filled capsules 
2X liquid filled capsules 
Route of Administration 
Oral 
Oral 
Usage Instructions 
x 
Administer study 
medication with 240 mL 
of ambient temperature 
water 
x 
Instruct subjects to 
consume the entire 
amount of water along 
with their investigational 
product 
x 
Administer study 
medication with 240 mL 
of ambient temperature 
water 
x 
Instruct subjects to 
consume the entire 
amount of water along 
with their investigational 
product 
Return Requirements 
All unused samples and empty 
packaging bottles to be returned  
All unused samples and empty 
packaging bottles to be returned 
Retain samples 
To keep at site 
To keep at site 
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Table 6-2 
Sundry Items 
Sundry Items to be supplied: 
Item* 
Supplied 
By 
Pack 
Design 
Dispensing 
Details 
Return/Disposal Details 
Used Samples 
Unused 
Samples 
Alere 10 Drugs 
Integrated E-Z Split 
Cup 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
BD Vacutainer®, Urine 
Collection Tubes and 
Kits, BD Medical 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Alere hCG Combo 
Cassette 20/10 
mlU/mL Pregnancy 
Tests REF#
 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
COT Cotinine Test 
Device DCT-102 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Sarstedt Microtube 
2mL PP 
REF:
 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Vacuette tube 
K2EDTA 3 mL 13x75 
lavender cap-black 
ring, non-ridged 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
VACUETTE® Blood 
Collection Tubes 
Serum CAT Serum 
Sep Clot Activator 
3.5 mL 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Urine Collection Cup 
with Transfer Device 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Urine Collection Tube 
Plastic 10 mL 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Regular Polyester 
Swab with Plastic 
Applicator 
Biomedical 
Laboratory  
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
biomedical 
laboratory facility 
using biomedical 
laboratory disposal 
procedures 
To keep 
at site 
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Smiths Medical 
Peripheral IV Catheter 
Protectiv® Plus 20 G x 
1" 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
BD Peripheral IV 
Catheter Insyte™ 
Autoguard™ BC 18 G 
x 1.16" Winged, Safety 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
3M Tegaderm 
Transparent Dressing 
2 3/8 x 2 3/4" 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Surgical Tape 
Transparent Plastic 1" 
X 10 Yard 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Kendall Underpad 
Tendersorb 23 x 36 ", 
Disposable 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Medline OnGuard 
Blood Collection Tube 
Holder 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
3M Compression 
Bandage Coban™ 
NonWoven Material / 
Elastic Fibers 1" X 5 
Yard NonSterile 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
BD IV Flush 
Solution,PosiFlush™ 
Sodium Chloride, 
Preservative Free 
0.9% Intravenous, 
Prefilled Syringe 3 ml 
in 10 mL 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Medline MediGuard 
ES S, M, L ,X-L 
Powder-Free Nitrile 
Exam Gloves 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Kendall Alcohol Prep- 
Pads, Medium,Sterile 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Gauze Sponge 2 x 2" 
8-Ply Non-Sterile 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
BD Vacutainer® 
Eclipse™ Blood 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
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Collection Needle 21 
G x 1¼", Safety Shield 
Dukal Dawnmist 
Tourniquet, Flat, White Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
covidien Sharps 
Container Monoject™, 
14 Quart Red Base 
/Translucent Lid 
Vertical Drop Chimney 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
K-Shield Advantage 
Winged Blood 
Collection Set 21 G x 
3/4" Safety Shield 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
BD Vacutainer® Blood 
Collection Tube, 
Discard Tube, Plain, 
Plastic, Hemogard™, 
6 mL 13 X 100 mm 
Site/CRO 
Commercial 
pack 
Use as per 
study schedule 
Discard/destroy at 
site using site 
disposal procedures 
To keep 
at site 
Equivalent items can also be used based on supplier availability. Detailed instructions for the 
return of study product/study supplies for the accountability checks and subsequent destruction 
which will be provided by GSK CH during the study in time for study close out visit. Sundry 
items will be supplied by the site/vendor and will be discarded or destroyed at the clinical site. 
6.1.1 
Dosage Form and Packaging 
Liquid filled capsules will be supplied to the clinical site as packaged bottles for dispensing by 
the pharmacy.  
The content of the product labels will be in accordance with all applicable regulatory 
requirements and will be the responsibility of the GSK CH Global Clinical Supplies group. 
Each study label will contain, but not be limited to, protocol number, directions for use and 
storage requirements.  
Care should be taken with the supplied products and their labels so that they are maintained in 
good condition. It is important that all labels remain intact and legible for the duration of the 
study. 
All products supplied are for use only in this clinical study and should not be used for any other 
purpose. 
6.1.2 
Preparation and Dispensing  
Subjects will be assigned to products in accordance with the randomization schedule generated 
by
, prior to the start of the study, using validated software. 
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Study product will be dispensed by qualified site personnel per the dosage/administration 
instructions. An additional member of site staff should ensure the dispensing procedures are 
completed accurately. 
6.2 
Administration 
Only subjects enrolled in the study may receive study products and only authorized site staff 
may supply or administer study products. All study interventions must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the authorized site staff only. 
Following an overnight fast of least 10 hours, subjects will receive investigational product. 
Investigator site personnel will administer investigational product during each period with 
ambient temperature water to a total volume of 240 mL and will instruct subjects to consume 
the entire amount of water along with their investigational product. A hand and mouth check 
will be performed to ensure consumption of the medication.  
Subjects will swallow the investigational product whole and will not manipulate or chew the 
medication prior to swallowing. To standardize the conditions on PK sampling days, all subjects 
will be required to refrain from lying down (except when required by procedures), eating, and 
drinking beverages for the first 4 hours after dosing. Water may be given after 1 hour 
post-dosing.  
6.2.1 
Medication/Dosing Errors 
Medication/dosing errors may result, in this study, from the administration or consumption of:  
x the wrong product, 
x by the wrong subject,  
x at the wrong time,  
x or at the wrong dosage.  
Such medication/dosing errors occurring to a study subject are to be captured in the CRF. In the 
event of medication dosing error, the sponsor should be notified immediately and under no 
circumstance should this exceed 24 hours. 
Medication/dosing errors are reportable irrespective of the presence of an associated AE, 
including: 
x Medication/dosing errors involving subject exposure to any of the study products; 
x Potential medication/dosing errors or uses outside of what is foreseen in the protocol 
that do or do not involve the participating subject. 
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If a medication/dosing error is accompanied by an AE, as determined by the investigator, the 
medication/dosing error and, any associated AEs are to be captured in the CRF AE form.  
6.2.2 
Overdose 
An overdose is a deliberate or inadvertent administration of a product at an amount higher than 
specified in the protocol. 
Overdose is not likely to occur in this study. 
Overdose per se is not an AE. However, any clinical sequelae of an overdose should be reported 
as an AE (and SAE, if appropriate). For reporting, follow the AE and SAE reporting 
instructions. 
6.3 
Investigational/Study Product Storage  
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study products received and any discrepancies are reported and 
resolved before use according to the supplied shipping documentation. 
The investigator, or designee, will ensure that all study products are stored in a secured area 
with controlled access under required storage conditions and in accordance with applicable 
regulatory requirements and the product label.   
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products). This should be 
captured from the time of first product receipt throughout the study. Even for continuous 
monitoring systems, a log or site procedure that ensures active daily evaluation for excursions 
should be available. The operation of the temperature-monitoring device and storage unit (for 
example, refrigerator), as applicable, should be regularly inspected to ensure it is maintained in 
working order.  
Any excursions from the product-label storage conditions should be reported to appropriate site 
staff upon discovery and communicated to sponsor as soon as possible. The site should actively 
pursue options for returning the product to the storage conditions as described in the labeling, 
as soon as possible. Excursions from the storage requirements, including any actions taken, 
must be documented as a protocol deviation and reported to the sponsor.   
Once an excursion is identified, the affected product (or products) must be quarantined and not 
used until the sponsor provides documentation of permission to use. Use of any of the affected 
product(s) prior to sponsor approval will be considered a protocol deviation.   
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6.4 
Investigational/Study Product Accountability 
All products supplied are for use only in this clinical study and should not be used for any other 
purpose. 
All study products must be received by a designated person at the study sites, handled and stored 
safely and properly, and kept in a secured location to which only the staff have access. Upon 
receipt, all study products should be stored according to the instructions specified on the product 
labels. Study products are to be dispensed only to subjects enrolled in the study in accordance 
with the protocol, by authorized site staff. 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of all the product supplies. All study products will be accounted for using the 
investigational/study product accountability form/record. The investigator is responsible for 
study product accountability, reconciliation, and record maintenance.  
The accountability records must be available for inspection by the study monitor during the 
study. Monitoring of product accountability will be performed by the monitor during site visits 
and at the completion of the study.  
6.4.1 
Destruction of Investigational/Study Product Supplies  
At the end of the study, the investigator or an appropriate designee, and a representative of GSK 
CH (study monitor) will inventory all used and unused study products and sundry items. The 
investigational/study product accountability record for returned study products will then be 
completed. All study product (used and unused) for this clinical study (including empty 
packaging bottles), will be returned for destruction to the GSK CH Clinical Supplies 
Department or designated vendor using the return instructions provided. Detailed instructions 
for the return of study product/study supplies for the accountability checks and subsequent 
destruction will be provided by GSK CH during the study in time for study close out visit. 
6.5 
Blinding and Allocation/Randomization 
The investigator’s knowledge of the product allocation should not influence the decision to 
enroll a subject or affect the order in which subjects are enrolled. 
Dummy randomization will be supplied by 
to the Sponsor. Upon confirmation 
of general layout, an unblinded statistician not directly involved in the study will generate the 
final randomization. 
 will provide the final randomization schedule to the investigator and, in 
accordance with the randomization numbers and treatment allocations, the subject will receive 
the study treatment sequence assigned to the corresponding randomization number. 
Treatments will be provided in an open-label manner. However, the analytical laboratory will 
remain blinded to treatment during the analysis of the plasma samples. 
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6.6 
Breaking the Blind 
Not applicable given the open-label study design.  
6.7 
Compliance 
Study products will be administered under the supervision of investigator site personnel. A hand 
and mouth check will be performed to ensure consumption of the medication. 
6.8 
Concomitant Medication/Treatment(s) 
Subjects will abstain from all concomitant treatments, except for contraceptives and hormone 
replacement therapy, and those used for the treatment of AEs unless they jeopardize the 
integrity of the study. The study sponsor should be immediately informed when the integrity of 
the study is at jeopardy. Any medications, treatments, or vaccine (including OTC or prescription 
medicines, vitamins, and/or herbal supplements) taken during the study, from signing the 
informed consent, must be recorded in the CRF with indication, reason for use, unit dose, daily 
dose, and start and stop dates of administration. All subjects will be questioned about 
medications/treatments at each site visit. 
Medication/treatments taken within 90 days of signing the informed consent form will be 
documented as a prior medication/treatment. Medications/treatments taken after the first dose 
will be documented as concomitant medication/treatments. 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Subject Discontinuation/Withdrawal  
A subject may withdraw from the study at any time at his or her own request or may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral 
reasons, major non-compliance with protocol requirements, or the inability of the subject to 
comply with the protocol-required schedule of study visits or procedures.  
The following circumstances require discontinuation of study product and/or premature subject 
withdrawal: 
x Protocol violation that may impact the subject’s safety 
x Positive test for COVID-19, conducted during the study, at times deemed necessary by 
investigator 
x Pregnancy 
x Withdrawal of informed consent 
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x Subject lost to follow- up  
If a subject is discontinued or prematurely withdraws from the study, the reason(s) for 
discontinuation or withdrawal and the associated date must be documented in the relevant 
section(s) of the CRF.  
7.2 
Lost to Follow up 
If a subject fails to return to the site for a required study visit the site must attempt to contact 
the subject and reschedule the missed visit as soon as possible and counsel the subject on the 
importance of maintaining the assigned visit schedule and ascertain whether the subject wishes 
to and/or should continue in the study. 
A subject will be considered lost to follow up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. Before a subject is deemed lost to follow 
up, the investigator or designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented. If contact 
is made with the subject, the investigator should inquire about the reason for withdrawal and if 
appropriate request that the subject return for a final visit and follow-up with the subject 
regarding any unresolved AEs. 
Final safety assessments may be carried out when the subject returns to the study site, at the 
investigator’s discretion, which could include the following: 
x urine pregnancy test, 
x physical examination, 
x safety laboratory tests, 
x seated blood pressure, respiratory rate, oral body temperature and pulse rate measurements. 
Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study and lost to follow up.  
Lack of completion of all or any of the early termination procedures will not be viewed as 
protocol deviations so long as the subject’s safety was preserved. 
If the subject withdraws from the study and withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such withdrawal 
of consent. 
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8 
STUDY PROCEDURES 
This section lists the procedures to be completed at each planned study visit. The timing of each 
procedure is listed in the Schedule of Activities section. 
Adherence to the study design requirements, including all procedures are essential and required 
for study conduct. 
8.1 
Screening 
Screening procedures will be conducted by the investigator, or suitably qualified designee. 
Subjects will be screened within 28 days prior to administration of the investigational product 
to confirm that they meet the subject selection criteria for the study. 
The following procedures will be completed: 
8.1.1 
Informed Consent 
The investigator, or designee, must obtain informed consent from each subject participating in 
this study after adequate explanation of the aims, methods, objectives, and potential hazards of 
the study. The informed consent form will be signed and dated by the subject. A copy will be 
given to the subject, and the original signed and dated ICF will be maintained in the subject’s 
records. 
The investigator, or designee, must also explain to the subjects that they are completely free to 
refuse to enter the study or to withdraw from it at any time. Appropriate forms for documenting 
a signed and dated consent will be provided by either the investigator or by GSK CH. 
The investigator, or designee, should sign and date each copy of the ICF to confirm that the 
consent process was completed correctly after the subject has signed. 
The time the subject signed the informed consent form will be captured as this is the point at 
which all AEs will be captured from. The date and time of consent will be captured in the CRF. 
If, during a subject’s participation in the study, any new information becomes available that 
may affect the subject’s willingness to participate in the study, each ongoing subject should 
receive a copy of this new information and be re-consented into the study. Each subject should 
be provided with a copy of the signed and dated amended consent form. The date of re-consent 
will be recorded on the CRF. 
After signing the ICF, subjects will undergo the screening assessments to confirm that they 
meet all the inclusion criteria and none of the exclusion criteria. If the subject is confirmed 
eligible by the investigator (or designee) to participate in the study the subject is considered 
enrolled in the study. 
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8.1.2 
Demographics 
The following demographic information will be recorded in the CRF: year of birth, gender, 
ethnicity, and race.  
Ethnicity and race of subjects will be recorded in accordance with FDA Guidance for Industry: 
Collection of Race and Ethnicity Data in Clinical Trials, 2005. 
8.1.3 
Inclusion/Exclusion Criteria 
Inclusion and exclusion criteria information, as specified in Section 5, will be documented in 
the CRF. 
8.1.4 
Medical History and Prior Medication/Treatment 
Details of relevant medical and surgical history (in the last 5 years), including allergies or drug 
sensitivity, will be documented in the CRF. 
Prior medications/treatments, including prescription and non-prescription drugs, dietary 
supplements and herbal remedies, taken in the last 90 days and prior to signing the informed 
consent form, will be documented in the CRF. 
8.1.5 
Subject Eligibility 
The investigator and/or medically qualified designee will review inclusion/exclusion criteria, 
medical history, prior medications to confirm subject eligibility to participate in the clinical trial. 
This will be documented in the CRF. 
To prepare for study participation, subjects will be instructed in the Lifestyle Considerations 
and any Concomitant Medication/Treatment(s) requirements of the protocol. 
8.1.6 
Screening Procedures 
The following procedures will be completed: 
x Obtain written informed consent and record in the CRF. 
x Review inclusion and exclusion criteria and record in the CRF. 
x Collect demography, including year of birth, gender, ethnicity and race and record in 
the CRF. 
x Collect height and weight and calculate BMI. The results for each measurement will 
be recorded in the CRF. 
x Obtain medical history as related to the inclusion/exclusion criteria, including any 
relevant medical or surgical history, allergies or drug sensitivity, history of drug and 
alcohol use. Significant findings that are present before consent must be included in 
the CRF. 
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x Obtain complete medication history of all prescription or nonprescription drugs, and 
dietary and herbal supplements taken within 90 days prior to consent, and record in 
the CRF. 
x Obtain seated blood pressure, pulse rate, respiratory rate, and oral body temperature. 
The results for each measurement will be recorded in the CRF. 
x Conduct full physical examination. Any clinically relevant findings will be noted in 
the AE CRF page and enrollment will be based upon investigator judgement. 
x Contraceptive review. 
x Collect single 12 lead ECG. Results (normal or abnormal) and clinical significance 
will be recorded on the CRF. 
x Following at least a 4 hour fast, collect blood and urine specimens for the following, 
and recorded on the CRF: 
x Safety laboratory tests and serology; 
x Urine drug screening; 
x Alcohol screening; 
x Cotinine screening; 
x Serum FSH concentration for any female who has been amenorrheic for at least 
12 consecutive months; 
x Urine pregnancy test for all females of childbearing potential. 
x Spontaneous reporting of AEs and those elicited by asking subjects to respond to a 
non-leading question such as ͆How do you feel?͇ will be assessed and any AEs 
recorded in the CRF. 
x Collect nasal/nasopharyngeal swab sample for COVID-19 test within 24 to 72 hours 
prior to check-in (Day -1) in Period 1. Date and time of sample collection and test 
results (positive or negative) will be documented in the CRF. 
8.2 
Study Periods 
For each study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to, where 
possible: 
x Vital signs: obtain as close as possible to scheduled time, but prior to blood specimen 
collection; 
x PK blood specimens: obtain at scheduled time. 
Obtain all other procedures as close as possible to the scheduled time but may be obtained 
before or after blood. 
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8.2.1 
Day -1   
In each period, subjects will be admitted to the clinical site the day prior to Day 1 dosing. 
The following procedures will be completed following admission to the clinical site: 
x Review inclusion and exclusion criteria and record in the CRF. 
x Obtain oral body temperature. The results for each measurement will be recorded in the 
CRF. 
x Brief physical examination including evaluation of general appearance, heart, lung. The 
results will be recorded in the CRF. 
x Collect urine for drug screening. The results will be recorded in the CRF. 
x Collect urine for cotinine screening. The results will be recorded in the CRF. 
x Obtain blood for serum ș-hCG for all females of childbearing potential. The results 
will be recorded in the CRF (note: blood for serum ș-hCG can be obtained at admission 
or in the morning of Day -1). 
x Collect nasal/nasopharyngeal swab sample for COVID-19 test. Date and time of sample 
collection and test results (positive or negative) will be documented in the CRF. 
x Confirm proper contraception is being used and the results will be recorded on the CRF. 
x Collect alcohol breath test. Result will be recorded on the CRF. 
x Meals as required in section 5.5.1. Time and consumption of meals will be recorded on 
CRF. 
x Subjects will begin fasting at least 10 hours prior to dosing on Day 1. 
x Changes in concomitant medication or non-drug treatments/procedures will be 
documented in the CRF. 
x Spontaneous reporting of AEs and those elicited by asking subjects to respond to a non-
leading question such as “How do you feel?” will be assessed and any AEs recorded in 
the CRF. 
8.2.2 
Day 1 
Prior to dosing in each period, within one hour of study drug administration, the following 
procedures will be completed: 
x Obtain seated blood pressure, pulse rate, respiratory rate, and oral body temperature. 
The results for each measurement will be recorded in the CRF. 
x Review inclusion and exclusion criteria and record in the CRF. 
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x Randomization (conducted prior to the first dosing in Period 1). 
x Collect a blood sample for PK analysis. Time of blood sampling will be recorded in 
the CRF. 
x After all pre-dose procedures have been completed, administer the investigational 
product (see Investigational/Study Products section) and record in the CRF. 
After dosing, the following procedures will be completed: 
x Acceptability: ease of swallowing (5-point ordinal scale). 
x Collect blood samples for PK analysis at the following time points after dosing on 
Day 1: 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 
3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, and 16 hours. The time tolerance 
window for blood samples will be ±1 minute for all samples collected before 8 hours 
post-dose and ±3 minutes for subsequent samples. Time of blood sampling will be 
recorded in the CRF. 
x Meals as required in section 5.5.1. Time and consumption of meals will be recorded 
on CRF. 
x Changes in concomitant medication or non-drug treatments/procedures will be 
documented in the CRF. 
x Spontaneous reporting of AEs and those elicited by asking subjects to respond to a 
non-leading question such as “How do you feel?” will be assessed and any AEs 
recorded in the CRF. 
8.2.3 
Day 2 
The following procedures will be completed on Day 2 of each period: 
x Obtain oral body temperature. The results for each measurement will be recorded in 
the CRF. 
x Collect blood samples for PK analysis (for diphenhydramine only) at 24 and 36 hours 
post dosing of Day 1 continuing into Day 2. The time tolerance window for blood 
samples will be ±3 minutes. Time of blood sampling will be recorded in the CRF. 
x Meals as required in section 5.5.1. Time and consumption of meals will be recorded 
on CRF. 
x Changes in concomitant medication or non-drug treatments/procedures will be 
documented in the CRF. 
x Spontaneous reporting of AEs and those elicited by asking subjects to respond to a 
non-leading question such as “How do you feel?” will be assessed and any AEs 
recorded in the CRF. 
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8.2.4 
Day 3 
The following procedures will be completed on Day 3 of each period: 
x Obtain oral body temperature. The results for each measurement will be recorded in 
the CRF. 
x Collect blood samples for PK analysis (for diphenhydramine only) at 48 hours post 
dosing of Day 1 continuing into Day 3. The time tolerance window for blood samples 
will be ±3 minutes. Time of blood sampling will be recorded in the CRF. 
x Meals as required in section 5.5.1. Time and consumption of meals will be recorded 
on CRF. 
x Changes in concomitant medication or non-drug treatments/procedures will be 
documented in the CRF. 
x Spontaneous reporting of AEs and those elicited by asking subjects to respond to a 
non-leading question such as “How do you feel?” will be assessed and any AEs 
recorded in the CRF. 
x Collect nasal/nasopharyngeal swab sample for COVID-19 test. Date and time of 
sample collection and test results (positive or negative) will be documented in the 
CRF. 
x After all procedures are completed, subjects are discharged from the clinical site. 
8.2.5 
Washout Period 
The washout period between each drug administration will be at least 7 days. The following 
procedure will be completed during the washout period: 
x Collect nasal/nasopharyngeal swab sample for COVID-19 test within 24 to 72 hours 
prior to check-in (Day -1) in Period 2. Date and time of sample collection and test 
results (positive or negative) will be documented in the CRF. 
8.2.6 
End of Study 
The exit examination procedures will be done before check-out from the clinic, on study Day 3 
of Period 2. 
x Obtain seated blood pressure, pulse rate, respiratory rate and oral body temperature. The 
results for each measurement will be recorded in the CRF. (Note: the oral body 
temperature obtained on Day 3 of Period 2 can be used as the oral body temperature 
required at End of Study) 
x Conduct brief physical examination. The results will be recorded in the CRF. 
x Collect nasal/nasopharyngeal swab sample for COVID-19 test. Date and time of sample 
collection and test results (positive or negative) will be documented in the CRF. (Note: 
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the COVID-19 test performed on Day 3 of Period 2 can be used as the test required at 
End of Study) 
x Obtain blood and urine samples for safety laboratory tests. 
x Collect urine pregnancy test for all females of childbearing potential. The results will 
be recorded in the CRF. 
x Changes in concomitant medication or non-drug treatments/procedures will be 
documented in the CRF. 
x Spontaneous reporting of AEs and those elicited by asking subjects to respond to a non-
leading question such as “How do you feel?” will be assessed and any AEs recorded in 
the CRF. 
8.3 
Study Conclusion 
The Study Conclusion page of the CRF will be completed for all subjects whether they 
completed all study procedures or if they were discontinued from the study early. If the subject 
discontinued early, at any point during the study, the primary reason for withdrawal should be 
recorded on the Study Conclusion page. 
If a subject has any clinically significant, study-related abnormalities or AEs at the end of the 
study, the GSK CH medical monitor (or designated representative) should be notified and, the 
subject may be asked to remain at the clinical site or be asked to return for a follow-up visit to 
ensure any issue is resolved or deemed not clinically significant.  
8.4 
Follow-up Visit 
The study site may contact a subject to follow up an AE post-study completion/withdrawal and, 
in some circumstances, request they return to the site for additional follow-up visits (final safety 
assessments). If needed, additional examinations may be carried out at such visits. 
9 
STUDY ASSESSMENTS 
Every effort should be made to ensure that protocol-required tests and procedures are completed 
as described. However, it is anticipated that from time to time there may be circumstances, 
outside the control of the investigator that may make it unfeasible to complete an assessment. 
In these cases, the investigator must take all steps necessary to ensure the safety and well-being 
of the subject. When a protocol-required assessment cannot be performed, the investigator (or 
designee) will document the reason for the missed assessment as a protocol deviation and any 
corrective and preventative actions that he or she has taken to ensure that required processes are 
adhered to as soon as possible. The sponsor must be informed of any missed assessments in a 
timely manner. 
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9.1 
Screening Assessments 
Screening assessments will be performed by appropriately trained staff/clinical examiners at 
the times, and in the order, defined in the Study Procedures section of this protocol  
9.2 
Safety and Other Assessments 
The following safety assessments will be performed by appropriately trained staff/clinical 
examiners, at the times and in the order defined in the Study Procedures section of this protocol. 
9.2.1 
Laboratory Tests  
The following laboratory tests/analytical measures will be performed by appropriately trained 
staff/clinical examiners, at the times and in the order defined in Study Procedures of this 
protocol. 
Table 9-1 
Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Drug, cotinine, and 
alcohol screens 
Hematocrit 
Hemoglobin 
MCH 
MCHC 
MCV 
Platelet count 
RBC count 
WBC count and 
differential: 
x Basophils 
x Eosinophils 
x Lymphocytes 
x Monocytes 
x Neutrophils 
 
Albumin 
ALP 
ALT 
AST 
Calcium 
Chloride 
Creatine kinase 
Creatinine 
GGT 
Glucose 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Urea (BUN) 
Bilirubin 
Blood (occult) 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examinationa  
Amphetamines 
/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine 
MDMA 
Methadone 
Opiates 
PCP 
THC 
 
Urine cotinine test 
Alcohol breath test  
Serology 
Hormone 
panel - females only 
Other tests 
 
HBsAg 
HBc-Ab (IgG + IgM) 
HCV-Ab 
HIV antigen/antibody 
Serum FSHb 
Serum pregnancy 
testc 
Urine pregnancy 
testd 
COVID-19 PCR or 
antigen 
 
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Definitions: ALP= alkaline phosphatase; ALT= alanine transaminase; AST= aspartate transaminase; 
BUN= blood urea nitrogen; HBc-Ab= Hepatitis B core antibody; HBsAg= hepatitis B surface antigen; 
HCV-Ab= hepatitis C virus antibodies; HIV= human immunodeficiency virus; FSH= follicle-stimulating 
hormone; GGT= gamma-glutamyl transpeptidase; MCH = mean cell hemoglobin; MCHC = mean cell 
hemoglobin concentration; MCV = mean cell volume; MDMA= 3,4- methylenedioxymethamphetamine; 
PCP=  phencyclidine; RBC= red blood cell; THC= tetrahydrocannabinol; WBC= white blood cells. 
aIn the event of abnormal findings (per safety laboratory internal protocols) 
bFSH done at screening only in females who have been amenorrhoeic for at least 12 months 
cAll female subjects of childbearing potential will be tested for serum human chorionic gonadotropin 
(hCG) at Day -1 of each period 
dAll female subjects of childbearing potential will undergo a urine pregnancy test at Screening and End 
of Study 
Additional laboratory results may be reported on these samples because of the method of 
analysis or the type of analyzer used by the clinical laboratory; or as derived from calculated 
values. These additional tests would not require additional collection of blood. Unscheduled 
clinical labs may be obtained at any time during the study to assess any perceived safety 
concerns. 
Subjects may undergo random urine drug screening at the discretion of the investigator. Drug 
screening conducted prior to dosing must be negative for subjects to receive investigational 
product.  
Any remaining serum/plasma from samples collected for clinical safety labs will be destroyed 
at the end of the study. 
9.2.2 
Serology 
Virus serology will be performed at times specified in the Study Procedures section of this 
protocol for HIV antigen and antibody, HBsAg, HBc-Ab (IgG + IgM) and HCV-Ab. In case of 
a positive finding in virus serology screen, the subject must be excluded from trial participation. 
9.2.3 
Urine drug screen 
Urine will be collected at times specified in the Study Procedures section of this protocol. In 
case of a positive finding for any substance class, the subject must be discontinued from the 
trial (or excluded from trial participation in case of positive findings at the screening visit). 
9.2.4 
Alcohol test 
An alcohol breath test will be conducted at times specified in the Study Procedures section of 
this protocol. In case of a positive finding in the alcohol test, the subject must be discontinued 
from the trial. 
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9.2.5 
Pregnancy Testing 
For female subjects of childbearing potential, a urine pregnancy test, will be performed at 
screening and End of Study and a serum pregnancy test will be performed on Day -1 of each 
period. Results will be obtained prior to dosing during each period.  
The investigator and site personnel will remind subjects at each visit to inform site personnel if 
their menstrual cycle has changed or if they have any other reason to suspect they may be 
pregnant (e.g. had unprotected intercourse since the last visit). 
A negative pregnancy result is required before the subject may receive the investigational 
product. Pregnancy tests will also be done whenever one menstrual cycle is missed during the 
active study period (or when potential pregnancy is otherwise suspected). Pregnancy tests may 
also be repeated as per request of IRBs/ECs or if required by local regulations. 
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of investigational product and from the study. 
9.2.6 
Physical Examinations  
Physical examinations may be conducted by a physician, trained physician's assistant, or nurse 
practitioner as acceptable according to local regulation. A full physical examination will include 
head, ears, eyes, nose, throat, mouth, skin, heart and lung examinations, lymph nodes, 
abdominal, musculoskeletal, vascular, and neurological systems.   
A brief physical examination will be focused on general appearance, heart and lung 
examinations, as well as towards subject reported symptoms. 
Any untoward findings identified on physical exams conducted after the administration of the 
first dose of investigational product will be captured as an AE, if those findings meet the 
definition of an AE. 
9.2.7 
Height and Weight  
Height in centimeters (cm) and body weight in kilograms (kg) to the nearest 0.1 kilogram will 
be measured. 
For measuring weight, a scale with appropriate range and resolution is used and must be placed 
on a stable, flat surface. Subjects must remove shoes, bulky layers of clothing, and jackets so 
that only light clothing remains. They must also remove the contents of their pockets and remain 
still during measurement of weight.  
BMI will be calculated in kg/m2. 
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9.2.8 
Blood Pressure and Pulse Rate  
Additional collection times, or changes to collection times of blood pressure and pulse rate will 
be permitted, as necessary at the discretion of the investigator, to ensure appropriate collection 
of safety data. 
Seated blood pressure should be measured with the subject’s arm supported at the level of the 
heart with feet flat on the floor and recorded to the nearest mmHg after a minimum 5 minutes 
of rest.   
Subjects should be instructed not to speak during measurements.  
A calibrated blood pressure cuff of the same proper size will be used to measure blood pressure 
each time. The use of an automated device for measuring blood pressure and pulse rate is 
acceptable, although, when done manually, pulse rate will be measured in the brachial/radial 
artery for at least 30 seconds. When the timing of these measurements coincides with a blood 
collection, blood pressure and pulse rate should be obtained prior to the nominal time of the 
blood collection. 
9.2.9 
Respiratory Rate 
Respiratory rate will be measured after approximately 5 minutes rest in seated position by 
observing and counting the respirations of the subject for 30 seconds and multiplied by 2. When 
blood pressure is to be taken at the same time, respiration measurement will be done after the 
5 minutes of rest. 
9.2.10 
Temperature 
Body temperature will be measured orally. 
No eating or drinking is allowed for 15 minutes prior to the measurement. 
9.2.11 
Electrocardiogram 
A standard 12 lead ECG will be performed at screening after the subjects have been resting for 
at least 5 minutes in a supine position. Interpretation of the tracing must be made by a qualified 
physician or designee and documented on the ECG section of the CRF. Each ECG tracing 
should be kept in the source documents at the study site. Results or any clinically significant 
abnormalities should be reported in the CRF. Clinically significant findings must be discussed 
with the GSK CH Clinical Project Lead (CPL) prior to enrolling the subject in the study. 
Subjects should be in a quiet environment and not speak during the resting period or 
measurement. 
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9.2.12 
COVID-19 Test 
Nasal/nasopharyngeal swab will be collected to test for COVID-19 using PCR or antigen test, 
at times specified in the Study Procedure section. Two consecutive negative tests for active 
COVID-19 separated by > 24 hours are required for inclusion in the study: one test will be done 
at screening within 72 hours of admission and one test will be done on Day -1 in Period 1. 
For detection of COVID-19, test/s are to be performed as follows: 
x During the screening 
x At check-in (Day -1 of each period)  
x During the washout period 
x At discharge from Period 1 and End of Study or early discontinuation 
x At any time during residential period in study, when subjects report symptoms suggestive 
of COVID-19 
If the first test is > 72 hours prior to unit admission, subjects should be advised to self-quarantine 
until entrance to the unit while awaiting final testing clearance. Subjects who report symptoms 
suggestive of COVID-19 while in the research unit should be isolated in the unit or at home and 
tested for COVID-19 infection using an approved molecular test. 
9.3 
Pharmacokinetics (PK) 
Thirty-two (32) blood samples will be collected for PK analysis: within one hour prior to dosing 
(pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 
3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, and 48 hours following dosing in 
each treatment period (24, 36, and 48 hours for diphenhydramine only). Time zero (“0”) as 
reference for post-dose PK samplings is defined as the time of drug administration. Time zero 
will be recorded in the CRF. A dead-volume intravenous catheter will be used for blood 
collection to avoid multiple skin punctures, when appropriate. Otherwise, blood samples will 
be collected by direct venipuncture. 
9.3.1 
Plasma for Analysis of Ibuprofen and Diphenhydramine 
During all study periods, blood samples (3 mL for ibuprofen and 3 mL for diphenhydramine) 
to provide a minimum of 1 mL plasma for PK analysis of each analyte will be collected into 
appropriately labeled tubes containing K2EDTA at times specified in the protocol. 
The actual times may change but the number of samples will remain the same. All efforts will 
be made to obtain the PK samples at the exact nominal time relative to dosing. 
Samples will be analyzed using a validated analytical method in compliance with applicable 
 standard operating procedures. 
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The PK samples must be processed and shipped as indicated in the Analytical Methodology 
Information Sheet (AMIS) to maintain sample integrity. Any deviations from the PK processing 
steps, including any actions taken, must be documented and reported to the sponsor. On a 
case-by-case basis, the sponsor may make a determination as to whether sample integrity has 
been compromised. Any sample deemed outside of established stability, or of questionable 
integrity, will be considered a protocol deviation. 
9.3.2 
Shipment of Pharmacokinetic Samples 
When applicable, samples will be transported to the assay lab in at least two separate shipments, 
with each set of aliquots in separate shipments. Once the assay lab confirms receipt of the first 
shipment, the second set of aliquots may be sent. The samples should be packed on sufficient 
dry ice to keep them frozen for at least 72 hours.  
All PK samples will be stored until they are properly disposed of at the end of its retention 
period (i.e., until study report is issued), or useful life (i.e., until expiry of stability), upon written 
request by sponsor, or upon receipt of a request to destroy the PK samples due to withdrawal of 
consent. No sample will be retained beyond 2 years from last participant last visit. 
9.4 
Acceptability of “ease of swallowing”  
Immediately after dosing the subject will answer the following questions. 
“Do you agree or disagree that the product is Easy to swallow?  
  
Rank the ‘ease of swallowing’ of the product on the following scale from 1 to 5: 
5= very easy to swallow 
4 = above average to swallow 
3 = average to swallow 
2 = somewhat easy to swallow 
1 = not easy to swallow 
9.5 
Blood Volume 
The total blood sampling volume for each subject in this study is approximately 417 mL. The 
table below reflects approximate sample volumes needed for each measured endpoint. The 
actual collection times of blood sampling may change, but the total number of PK blood samples 
will not increase. Additional blood samples may be taken for safety assessments at the 
discretion of the investigator or GSK CH. 
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Table 9-2 
Blood Volume 
Sample Type 
Sample 
Volume 
(mL) 
Number of Sampling Times 
Total 
Volume 
(mL) 
Screening 
Study Period 
End of Study 
Safety Labs screening 
21 
1 
 
 
21 
Safety Labs end of 
study 
12.5 
 
 
1 
12.5 
Serum Pregnancy Test 
8.5 
 
2 
 
17 
PK (ibuprofen) 
3 
 
58 
 
174 
PK (diphenhydramine) 
3 
 
64 
 
192 
TOTAL 
 
 
 
 
416.5 
This total volume does not include discarded blood from pre-draws used to remove fluid from flushed 
catheters, if applicable.   
10 
ADVERSE EVENT AND SERIOUS ADVERSE EVENTS 
The investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study product or the study, or that caused the 
subject to discontinue the study product or study. 
10.1 
Definition of an Adverse Event (AE) 
An AE is any untoward medical occurrence in a clinical study subject, temporally associated 
with the use of a study product including any washout or lead-in product (or medical device), 
whether or not considered related to the study product, including any washout or lead-in product 
(or medical device). 
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 study product including any washout or lead-in product (or medical device). 
Events Meeting the AE Definition:   
x Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g. ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease). 
x Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
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x New conditions detected or diagnosed after study product administration even though 
it may have been present before the start of the study. 
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
product or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
Events NOT meeting the AE definition:  
x Any clinically significant abnormal laboratory findings (if applicable) or other abnormal 
safety assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the subject’s condition.  
x The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.  
x Medical or surgical procedure (e.g. endoscopy, appendectomy) is not the AE. The 
condition that leads to the procedure is an AE (e.g. appendicitis). 
x Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
x 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.  
10.2 
Definition of a Serious Adverse Event (SAE) 
A SAE is a particular category of an AE where the adverse outcome is serious. If an event is 
not an AE per definition above, then it cannot 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). 
A SAE is any untoward medical occurrence at any dose that: 
x Results in death 
x Is life-threatening 
 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; 
x Requires inpatient hospitalization or prolongation of existing hospitalization  
 In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
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observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient 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. 
x Results in persistent or significant disability/incapacity 
 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 with or 
prevent everyday life functions but do not constitute a substantial disruption. 
x Results in congenital anomaly/birth defect 
x Other situations: 
 Medical or scientific judgment should be exercised in deciding whether SAE 
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 events 
should usually be considered serious. 
 Examples of such events include 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. 
Note: Classification of an AE as ‘serious’ is based on the outcome of the event and is a factor 
in determining reporting requirements. 
10.3 
Time Period and Frequency for Collecting AE and SAE 
Information 
All AEs, and therefore all SAEs will be collected immediately after a subject provides consent 
to participate in the study by the completion (signature) of the ICF and until 5 days following 
last administration of the study product (or last procedure). 
Medical occurrences that began before obtaining informed consent will be recorded in the 
Medical History/Current Medical Conditions section of the CRF not the AE section. 
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Details recorded by the subject on a diary or similar document that meet the definition of an AE 
must also be discussed with the subjects and transcribed in the AE section of the CRF. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours. The investigator will submit any updated SAE data 
to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of the study 
participation. 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 to be 
reasonably related to the study product or study participation, the investigator must promptly 
notify the sponsor. 
10.4 
Reporting Procedures 
The investigator and any designees are responsible for detecting, documenting and reporting 
events that meet the definition of an AE and remain responsible for following up on AEs that 
are serious, considered related to the study product(s), participation in the study, or a study 
procedure, or that caused the subject to discontinue the study product or study. 
Spontaneous reporting of AEs and those elicited by asking subjects to respond to non-leading 
such as “How do you feel” will be assessed and any AE’s recorded in the CRF and reported 
appropriately. 
The investigator (or medically qualified designee) is to report all directly observed AEs and all 
AEs spontaneously reported by the study subject. In addition, each study subject will be 
questioned about AEs. 
Each AE is to be assessed to determine if it meets the criteria for a SAE. If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 
When an AE occurs, it is the responsibility of the investigator (or medically qualified designee) 
to review all documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
The investigator or site staff will then record all relevant information regarding an AE in the 
CRF and all details relating to an SAE in the paper SAE Form provided. 
It is not acceptable for the investigator (or medically qualified designee) to send photocopies 
of the subject’s medical records to GSK CH in lieu of completion of the AE CRF page/SAE 
form. 
There may be instances when copies of medical records for certain cases are requested by GSK 
CH.  In this instance, all subject identifiers, except for the subject number, will be redacted on 
the copies of the medical records prior to submission to GSK CH. 
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The investigator (or medically qualified designee) will attempt to establish a diagnosis of the 
event based on signs, symptoms, and/or other clinical information.  The diagnosis will be the 
documented as the AE/SAE where known and not the individual signs/symptoms. (e.g. upper 
respiratory tract infection, seasonal allergy, etc. instead of runny nose). 
AEs elicited by the investigator (or medically qualified designee) in a standard manner at the 
study visits should also be recorded in the AE section of the CRF and/or using the SAE form 
(subject to the classification of the AE). Care will be taken not to introduce bias when 
questioning a subject about any changes in their health. Open-ended and non-leading verbal 
questioning should be used. 
10.4.1 
Reporting of an Adverse Event 
All AEs will be reported on the AE page of the CRF by the investigator or site staff. It should 
be noted that the form for collection of SAE information is not the same as the AE CRF. Where 
the same data are collected, the AE CRF page and the SAE form must be completed in a 
consistent manner.  For example, the same AE term should be used on both. AEs should be 
reported using concise medical terminology on the CRF as well as on the form for collection of 
SAE information. 
10.4.2 
Reporting of a Serious Adverse Event 
In addition to recording the details of each AE on the AE CRF page, an SAE form should be 
completed, as fully as possible. Hard copies of the ‘paper’ SAE form will be provided in the 
investigator study master file. Original SAE forms will be retained in the investigator study 
master file. 
It is essential to enter the following information:  
x Protocol and subject identifiers 
x Subject demography 
x Description of events, with diagnosis if available 
x Investigator opinion of relationship to study product (or study procedure, if appropriate) 
x Criterion for seriousness. 
The following are desirable and are of particular relevance for investigator and GSK CH 
assessment of the SAE report: 
x Date of onset of AE  
x Date AE stopped, if relevant 
x Study product start date 
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x Study product end date if relevant 
x Action taken in relation to the study product 
x Outcome if known 
The SAE form, completed as fully as possible, must be scanned and e-mailed to the Case 
Management Group mailbox 
, with copy to the appropriate 
CH Study Manager, with the study number and subject number in the subject line of the email 
immediately and under no circumstance should this exceed 24 hours after study site 
personnel learn of the event. The investigator will submit any updated SAE data to the sponsor, 
immediately and under no circumstance should this exceed 24 hours of it being available.  
The initial report will be followed up with more information as relevant, or as requested by the 
CH study manager. 
The CH Study Manager will be responsible for forwarding the SAE form to other CH personnel 
as appropriate. 
. 
10.5 
Evaluating Adverse Events  
10.5.1 
Assessment of Intensity 
The investigator or medically qualified designee will make an assessment of intensity for each 
AE reported during the study and will assign it to one of the following categories: 
x Mild: An event that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities. 
x Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities 
x Severe: An event that prevents normal everyday activities.  
NOTE: An AE that is assessed as severe should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event; and both non-serious AEs and SAEs can 
be assessed as severe. For example, a headache may be severe (interferes significantly with the 
subject's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs, listed above. An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe. 
10.5.2 
Assessment of Causality 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.  
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For each AE (serious and non-serious), the investigator (or medically qualified designee) must 
provide an assessment of causality on the AE CRF page and the SAE form (subject to the 
classification of the AE). The investigator will also document in the medical notes that he/she 
has reviewed the AE and assessed causality, where applicable.  
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
Generally, the facts (evidence) or arguments to suggest a causal relationship should be provided. 
The investigator will use clinical judgment to determine the relationship and will also consult 
the approved US Drug Facts Label for the reference product Advil PM Liqui-Gels, in the 
determination of his/her assessment. Alternative causes, such as underlying disease(s), 
concomitant therapy, other risk factors, and the temporal relationship of the event to the study 
product will be considered and investigated. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious); the investigator must record the causal relationship in the CRF, as appropriate, and 
report such an assessment in accordance with the SAE reporting requirements if applicable. 
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 CH. The investigator may change his/her opinion of 
causality in light of follow-up information and send an SAE follow-up report with the updated 
causality assessment.  
10.6 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow up with each 
subject and provide further information on the subject’s condition. 
All AEs (serious and non-serious) 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 CH to elucidate 
as fully as possible the nature and/or causality of the AE. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals. 
New or updated information will be recorded on the AE CRF page and on the SAE form (subject 
to the classification of the AE). 
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The investigator will submit any updated SAE data to GSK CH within 24 hours of receipt of 
the information. 
Investigators are not obliged to actively seek AEs in former subjects. However, if the 
investigator learns of a SAE, including death, at any time after a subject has been discharged 
from the study, and considers the event reasonably related to the study product or study 
participation, the investigator will promptly notify GSK CH by emailing the information to the 
Case Management Group mailbox 
, with copy to the 
appropriate  CH Study Manager. 
 
The investigator will submit any updated SAE data to GSK CH within the designated reporting 
time frames. 
10.7 
Withdrawal Due to an Adverse Event  
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, according 
to the definition of an AE noted earlier, and recorded on the appropriate AE CRF page.  
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined. 
10.8 
Regulatory Reporting Requirements for SAEs 
GSK CH has a legal responsibility to notify, as appropriate, the local regulatory authority and 
other regulatory authorities about the safety of a product under clinical investigation.  Prompt 
notification of SAEs by the investigator to GSK CH is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects are met. 
GSK CH will comply with country specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/EC and investigators. 
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements  
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSAR) according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information e.g. summary or listing of SAE from the sponsor will review and then file it 
along with the Investigator’s Brochure in the investigator study master file, and will notify the 
IRB/IEC, if appropriate according to local requirements. 
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10.9 
Pregnancy 
10.9.1 
Time Period for Collecting Pregnancy Information 
Pregnancy information will be collected on all pregnancies reported while a female subject is 
participating in the study from the signing of informed consent until 5 days after last 
administration of study product. 
10.9.2 
Action to be Taken if Pregnancy Occurs 
The investigator will record pregnancy information on the appropriate form scan and e-mail it 
to the Case Management Group mailbox 
, with copy to the 
appropriate CH Study Manager.  Original pregnancy information forms will be retained in the 
investigator study master file.  
The subject will be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and infant / neonate (including concomitant medications taken by the 
mother during the pregnancy) will be forwarded by the investigator to the Case Management 
Group mailbox 
 with copy to the appropriate CH Study 
Manager. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, abnormal pregnancy outcomes 
(e.g. spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are, 
and should be recorded as an SAE. 
Any female subject who becomes pregnant while participating will be withdrawn from the study. 
10.10 
Medical Device Incidents 
The definitions and procedures detailed are in accordance with ISO 14155. 
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements. 
10.10.1 Definition of an Incident 
A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a subject/user/other 
person or to a serious deterioration in his/her state of health. 
Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such a 
result might have been due to other fortunate circumstances or to the intervention of health care 
personnel. 
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It is sufficient that: 
An incident associated with a device happened and 
x The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health. 
x A serious deterioration in state of health can include any of the following: 
x Life-threatening illness 
x Permanent impairment of body function or permanent damage to body structure 
x Condition necessitating medical or surgical intervention to prevent one of the 
above  
x Fetal distress, fetal death, or any congenital abnormality or birth defects 
Examples of incidents: 
x A subject, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse. 
x A subject’s study treatment is interrupted or compromised by a medical device failure. 
x A misdiagnosis due to medical device failure leads to inappropriate treatment. 
x A subject’s health deteriorates due to medical device failure. 
10.11 
Reporting of Incidents and Malfunctions 
All incidents must be reported to GSK CH immediately and under no circumstance should 
this exceed 24 hours of the investigator or designee becoming aware of the situation. 
Any medical device incident occurring during the study will be documented in the subject's 
medical records, if in accordance with the investigator's normal clinical practice, and on the 
appropriate Incident Report Form. In addition, for incidents fulfilling the definition of an AE 
(serious and non-serious), the appropriate AE CRF page and SAE form will be completed and 
reported as per the AE and SAE reporting sections. 
The Incident Report Form will be completed as thoroughly as possible and signed by the 
investigator before transmittal to GSK CH. It is very important that the investigator describes 
any corrective or remedial actions taken to prevent recurrence of the incident. 
The completed Incident Report Form should be scanned and emailed to the Case Management 
Group mailbox 
 with copy to the appropriate CH Study 
Manager with the study number and subject number in the subject line of the email immediately 
and under no circumstance should this exceed 24 hours after study site personnel learn of 
the event. If there is an SAE, the completed SAE form should be sent together with this report 
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form. However, if a copy of the SAE report is sent with this form, this does not replace the 
procedure to report an SAE. The original Incident Report Form will be retained in the 
investigator study master file.  
The initial report will be followed up with more information as relevant, or as requested by the 
GSK CH study manager. 
The investigator will follow the following directions regarding the reporting of a device failure 
(malfunction): 
x Notify GSK CH immediately (by following the process described above). 
x Schedule the subject to return to the site promptly to return the failed device. 
x Record any incidents on the CRF and Incident Report Form following instructions given 
in the section above. 
x For any incident/malfunction occurring with a medical device (including those that are 
part of combination products) supplied by GSK CH, return the failed device to the 
sponsor as soon as possible, including documentation of the details of the failure. 
x For any incident/malfunction occurring with a medical device (including those that are 
part of combination products) supplied by the investigator site, report the incident to the 
device manufacturer and follow the manufacturer instructions for the return of the failed 
device (whilst keeping GSK CH informed). 
10.12 
Follow-up of Medical Device Incidents 
Medical device incidents involving an AE will be followed and reported in the same manner as 
other AEs. This applies to all subjects, including those who discontinue study product or are 
withdrawn from the study. 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident. 
New or updated information will be recorded on the originally completed Incident Report form 
with all changes signed and dated by the investigator. 
10.13 
Regulatory Reporting Requirements for Medical Device Incidents 
To fulfill regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction that 
occur during all periods of the study in which the medical device is used.  
The investigator will promptly report all incidents occurring with any medical device provided 
for use in the study in order for the sponsor to fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to medical 
devices being used in clinical studies. 
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The investigator, or responsible person according to local requirements (e.g. the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of incidents to the IRB/IEC. 
11 
DATA MANAGEMENT 
As used in this protocol, the term CRF is understood to refer to either a paper form or an 
electronic data record or both, depending on the data collection method.  
For this study, subject data will be entered into an electronic CRF (eCRF), using a validated 
system. Data relating to SAEs, pregnancy and incidents will also be collected on paper forms. 
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
The source documents (e.g. hospital records, clinical and office charts, laboratory notes, 
memoranda, subject diaries, questionnaires, evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files and records kept at the pharmacy, at the laboratory and at 
the medico-technical departments involved in the clinical study) which contain the source of 
data recorded in the CRF should be specified. The CRF can be used as a source document at 
the discretion of data management. 
Each subject will be assigned and identified by a unique Subject Number. Any reference made 
to an individual subject within the study must be done using their unique Subject Number. 
11.1 
Case Report Form 
A CRF is a printed, optical, or electronic document designed to record the protocol required 
information to be reported to the sponsor on each trial subject. 
For each subject who has given informed consent/assent the CRF must be completed and signed 
by the Principal Investigator (or authorized designee) to certify that the data are complete and 
correct.  The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Management of clinical data will be performed in accordance with 
 applicable 
standards and data cleaning procedures with oversight by GSK CH to ensure integrity of the 
data, for example, to remove errors and inconsistencies in the data.  
To protect the privacy of subjects, no Personally Identifiable Information (PII) (including the 
subject's name or initials or full birth date) is to be recorded in the CRF or as part of the query 
text. 
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All CRF pages should be completed during a subject assessment when the CRF has been 
designated as the source. Data that is sourced elsewhere should be entered into the CRF in an 
agreed upon timeframe between the investigator and Sponsor. 
GSK CH will obtain and retain all CRFs and associated study data as applicable at the 
completion of the study.  
11.2 
Data Handling 
Documentation of all data management activities should allow step-by-step retrospective 
assessment of data quality and study performance.  
Any changes or corrections to data will be performed in the Electronic Data Capture (EDC) 
System, and it will include rationale for changes. The EDC system has an audit trail, which will 
provide a complete record of the changes and corrections endorsed by the investigator. 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and any 
concomitant medications terms (if applicable) using WHO Drug Dictionary (WHO DD). 
11.2.1 
Data Queries 
Programmed edit checks will be generated automatically, as the data are being entered into the 
system. Reports and listings on the CRF data will also be run, in addition to the queries already 
programmed and generated by the system, to raise manual queries as needed for site 
clarification or correction. A query should be issued to update the verbatim towards a codable 
description.  
The study monitor will perform ongoing review of the CRFs in accordance with the monitoring 
plan, to confirm that data entered into the CRF by authorized site personnel are accurate, 
complete, and verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
Any queries will be generated in the EDC System to the investigator or designee, enabling the 
errors to be addressed in parallel with Data Management review. The study monitor can also 
run reports and listings on the CRFs, to raise manual queries as needed for site clarification or 
correction. 
11.3 
External Data  
External Data are subject data obtained externally to the CRF. These data are generated from 
laboratory instruments, computers or other sources and then transcribed into a file and format 
agreed upon by GSK CH to identify the subject and time point referenced in the CRF and/or 
protocol.  
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An agreed quality control process will be performed against the transcribed data to the source 
to ensure the accuracy of the transcription. The transcribed data is transmitted in an agreed upon 
format to GSK CH.  
Reconciliation will be performed between the transcribed data and the clinical database to 
ensure subject and time point referenced in the Clinical Database match before Clinical 
Database Freeze (locking of the database) can occur. 
12 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
12.1 
Sample Size Determination 
A sufficient number of subjects will be screened to randomize approximately 44 to ensure at 
least 37 evaluable subjects complete the entire study.  
Assuming the true bioavailability of Advil PM Liqui-Gels Minis is within 8.0% of Advil PM 
Liqui-Gels, a sample size of 37 subjects will provide at least 80% power to establish (using a 
one-sided alpha of 0.05) that the bioavailability of Advil PM Liqui-Gels Minis is within 80% 
and 125% of Advil PM Liqui-Gels for the log transformed AUC and Cmax parameters for both 
ibuprofen and diphenhydramine components. This assumes a variability (intra-subject 
coefficient of variation [CV%]) of
 for the log transformed Cmax for ibuprofen [the highest 
observed CV% out of the primary parameters in previous legacy GSK CH studies where Advil 
PM Liqui-Gels were a treatment arm 
and 
]. Considering a drop out or 
discontinuation rate of approximately 10%, a total of 44 subjects will need to be enrolled. 
12.2 
Populations for Analysis 
The screened population is defined as all subjects who were screened with the intentions to 
receive with the investigational product. 
The safety population is defined as all randomized subjects who receive at least one dose of 
study medication. 
The PK population is defined as all randomized subjects who have at least one post-dose PK 
value, and who have no major protocol deviations concerning PKs. 
The following PK analysis set is defined to address the PK objectives and further PK 
considerations within this study: 
x PK analysis set includes all subjects of the PK population who complete both 
treatment periods, and for which the relevant PK parameters (at least one AUC or 
Cmax) can be derived. Subjects with baseline concentration >5% of the individual Cmax 
for either period will be excluded from the PK analysis set. This analysis set will be 
used in summaries, the primary PK analysis, and the secondary PK analysis. 
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12.3 
Statistical Analyses 
Additional details of the proposed statistical analysis will be documented in the statistical 
reporting and analysis plan (SAP), which will be written following finalization of the protocol 
and prior to study analysis and finalized prior to database lock. This section is a summary of 
the planned statistical analyses of the most important endpoints including primary and key 
secondary endpoints. The SAP creation and statistical analysis will be performed by 
  
PK variables will be calculated by 
. 
All concentration and PK data will be listed. This includes any data for subjects who are not 
included in the analysis (e.g. subjects withdrawn from the study due to AEs). 
12.3.1 
Primary Analysis(es)  
Primary Pharmacokinetics Analysis Variables 
For ibuprofen and diphenhydramine, PK parameters will be derived using the actual sampling 
times after database lock and unblinding and are defined as follows: 
x Cmax: maximum observed post-dose concentration; obtained without interpolation. 
x AUC0-t: area under the plasma concentration versus time curve calculated from time 0 
to the last measurable sampling time point, t, computed using the linear trapezoidal 
rule. 
x AUC0-inf: area under the plasma concentration versus time curve calculated from time 
0 to infinity AUC0-inf = AUC0-t + C(lastȜz where C(last) is the concentration at the 
ODVWPHDVXUDEOHVDPSOLQJWLPHSRLQWDQGȜz is the terminal elimination rate constant. 
Statistical Methods: 
The BE between Advil PM Liqui-Gels Minis (test) and Advil PM Liqui-Gels (reference) under 
fasted conditions will be declared as per FDA requirements: 
x if the 90% CIs for the ratio of the geometric means of the primary PK parameters 
Cmax, AUC0-t, and AUC0-inf is between 80% and 125% for ibuprofen and 
diphenhydramine.  
For ibuprofen and diphenhydramine separately, a linear mixed effects model will be fit to the 
log-transformed PK parameters (AUC0-t, AUC0-inf, and Cmax), as the dependent variable, and 
treatment, sequence, and period as fixed effects. Subject nested within sequence will be a 
random effect. The treatment LSMs, difference between treatment LSMs, and 90% CI for the 
difference will be computed. The adjusted LSM and LSM difference with 90% CIs for the 
differences will be exponentiated to provide estimates of the adjusted treatment effects, ratio of 
adjusted geometric means (Test/Reference) and 90% CIs for the ratio. If all study subjects are 
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not recruited from the same enrollment pool and the study doses in more than one group, the 
statistical model may be modified to reflect the multigroup nature of the study. As noted above 
BE will be declared for a given parameter/analyte if the 90% 2-sided CI for the ratio is between 
80% and 125% for ibuprofen and diphenhydramine. 
12.3.2 
Secondary Analysis(es) 
Secondary Pharmacokinetics Analysis Variables 
To further assess the PK profiles of ibuprofen and diphenhydramine the following PK 
parameters will be derived also using actual sampling times:  
x Ȝz - terminal elimination rate constant computed as the negative of the slope of the 
regression line of ln (C(t)) on time. The regression should generally involve at least 
3 consecutive measurable concentrations that decrease over time excluding Cmax.  
x tmax - time of the maximum observed post-dose concentration. 
x t1/2 - elimination half-life computed as t1/2  OQȜz. 
x Vz/F - apparent volume of distribution calculated by the dose 
DGPLQLVWHUHGȜz x AUC0-inf) 
x Cl/F - apparent total clearance calculated by dose administered/ AUC0-inf 
Statistical Methods: 
7KH3.SDUDPHWHUVȜ]Wmax, t1/2, Vz/F, and Cl/F) will be summarized for each treatment and 
analyte using descriptive statistics same as for the primary PK parameters. 
12.3.3 
Safety Analysis(es) 
The assessment of safety will be based on the frequency and severity of treatment emergent 
AEs (TEAEs) i.e. AEs that are emergent or that worsen after the first study product (Test or 
Reference) administration. 
The incidence of TEAEs will be summarized by presenting, for each treatment, the number and 
percentage of subjects having any AE, any AE in each MedDRA System Organ Class (SOC) 
and having each individual AE. The subset of AEs suspected of a relationship to study drug will 
be presented in a similar manner. All TEAEs will be also tabulated by severity. Any other 
information collected (e.g. action taken, duration, outcome) will be listed. AEs will be assigned 
to the treatment administered immediately prior to the onset. AEs due to COVID-19, if any, 
will be listed and tabulated separately. 
Vital signs (blood pressure, pulse rate, respiratory rate, oral body temperature) data will be 
reviewed and summarized on an ongoing basis during the study, as applicable, to evaluate the 
safety of the subjects. Any clinical laboratory or vital signs abnormalities of potential concern 
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will be described. Safety data will be presented in a tabular format and summarized 
descriptively, where appropriate.  
Medical history and physical examination, as applicable, will be listed with abnormal values 
flagged.  
Laboratory data and ECGs collected at screening and used for inclusion/exclusion criteria will 
be considered source data, and will not be required to be reported, unless otherwise noted. 
12.3.4 
Ease of Swallowing  
On Day 1 of each period, immediately after dosing, the assessment of ͂ease of swallowing̓ 
will be done via one question with a categorical response (͆Do you agree or disagree that the 
product is Easy to swallow?͇) and one question with an ordinal response (͆Rank the ͂ease 
of swallowing̓of the product on the following scale from 1 to 5͇).  
Descriptive statistics for the categorical response will be summarized by n (frequency count) 
and percent, for each treatment, separately. Similarly, descriptive measures for the ordinal 
response will be summarized by a frequency distribution of treatment by response.   
In addition, descriptive statistics (n, mean, SD, Min, median, and Max) will be calculated for 
the ordinal response, for each treatment. 
12.3.5 
Exclusion of Data from Analysis  
Exclusion of any data from the analyses will be determined during a Blind Data Review (BDR) 
Meeting prior to database lock. Any reasons for exclusion from an analysis population will be 
listed, if applicable. 
Data from subjects who experience emesis during the study should be deleted from statistical 
analysis if vomiting occurs at or before 2 times median Tmax. Plasma concentration data from 
subjects who vomited during the study should be flagged and reported even though they were 
excluded from the analysis. 
12.3.6 
Demographic and Baseline Characteristics 
Baseline data, relevant screening data, and demographic characteristics will be summarized for 
all randomized subjects. 
12.3.7 
Study Drug/Product Compliance and Use of Other Therapies 
12.3.7.1 Study Drug/Product Compliance 
The number of subjects exposed to each treatment will be tabulated for the safety population. 
Treatment deviations for individual subjects will be listed and summarized.  
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12.3.7.2 Prior and Concomitant Medications 
Prior and concomitant medications will be listed for the safety population. 
12.3.8 
Handling of Dropouts and Missing Data  
All existing data for subjects who are dropouts from the study will be included in the PK 
statistical analysis. 
If any concentration data is missing or deviates from the planned time of collection, then the 
pharmacokineticist may calculate the PK parameters using the available data.  
0LVVLQJYDOXHVRIȜz FDQEHHVWLPDWHGIURPWKHVXEMHFW¶VPHDQȜz value from the other treatments. 
,IDȜz YDOXHFDQQRWEHFDOFXODWHGIURPWKHRWKHUWUHDWPHQWVWKHQWKHȜz will be obtained from 
the treatment mean value for subjects with non-PLVVLQJYDOXHVRIȜz in the period in which it is 
QRWDYDLODEOH7KLVHVWLPDWHGȜz FDQEHXVHGWRFDOFXODWHRWKHUȜz GHSHQGHQWYDULDEOHV7KLVȜz 
value derivation is only applied for pre-dose concentration adjustments. 
For ibuprofen and diphenhydramine concentrations: 
x Below the limit of quantification (BLOQ) values obtained before the first measurable 
concentration will be imputed as zero. 
x BLOQ values obtained after the first measurable concentration will be “Not 
detectable” (ND), which will be shown as missing (explanations will be specified in 
the footnote of TFLs). 
12.3.9 
Interim Analysis  
No interim analysis is planned for this study 
13 
STUDY GOVERNANCE CONSIDERATIONS 
13.1 
Quality Control  
In accordance with applicable regulations including GCP, and GSK CH procedures, GSK CH 
or designee (i.e. third-party vendor) 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 CH requirements. 
When reviewing data collection procedures, the discussion will include identification, 
agreement and documentation of data items for which the CRF will serve as the source 
document. 
GSK CH or designee will monitor the study and site activity to verify that the: 
x Data are authentic, accurate, and complete. 
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x Safety and rights of subjects are being protected. 
x Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements. 
The extent and nature of monitoring will be described in a written monitoring plan on file at 
GSK CH. The investigator (or designee) agrees to allow the monitor direct access to all relevant 
documents and agrees to co-operate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
13.2 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, GSK CH may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of the 
study.  
In the event of an assessment, audit or inspection, the investigator (and institution) must agree 
to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and 
to allocate their time and the time of their staff to discuss the conduct of the study, any 
findings/relevant issues and to implement any corrective and/or preventative actions to address 
any findings/issues identified. 
The investigator(s) will notify GSK CH or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with GSK CH 
or its agents to prepare the study site for the inspection and will allow GSK CH or its agent, 
whenever feasible, to be present during the inspection. The investigator will promptly apply 
copies of the inspection finding to GSK CH or its agent. Before response submission to the 
regulatory authority, the investigator will provide GSK CH or its agents with an opportunity to 
review and comment on responses to any such findings.  
The sponsor will be available to help investigators prepare for an inspection. 
13.3 
Regulatory and Ethical Considerations 
13.3.1 
Institutional Review Board/ Ethics Committee  
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, investigator brochure/safety statement 
(including any updates) and other relevant documents, e.g. recruitment advertisements, if 
applicable, from the IRB/EC. All correspondence with the IRB/EC should be retained in the 
investigator file. Copies of IRB/EC approvals should be forwarded to GSK CH prior to the 
initiation of the study, and also when subsequent amendments to the protocol are made. 
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The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the investigator must notify the IRB/EC and GSK CH in writing immediately after the 
implementation. 
13.3.2 
Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol and legal and regulatory 
requirements, as well as the general principles set forth in the International Ethical Guidelines 
for Biomedical Research Involving Human Subjects (Council for International Organizations 
of Medical Sciences 2002), International Ethical Guidelines for Health-Related Research 
Involving Humans (Council for International Organizations of Medical Sciences, 2016), 
guidelines for GCP (ICH 1996 and revision 2), and the Declaration of Helsinki (World Medical 
Association 2013).  
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 
13.3.3 
Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names or 
other identifiable data in any reports, publications, or other disclosures, except where required 
by laws.  
When study data are compiled for transfer to GSK CH and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by GSK CH in order to de-identify study subjects. The use of 
initials should be avoided.  
The study site will maintain a confidential list of subjects who participated in the study, linking 
each subject’s numerical code to his or her actual identity. In case of data transfer, GSK CH 
will maintain high standards of confidentiality and protection of subjects’ personal data 
consistent with applicable privacy laws. 
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws. 
The informed consent documents used during the informed consent process must be reviewed 
and approved by the sponsor, approved by the IRB/EC before use, and available for inspection. 
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation.  
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed. The investigator will 
retain the original of each subject's signed informed consent document. 
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13.3.4 
Subject Recruitment  
Advertisements approved by IRBs/ECs and investigator databases may be used as recruitment 
procedures. Use of ethics committee approved, generic, prescreening questionnaire to assess 
basic subject characteristics to determine general eligibility for this study is allowed. This 
generic questionnaire may be used by sites as a phone script and/or to review internal databases 
to identify subjects.   
GSK CH will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used.  
13.3.5 
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP  
Within GSK CH a serious breach is defined as a breach likely to affect to a significant degree 
the safety and rights of a subject or the reliability and robustness of the data generated in 
GSK CH-sponsored human subject research studies.  
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, GSK CH should be informed immediately.  
In addition, the investigator will inform GSK CH immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
13.4 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of subjects begins in accordance with applicable GSK CH processes. 
GSK intends to make anonymized subject-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help advance medical 
science or improve patient care. This helps ensure the data provided by trial participants are 
used to maximum effect in the creation of knowledge and understanding. 
13.5 
Provision of Study Results to Investigators 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the opportunity 
to review the complete study results at a GSK CH site or other mutually-agreeable location. 
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Clinical Protocol 
 
 
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GSK CH will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as appropriate. 
The procedures and timing for public disclosure of the results summary and for development of 
a manuscript for publication will be in accordance with GSK CH Policy. 
A manuscript will be progressed for publication in the scientific literature if the results provide 
important scientific or medical knowledge. 
13.6 
Records Retention 
Following closure of the study, the investigator must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and secure location.   
The records (study/ site master file) must be maintained to allow easy and timely retrieval, when 
needed (e.g. for a GSK CH audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 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 ensure 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. 
The investigator must assure that the subject’s anonymity will be maintained. On CRFs or other 
documents submitted to GSK CH, subjects should not be identified by their names or initials, 
but by an identification code. The investigator should keep a separate log of subjects’ codes, 
names and addresses. Documents not for submission to GSK CH, e.g. subjects’ written consent 
forms, should be maintained by the investigator in strict confidence. 
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the investigator as per the signed contractual agreement, from the issue of the final 
Clinical Study Report (CSR) or equivalent summary, unless local regulations or institutional 
policies require a longer retention period. 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, GSK CH standards/procedures, and/or institutional requirements.   
No study document should be destroyed without a prior written agreement between GSK CH 
and the investigator. The investigator must notify GSK CH 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 is no longer associated with the site. 
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13.7 
Conditions for Terminating the Study  
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or study product safety problems, or at the discretion of 
GSK CH. In addition, GSK CH retains the right to discontinue development of 
ibuprofen/diphenhydramine hydrochloride formulation at any time.  
If a study is prematurely terminated, GSK CH will promptly notify the investigator. After 
notification, the investigator must promptly contact all participating subjects and should assure 
appropriate therapy/ follow-up for the subjects.  As directed by GSK CH, all study materials 
must be collected and all CRF’s completed to the greatest extent possible. Where required by 
the applicable regulatory requirements, GSK CH should inform the regulatory authority(ies) 
and the investigator should promptly inform the IRB/EC and provide the IRB/EC a detailed 
written explanation of the termination or suspension.  
If the IRB/EC terminates or suspends its approval/favorable opinion of a trial, the investigator 
should promptly notify the GSK CH and provide GSK CH with a detailed written explanation 
of the termination or suspension. 
Upon completion or premature discontinuation of the study, the GSK CH monitor will conduct 
site closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations including GCP, and GSK CH Standard Operating Procedures. 
14 
REFERENCES 
1. Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28. Available 
on request 
2. ICH Topic E6 (R2) Guideline for Good Clinical Practice, Nov 2016. 
3. World Medical Association Declaration of Helsinki, 64th General Assembly, Fortaleza 
2013. 
4. [FDA Draft Guidance, Bioavailability and Bioequivalence Studies Submitted in NDAs or 
INDs— General Considerations March 2014] 
5. [FDA Draft Guidance, Bioavailability Studies Submitted in NDAs or INDs— General 
Considerations February 2019] 
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15 
APPENDICIES 
15.1 
ABBREVIATIONS 
The following is a list of abbreviations that may be used in the protocol. 
Table 15-1 
Abbreviations 
 
Abbreviation 
Term 
Ȝz 
terminal elimination rate constant 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AMIS 
analytical methodology information sheet 
AST 
aspartate transaminase 
AUC 
area under the curve 
AUC0-t 
area under the plasma concentration versus time curve calculated from time 
0 to the last measurable sampling time point, t 
AUCinf 
area under the plasma concentration versus time curve calculated from time 
0 to infinity 
BDR 
blinded data review 
BE 
bioequivalence 
BLOQ 
below the limit of quantification 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
BUN 
blood urea nitrogen 
CI 
confidence interval 
Cl/F 
apparent total clearance 
Cmax 
maximum observed post-dose concentration 
COX 
cyclooxygenase 
CPL 
clinical project lead 
CRF 
case report form 
CRO 
contract research organization 
CSR 
clinical study report 
CV 
coefficient of variation 
CYP 
cytochrome P450 
EC 
ethics committee 
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Abbreviation 
Term 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
electronic data capture 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration (United States) 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
GSK CH 
GlaxoSmithKline Consumer Healthcare 
HBc-Ab 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV-Ab 
hepatitis C virus antibodies 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G  
IgM 
immunoglobulin M  
IND 
Investigational New Drug 
IRB 
institutional review board 
IUD 
intrauterine device 
K2EDTA 
dipotassium ethylene diamine tetraacetic acid 
LSM 
least-squares mean 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDMA 
3,4- methylenedioxymethamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
N/A 
not applicable 
ND 
not detectable 
NSAID 
nonsteroidal anti-inflammatory drug 
OT 
oral body temperature 
OTC 
over-the-counter 
PCP 
phencyclidine 
PII 
personally identifiable information 
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Abbreviation 
Term 
PK 
pharmacokinetic(s) 
PR 
pulse rate 
QTcF 
Fridericia’s corrected QT interval 
RBC 
red blood cell 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical reporting and analysis plan 
SOC 
system organ class 
SOP 
standard operating procedure 
SRSD 
single reference study document 
SUSAR 
suspected unexpected serious adverse reactions 
t1/2 
elimination half-life 
TEAE 
treatment emergent adverse event 
TFL 
tables, figures, and listings 
THC 
tetrahydrocannabinol 
tmax 
time of the maximum observed post-dose concentration 
ULN 
upper limit of normal 
UK 
United Kingdom 
USA 
United States of America 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
WHO 
World Health Organization 
WHO DD 
WHO drug dictionary 
 
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SAP_001.pdf: 
GSK Consumer Healthcare 
Clinical Study Report 
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16.1.9 
Documentation of Statistical Methods 
Table of contents 
16.1.9 
Documentation of Statistical Methods .................................................... 1 
Table of contents ................................................................................................................. 1 
Statistical Analysis Plan Version Final 1.0 dated 22-MAR-2023 ....................................... 2 
Table/Figure/Listing Shells Version Final 1.0 dated 22-MAR-2023 ................................3 
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GSK Consumer Healthcare 
 
Clinical Study Report 
 
 
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Statistical Analysis Plan Version Final 1.0 dated 22-MAR-2023 
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This document is confidential. 
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Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 1 of 28 
 
Statistical Analysis Plan for Interventional Studies (Early Phase) 
 
 
Sponsor Name: GlaxoSmithKline Consumer Healthcare (GSK CH) 
 
Protocol Number: 218677 
 
Protocol Title: A Randomized, Open label, Single Center, Single Dose, Two Treatment, Two 
Period, Two Sequence Crossover Bioequivalence Study of Advil PM Liqui-Gels Minis 
(ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg) To Advil PM Liqui-Gels 
(ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg) in Healthy Adult Subjects Under 
Fasted Conditions 
 
Protocol Version and Date: Amendment 2, 30-Nov-2022 
 
Project Code: 222003 
 
Authors:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to GSK CH. Acceptance of this 
document constitutes agreement by the recipient that no information contained herein will be published or 
disclosed without prior written authorization from an official of GSK CH. However, this document may 
be disclosed to appropriate Institutional Review Board and ethics committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, 
 should be 
notified promptly. 
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Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 2 of 28 
Revision History 
Version 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
0.1 
14-Feb-2023 
Initial Draft 
1.0 
22-Mar-2023 
Incorporation of medical writer 
input 
 
PPD
PPD


Statistical Analysis Plan for Interventional Studies (Early Phase)
Sponsor: GSK CH; Protocol: 218677
This document is confidential.
SAP Version: Final 1.0 22-Mar-2023
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019
Filing requirements: TMF
Page 3 of 28
Approvals 
I confirm that I have reviewed this document and agree with the content.
Approval
Name, Title
Signature
Date 
(DD-Mmm-YYYY)
Name, Title
Signature
Date 
(DD-Mmm-YYYY)
Name, Title
Signature
Date 
(DD-Mmm-YYYY)
Name, Title
Signature
Date 
(DD-Mmm-YYYY)
GSK CH Approval
Name, Title
Signature
Date 
(DD-Mmm-YYYY)
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Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 4 of 28 
Table of Contents 
Revision History .......................................................................................................................2 
Approvals ..................................................................................................................................3 
Table of Contents ......................................................................................................................4 
1.
Glossary of Abbreviations ........................................................................................................6 
2.
Purpose .....................................................................................................................................8 
2.1 Responsibilities ....................................................................................................................8 
2.2 Timings of Analyses ............................................................................................................8 
3.
Study Objectives .......................................................................................................................9 
4.
Study Description .....................................................................................................................9 
4.1 Subject Selection .................................................................................................................9 
4.2 Determination of Sample Size .............................................................................................9 
4.3 Treatment Assignment .......................................................................................................10 
4.4 Randomization ...................................................................................................................10 
4.5 Blinding .............................................................................................................................10 
4.6 Subject Withdrawal and Replacement ...............................................................................11 
5.
Endpoints ................................................................................................................................12 
6.
Analysis Populations ..............................................................................................................12 
6.1 Screened Population ..........................................................................................................12 
6.2 Safety Population ...............................................................................................................12 
6.3 PK Population ....................................................................................................................13 
6.4 PK Analysis Set .................................................................................................................13 
7.
General Aspects for Statistical Analysis .................................................................................13 
7.1 General Methods ................................................................................................................13 
7.2 Summary Statistics: ...........................................................................................................13 
7.3 Key Definitions ..................................................................................................................14 
7.4 Missing Data ......................................................................................................................15 
8.
Study Population .....................................................................................................................16 
8.1 Subject Disposition ............................................................................................................16 
8.2 Protocol Deviations ...........................................................................................................16 
8.3 Inclusion and Exclusion Criteria .......................................................................................16 
8.4 Demographics and Other Baseline Characteristics ...........................................................16 
8.5 Medical History .................................................................................................................17 
8.6 Medications .......................................................................................................................17 
8.7 Drug, Cotinine, and Alcohol Screens ................................................................................17 
8.8 Pregnancy Screening .........................................................................................................17 
8.9 Additional Screening Tests ................................................................................................17 
8.10 Study Drug Administration .............................................................................................17 
9.
PK Analyses ............................................................................................................................18 
9.1 Handling of Concentrations Below the Lower Limit of Quantification (BLOQ), No 
Reportable Concentration Values, and Missing Data ................................................................18 
9.2 Handling of the Difference between the Scheduled and the Actual Sampling Times ......18 
9.3 PK Sampling Schedule ......................................................................................................18 
9.4 PK Parameters ...................................................................................................................19 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 5 of 28 
9.5 Statistical Analysis ............................................................................................................20 
9.6 Bioequivalence Assessment ..............................................................................................20 
10. 
Safety...................................................................................................................................21 
10.1 Adverse Events (AEs) .....................................................................................................21 
10.2 Clinical Laboratory Evaluations ......................................................................................22 
10.3 Vital Signs .......................................................................................................................23 
10.4 Physical Examination ......................................................................................................23 
11. 
Acceptability .......................................................................................................................23 
12. 
Changes from Analysis Planned in the Protocol .................................................................23 
13. 
Programming Considerations ..............................................................................................23 
13.1 General Considerations ....................................................................................................24 
13.2 Table, Listing, and Figure Format ...................................................................................24 
13.2.1 General ......................................................................................................................24 
13.2.2 Headers and Footers ..................................................................................................24 
13.2.3 Display Titles ............................................................................................................25 
13.2.4 Column and Row Headings ......................................................................................25 
13.2.5 Body of the Data Display ..........................................................................................25 
13.2.6 Footnotes ...................................................................................................................27 
14. 
Quality Control ...................................................................................................................27 
15. 
Reference List .....................................................................................................................28 
 
 
 
 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 6 of 28 
1. Glossary of Abbreviations 
Abbreviation 
Description 
z 
terminal elimination rate constant 
z Lower 
timepoint where ln-linear terminal elimination rate constant calculation 
begins 
z Upper 
actual sampling time of the last measurable concentration used to estimate 
the terminal elimination rate constant  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
AST 
aspartate transaminase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the concentration-time curve 
AUC0-inf 
area under the plasma concentration versus time curve calculated from 
time zero to infinity 
AUC0-t 
area under the plasma concentration versus time curve calculated from 
time zero to the last measurable sampling time point 
BDR 
blind data review 
BLOQ 
below the limit of quantification  
BMI 
body mass index 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cl/F 
apparent total clearance 
Cmax 
maximum observed concentration 
CRF 
case report form 
C(t) 
concentration at the last measurable sampling time point 
CV 
coefficient of variation 
ECG  
electrocardiogram 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GGT 
gamma-glutamyl transpeptidase 
GSK CH 
GlaxoSmithKline Consumer Healthcare 
HBc-Ab 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCV-Ab 
hepatitis C virus antibodies 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
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This document is confidential. 
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Abbreviation 
Description 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
ln 
natural logarithm 
LSM 
least-squares mean 
max 
maximum 
MCH 
mean cell hemoglobin 
MCHC 
mean cell hemoglobin concentration 
MCV 
mean cell volume 
MedDRA® 
Medical Dictionary for Regulatory Activities 
min 
minimum 
N 
number of subjects 
n 
number of observations 
N/A 
not applicable 
OT 
oral body temperature 
PK 
pharmacokinetic(s) 
PT 
preferred term 
P-value 
probability value 
R2 
R-squared 
RBC 
red blood cell 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SOP 
standard operating procedure 
t1/2 
elimination half-life 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
tmax 
time of maximum observed concentration 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
WHO DD 
World Health Organization Drug Dictionary 
 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
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2. Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary 
tables, and figures which will be produced, and the statistical methodologies that will be used, 
are complete and appropriate to allow valid conclusions regarding the study objectives. 
This SAP is based on the following documents: 
Protocol 218677 Amendment 2, dated 30-Nov-2022 
Case Report Form (CRF) version 0.38, dated 13-Dec-2022 
The plan may change due to unforeseen circumstances; any changes made after the plan has been 
finalized will be documented. No revision to the SAP is required for changes which do not affect 
the statistical analysis methods, definitions, or rules defined in this document. If additional 
analyses are required to supplement the planned analyses described in the SAP, the changes and 
justification for the changes will be outlined in the associated clinical study report. No change 
will be made without prior approval of the Sponsor. 
When applicable, all methodologies and related processes will be conducted according to 
 
standard operating procedures (SOPs) as appropriate. Shells for all statistical tables, 
listings, and figures referred to in this SAP will be presented in a separate document. 
2.1 
Responsibilities 
 will perform the statistical analyses and are responsible for the production and 
quality control of all tables, figures, and listings (TFLs).  
2.2 
Timings of Analyses 
No Interim analysis is planned for this study. 
Dry-run Analysis: 
A Dry-run analysis is planned for this study using dummy or available data before database 
softlock. This dry-run analysis will include a set of all unique tables, figures, and listings and are 
denoted in the accompanying SAP Shells.  
Blinded Data Review (BDR): 
After completion of database softlock, a BDR will be conducted. The details of the BDR will be 
compiled in a separate document. The purpose of the BDR is to assign the study populations 
outlined in Section 6 of this SAP. As this study is open-label
that the population determination will be done without respect to treatment.  
Topline TLFs: 
After completion of database hardlock, a subset of all TLFs will be generated intended to 
identify key results of the study (i.e. bioequivalence and safety). Please refer to the SAP shell 
document for more details.  
Final Analysis: 
The final analysis of safety and PK is planned to be completed after completion of Topline TLFs. 
The final analysis will include the Topline TLF. 
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Statistical Analysis Plan for Interventional Studies (Early Phase) 
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3. Study Objectives 
Primary objective: 
o
Demonstrate the bioequivalence of Advil PM Liqui-Gels Minis (Test) compared 
to Advil PM Liqui-Gels (Reference) 
Secondary objectives: 
o
Assess the PK profile 
o
Assess subject acceptability of each of the two products 
o
Assess the safety profile 
 
4. Study Description  
This is a single center, single dose, open-label, randomized, two-treatment, two-sequence, 
two-period crossover, bioequivalence study in healthy adult subjects with at least a 7-day 
washout period.  
Subjects will be randomly assigned to one of two treatment sequences and receive a single dose 
of one of the following treatments in each period, following a crossover design:  
Treatment A: 
2X 
Advil 
PM 
Liqui-Gels 
Minis; 
(ibuprofen/diphenhydramine 
hydrochloride 200mg/25mg) (Test) 
Treatment B: 2X Advil PM Liqui-Gels; (ibuprofen/diphenhydramine hydrochloride 
200mg/25mg) (Reference) 
The study is intended to dose in more than one group; all groups will be dosed at the same 
clinical site and the same protocol requirements and procedures will be followed within each 
group. For each subject, the duration of study participation is 38 days with up to 3 days confined 
in each period (total of up to 6 days confined). 
4.1 
Subject Selection 
Healthy, non-smoking, male and female adult volunteers, aged 18 to 55 years, with body mass 
index (BMI) 18.5 to 30.0 kg/m2, will be enrolled in this study. Detail of all the inclusion and 
exclusion criteria may be found in study protocol, Sections 5.2 and 5.3.  
4.2 
Determination of Sample Size 
A sufficient number of subjects will be screened to randomize approximately 44 to ensure at 
least 37 evaluable subjects complete the entire study.  
 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
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This document is confidential. 
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Assuming the true bioavailability of Advil PM Liqui-Gels Minis is within 8.0% of Advil PM 
Liqui-Gels, a sample size of 37 subjects will provide at least 80% power to establish (using a 
one-sided alpha of 0.05) that the bioavailability of Advil PM Liqui-Gels Minis is within 80% and 
125% of Advil PM Liqui-Gels for the log transformed area under the curve (AUC) and 
maximum observed post-dose concentration (Cmax) parameters for both ibuprofen and 
diphenhydramine components. This assumes a variability (intra-subject coefficient of variation 
[CV%]) of 25% for the log transformed Cmax for ibuprofen (the highest observed CV% out of the 
primary parameters in previous legacy GSK CH studies where Advil PM Liqui-Gels were a 
treatment arm). Considering a drop out or discontinuation rate of approximately 10%, a total of 
44 subjects will need to be enrolled. 
4.3 
Treatment Assignment 
Subjects enrolled in this study will be randomized to sequence AB or sequence BA. On Day 1 of 
each period, subjects will receive either Treatment A or Treatment B, under fasting conditions, 
according to the assigned sequence.  
Reference the table below. 
Sequence Treatment Period 1, Day 1 
Treatment Period 2, Day 1 
AB 
Treatment A (Test):  
2X Advil PM Liqui-Gels Minis 
Treatment B (Reference):  
2X Advil PM Liqui-Gels 
BA 
Treatment B (Reference):  
2X Advil PM Liqui-Gels 
Treatment A (Test):  
2X Advil PM Liqui-Gels Minis 
4.4 
Randomization  
Randomization schedules will be generated by 
 through SAS® for Windows 
software, prior to start of the study using block randomization. An unblinded statistician not 
directly involved in the study will generate the final randomization.  
 will provide the final randomization schedule to the investigator and, in 
accordance with the randomization numbers and treatment allocations, the subject will receive 
the study treatment sequence assigned to the corresponding randomization number. 
Randomization will occur prior to first dosing. Subjects will be randomized into the study 
provided they have satisfied all subject selection criteria.  
4.5 
Blinding 
This will be an open-label study. Blinding is not considered essential as study measurements 
(plasma ibuprofen and diphenhydramine concentrations) are biological. Treatments will be 
provided in an open-label manner. However, the analytical laboratory will remain blinded to 
treatment during the analysis of the plasma samples. Additionally, as the data review for the 
determination of the populations will be done without respect to treatment, the study statistician 
and pharmacokineticist participating in the BDR meeting will remain blinded to treatment.  
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Statistical Analysis Plan for Interventional Studies (Early Phase) 
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4.6 
Subject Withdrawal and Replacement 
A subject may withdraw from the study at any time at his or her own request or may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral 
reasons, major non-compliance with protocol requirements, or the inability of the subject to 
comply with the protocol-required schedule of study visits or procedures. The following 
circumstances require discontinuation of study product and/or premature subject withdrawal: 
 
Positive test for COVID-19, conducted during the study, at times deemed necessary by 
Investigator 
Pregnancy 
Withdrawal of informed consent 
Subject lost to follow-up 
If a subject is discontinued or prematurely withdraws from the study, the reason(s) for 
discontinuation or withdrawal and the associated date must be documented in the relevant 
section(s) of the CRF. Withdrawal due to AEs should be distinguished from withdrawal due to 
other causes, according to the definition of an AE noted earlier, and recorded on the appropriate 
AE CRF page. 
 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
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This document is confidential. 
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5. Endpoints 
Primary endpoints: 
o
The maximum observed post-dose concentration (Cmax) for ibuprofen and 
diphenhydramine 
o
The area under the plasma concentration versus time curve calculated from time 
zero to the last measurable sampling time point (AUC0-t) for ibuprofen and 
diphenhydramine  
o
The area under the plasma concentration versus time curve calculated from time 
zero to infinity (AUC0-inf) for ibuprofen and diphenhydramine 
Secondary endpoints: 
o
The terminal elimination rate constant ( z) for ibuprofen and diphenhydramine 
o
The time of the maximum observed post-dose concentration (tmax) for ibuprofen 
and diphenhydramine 
o
The elimination half-life (t1/2) for ibuprofen and diphenhydramine 
o
Apparent volume of distribution (Vz/F) for ibuprofen and diphenhydramine 
o
Apparent total clearance (Cl/F) for ibuprofen and diphenhydramine 
o
Ease of swallowing (5-point ordinal scale) 
o
Monitoring and recording of adverse events (AEs)  
o
Physical examination 
o
Vital signs  
o
Laboratory tests 
 
6. Analysis Populations 
Exclusion of any data from the analyses will be determined during a blind data review (BDR) 
meeting, prior to database lock. 
population, along with reasons for exclusions, will be presented by subject in a data listing. 
6.1 
Screened Population 
The screened population is defined as all subjects who were screened with the intentions to 
receive the investigational product. The screened population will be used for listings that include 
screen failure subjects and/or eligible subjects who were not randomized and for the assignment 
to analysis populations. 
6.2 
Safety Population 
The safety population is defined as all randomized subjects who receive at least one dose of 
study medication. The safety population will be used for all safety summaries and analyses. The 
safety population will also be used for all listings, unless otherwise specified.  


Statistical Analysis Plan for Interventional Studies (Early Phase) 
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6.3 
PK Population 
The PK population is defined as all randomized subjects who have at least one post-dose PK 
value, and who have no major protocol deviations concerning PK. PK population will be used 
for all PK concentration listings. 
6.4 
PK Analysis Set 
The PK analysis set is defined to address the PK objectives and further PK considerations within 
this study. The PK analysis set includes all subjects of the PK population who complete both 
treatment periods, and for which the relevant PK parameters (at least one AUC or Cmax) can be 
derived. Subjects with baseline concentration >5% of the individual Cmax for either period will be 
excluded from the PK analysis set. This analysis set will be used in summaries, the primary PK 
analysis, and the secondary PK analysis. 
Data from subjects who experience emesis during the study should be deleted from statistical 
analysis if vomiting occurs at or before 2 times median Tmax. Plasma concentration data from 
subjects who vomited during the study should be flagged and reported even though they were 
excluded from the analysis. 
 
7. General Aspects for Statistical Analysis 
7.1 
General Methods 
SAS for Windows software will be used to perform all statistical analyses. Unless otherwise 
stated, all listings will be sorted by treatment group, subject number, and assessment date/time. 
The following labels for treatment will be used on all tabulations where the results are displayed 
by treatment, in the following order: 
Advil PM Liqui-Gels Minis (Test) [A] 
Advil PM Liqui-Gels (Reference) [B]  
 
7.2 
Summary Statistics: 
Unless otherwise stated, continuous variables will be summarized using the number of 
observations (n), and the statistics arithmetic mean, standard deviation (SD), geometric mean, 
coefficient of variation (CV%), median, minimum, and maximum. The minimum and maximum 
values will be presented to the same number of decimal places as recorded in the CRF, 
arithmetic mean and median will be presented to one more decimal place than the raw data and 
the SD will be presented to two more decimal places than the raw data. Categorical variables will 
be summarized with frequency counts and percentages. Percentages (other than PK parameters) 
will be rounded to one decimal place, with the denominator being the number of subjects in the 
relevant population, unless otherwise stated. 
For the plasma PK data, the data will be rounded to two decimal places in the listings. The 
following rules will be applied to following situations: 
z data: Presentation of data in listings and calculated means (arithmetic and geometric), 
minimum, and maximum - rounded off to 4 decimal digits. Calculated SD will be 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
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Page 14 of 28 
presented to 5 decimal places.  
Pharmacokinetic parameters related to time such as Tmax, 
z Lower, and 
z Upper must be 
reported with the same precision as the actual sampling time: rounded off to 3 decimal 
digits. This applies to presentation in listings and calculated means (arithmetic and 
geometric), minimum, and maximum. SD will be presented to 4 decimal places. 
Concentration data as well as Cmax: reported as they appear in the corresponding dataset. 
Note: these rules are only intended as a guide and may be changed based on available data for 
the study and are not meant to override the number of decimal places in the data used as input for 
analysis. The full unrounded precision will be used for all calculation prior to rounding for 
display as applicable. 
Summary statistics including the geometric mean will be displayed to the same number of 
decimal places as the arithmetic mean and the coefficient of variation (CV) (%) will be rounded 
to 1 decimal place.  
Only data from nominal protocol scheduled visits will be included in the summary tables. Data 
from unscheduled visits will not be included in the summary tables but will be included in the 
listings. 
All assessments will be presented in the listings. 
7.3 
Key Definitions 
Baseline: 
Unless stated otherwise, baseline will be defined for each subject and will be defined as the last 
non-missing measurement (including repeated and unscheduled assessments) obtained prior to 
the first study drug administration. Post baseline will be considered as all measurements 
collected after study drug administration. Unknown , Not Done , Not Applicable , and other 
classifications of missing data will not be considered when calculating baseline observations 
unless the finding is a valid categorical observation. 
Study day: 
Study day will be calculated using first study drug administration (either test or reference) date 
as the reference date. If the date of interest occurs on or after the first study drug administration 
date, study day will be calculated as (date of interest  first study drug administration date) + 1. 
If the date of interest occurs prior to the first study drug administration date, study day will be 
calculated as (date of interest  first study drug administration date). There will be no study day 
0. 
Prior medication: 
Medication/treatments, including prescription and non-prescription drugs, dietary supplements, 
and herbal remedies, taken within 90 days prior to signing the informed consent form will be 
documented as a prior medication/treatment. 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
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Concomitant medication: 
Medications/treatments taken after the first dose will be documented as concomitant 
medication/treatments. 
Treatment: 
Treatment is assigned as the last received treatment, except in the case of pre-dose 
measurements. Any non-adverse event assessment occurring on the same calendar date as a 
given treatment before dosing would be attributed to the same treatment given on that calendar 
day. If no treatment was applied on the same calendar day, then any measurements pre-dose will 
not be summarized by treatment. Adverse events will be summarized only by the last received 
treatment.  
7.4 
Missing Data 
There will be no imputation for missing data, unless otherwise specified. Missing data shall be 
presented in 
-  (unknown or not evaluated) or 
 (not applicable), 
with the corresponding definition in the footnotes. Missing descriptive statistics, or probability 
values (p-values), which cannot be estimated shall be presented 
-  
For inclusion in concomitant medication and AE tables, incomplete start and stop dates on the 
CRF will be imputed as follows: 
If the stop date is incomplete, the following rules will be applied: 
o
Missing day: Assume the last day of the month 
o
Missing day and month: Assume the last day of the year 
o
Missing day, month, and year: Assume that the event/medication is continuing 
o
In the case of the death of a subject, and if the imputed end date is after the date of 
death, the end date will be imputed as the date of death. 
If the stop date is incomplete, imputed end date will be used instead of reported end date. 
If the start date is incomplete, the following rules will be applied: 
o
Missing day: Assume the first day of the month; however, if the partial date and 
the date of first study drug administration lie within the same month and year and 
the date of first study drug administration is not after the stop date of the 
event/medication, set to the date of study drug administration. Otherwise, set to 
the stop date of the event/medication. 
o
Missing day and month: Assume January 1st; however, if the partial date and the 
date of first study drug administration lie within the same year and the date of first 
study drug administration is not after the stop date of the event/medication, set to 
the date of first study drug administration. Otherwise, set the to stop date of the 
event/medication. 
o
Missing day, month, and year: Assume date of first study drug administration if it 
is not after the stop date for the event/medication. Otherwise, set the to stop date 
for the event/medication. 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
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Page 16 of 28 
In the case of withdrawal of consent, all data from subjects who withdraw from the study will be 
included in all safety summaries up to the time of withdrawal. For all other withdrawals, all data 
captured will be included in the safety summaries. 
For PK analysis, only observed concentration data will be used in the data analysis except for 
concentration values below the limit of quantification (BLOQ); reference Section 9.1. Missing 
z 
z 
z 
z will be obtained from the 
treatment mean value for subjects with non-
z in the period in which it is not 
available. This estimated 
z 
z 
z value 
derivation is only applied for pre-dose concentration adjustments if applicable. 
 
8. Study Population 
8.1 
Subject Disposition 
The number of subjects who were screened, enrolled, randomized, not randomized (along with 
reasons), entered each period, completed each period, did not complete each period (along with 
reasons), will be presented by sequence and overall (frequency and the percentage of subjects) 
for the screened population, and presented by subject in a data listing. 
8.2 
Protocol Deviations 
Subject data will be examined for evidence of protocol deviations. All protocol deviations will 
be categorized and presented by subject for the randomized population in a data listing. Major 
protocol deviations will be summarized by treatment and overall for the randomized population. 
8.3 
Inclusion and Exclusion Criteria 
All recorded inclusion and exclusion criteria status will be presented in a data listing. Each 
subject
 analysis population will also be presented in a data 
listing. 
8.4 
Demographics and Other Baseline Characteristics 
All demographics and body measurements will be summarized by sequence group and overall, 
and they will be presented by subject in a data listing.  
Descriptive statistics (n, mean, SD, min, median, and max) will be calculated for continuous 
variables using the last results obtained prior to study drug administration. Frequency counts and 
percentages will be tabulated for categorical variables. 
All demographic characteristics will be summarized for the safety population and PK population. 
If the safety population and PK population are the same, the table for the PK population will not 
be generated.  


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
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8.5 
Medical History 
Details of relevant medical and surgical history (in the last five years), including allergies or drug 
sensitivity, will be presented by subject in a data listing. The latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA) will be used to classify all medical history 
findings by system organ class (SOC) and preferred term (PT). Output data will include the 
MedDRA version used in the study. 
8.6 
Medications 
Prior and concomitant medications will be presented by subject in a data listing. The latest 
version of the World Health Organization Drug Dictionary (WHO DD) will be used to classify 
medications by anatomical therapeutic chemical (ATC) classification code (2nd level). When 
2nd level classification code is not available, 1st level classification will be used instead. Output 
data will include the WHO DD version used in the study. 
8.7 
Drug, Cotinine, and Alcohol Screens 
A urine drug screen will be performed at screening and Day -1 of each period. Testing includes: 
Amphetamines, 
Methamphetamines, 
Barbiturates, 
Benzodiazepines, 
Cocaine, 
s, 
Phencyclidine, 
and 
Tetrahydrocannabinol.  
A urine cotinine test will be performed at screening and Day -1 of each period. 
An alcohol breath test will be performed at screening and Day -1 of each period. 
The results will be presented by subject in data listings. 
8.8 
Pregnancy Screening 
For all female subjects of childbearing potential, a urine pregnancy test, will be performed at 
screening and end of study and a serum pregnancy test will be performed on Day -1 of each 
period. The follicle-stimulating hormone (FSH) level will be tested in females who have been 
amenorrhoeic for at least twelve consecutive months. All results will be presented by subject in 
data listings. 
8.9 
Additional Screening Tests 
Serology (HIV antigen and antibody, HBsAg, HBc-Ab (IgG + IgM) and HCV-Ab) tests and 
electrocardiograms (ECGs) will be performed at screening. COVID-19 test will be performed at 
screening, at check-in (Day -1 of each period), during the washout period, at discharge from 
Period 1 and End of Study or early discontinuation, and at any time during residential period in 
the study when subjects report s
. All these data will be 
presented by subject in data listings. 
8.10 Study Drug Administration 
The study drug administration details including date and time of administration, Treatment 
Description (frequency, route, formulating, dose (units)), Fasting status at time of administration, 
and if a medication/dosing error occurred will be listed by Subject. 
 


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9. PK Analyses 
Phoenix® WinNonlin® software will be used for all PK analyses. Inferential statistical analyses 
will be performed using SAS for Windows software. Bioanalysis of all samples should be 
completed prior to the initiation of the PK and statistical analyses. 
All plasma concentration and PK parameter summaries and analyses will be conducted on the 
PK analysis set. All concentration and PK data, including any data for subjects who are not 
included in the analysis (e.g., subjects withdrawn from the study due to AEs), will be listed for 
the PK population. The listing for plasma concentration will include planned timepoint, sample 
collection (yes or no), date and times of collection, and the calculated time deviations from the 
planned timepoint. 
9.1 
Handling of Concentrations Below the Lower Limit of Quantification (BLOQ), No 
Reportable Concentration Values, and Missing Data  
For the analysis of all individual plasma concentrations and all secondary PK parameter, all 
concentration BLOQ values that occur before the first measurable concentration (i.e. non-
BLOQ) will be treated as zero (0). Any BLOQ values after the first measurable concentration 
will be treated as 
missing for plasma PK 
concentrations and PK parameter estimation.  
Samples with invalid concentration (due to bioanalytical or clinical issue) will be replaced by 
when it occurs prior to study drug administration. Otherwise, they will be set to missing 
for tabulation, graphical representation and calculation purposes if it occurs after study drug 
administration.  
Listings will show the actual value of concentration at the timepoint. The value of BLOQ will be 
displayed as applicable in the listings. 
If any concentration data is missing or deviates from the planned time of collection, then the 
pharmacokineticist may calculate the PK parameters using the available data. 
9.2 
Handling of the Difference between the Scheduled and the Actual Sampling Times 
The actual clock time for dosing and the actual clock time for each PK sample collection will be 
recorded. For all sampling times, the actual sampling time relative to study drug administration 
will be calculated as the difference between the sample collection actual clock time and the 
actual clock time of dosing. The actual post-dose sampling times, expressed in hours and 
rounded off to three decimal digits, will be used to calculate the PK parameters. Pre-dose 
sampling times will always be reported as zero (0.000), regardless of the time difference. 
Nominal sampling times will be used in concentration tables and mean graphs, while actual 
sampling times for post-dose samples will be used in the individual graphs. Actual sampling 
times for post-dose samples also will be used for PK parameter derivation, unless the actual 
sampling time is missing, in which case, the nominal time will be used.  
9.3 
PK Sampling Schedule 
Blood samples for the determination of the PK of ibuprofen and diphenhydramine will be 
collected from each subject during this study according to the following schedule: 


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within one hour prior to dosing (pre-dose) and at 10, 15, 30, 45 minutes and 1, 1.25, 1.5, 1.75, 2, 
2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 6, 8, 10, 12, 16, 24, 36, and 48 
hours following dosing in each treatment period (24, 36, and 48 hours for diphenhydramine only). 
-dose PK samplings is defined as the time of drug 
administration. 
9.4 
PK Parameters 
After database lock and unblinding, the following PK parameters will be calculated, whenever 
possible, by standard non-compartmental methods for ibuprofen and diphenhydramine: 
Primary PK Parameters: 
Parameter Definition  
Cmax 
maximum observed post-dose concentration; obtained without interpolation 
AUC0-t 
area under the plasma concentration versus time curve calculated from time zero to 
the last measurable sampling time point, t 
AUC0-inf 
area under the plasma concentration versus time curve calculated from time zero to 
infinity, computed as AUC0-inf = AUC0-t 
z where C(t) is the concentration at 
z is the terminal elimination rate 
constant 
Secondary PK Parameters: 
Parameter Definition  
z 
terminal elimination rate constant, computed as the negative of the slope of the 
regression line of the natural logarithm (ln) concentration on time 
tmax 
time of the maximum observed post-dose concentration 
t1/2 
elimination half-life, computed as t1/2 = ln(2)/ z 
Vz/F 
z x AUC0-inf) 
Cl/F 
apparent total clearance, calculated as dose administered/ AUC0-inf 
AUC parameters will be calculated using linear up log down trapezoidal method, where the 
linear trapezoidal rule is used any time the concentration data is increasing, and the logarithmic 
trapezoidal rule is used any time that the concentration data is decreasing. 
z will be the negative of the estimated slope of the linear regression of the ln-transformed 
concentration versus time profile in the terminal elimination phase. The best fit method will be 
used to calculate the z from at least three concentration data points, excluding Cmax. R2 adjusted, 
the goodness of fit statistic for the terminal elimination phase, adjusted for the number of points 
used in the estimation of z 
z cannot be measured (e.g.: there are fewer than 
three non-zero concentrations in the terminal elimination phase), the PK parameters derived from 
z will be presented in listing(s) but excluded from descriptive statistics in tables. The timepoint 
where ln-linear 
z calculation begins ( z Lower), the actual sampling time of the last measurable 
concentration used to estimate the z ( z Upper), and the R2 adjusted for the ln-linear regression for 
the calculation of the elimination rate constant will be reported.  


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 20 of 28 
9.5 
Statistical Analysis 
For ibuprofen and diphenhydramine, individual and mean plasma concentration versus time 
curves will be presented for both linear and semi-log scale by treatment for the PK analysis set. 
The plasma concentrations at each timepoint, and all PK parameters will be summarized by 
treatment using descriptive statistics (n, arithmetic and geometric means, SD, CV%, min, max, 
and median) for the PK analysis set.  
9.6 
Bioequivalence Assessment 
The primary objective will be evaluated on the following comparison: 
Advil PM Liqui-Gels Minis (Test) versus Advil PM Liqui-Gels (Reference), in terms of Advil 
PM Liqui-Gels AUC0-t, AUC0-inf, and Cmax. 
For ibuprofen and diphenhydramine separately, a linear mixed effects model will be fit to the 
natural log-transformed PK parameters (AUC0-t, AUC0-inf, and Cmax), as the dependent variable, 
and treatment, sequence, and period as fixed effects. Subject nested within sequence will be a 
random effect. The treatment least-squares means (LSMs), difference between treatment LSMs, 
and 90% confidence interval (CI) for the difference will be computed. The adjusted LSM and 
LSM difference with 90% CIs for the differences will be exponentiated to provide estimates of 
the adjusted treatment effects, ratio of adjusted geometric means (Test/Reference) and 90% CIs 
for the ratio. The model will be fit using restricted maximum likelihood, and the Kenward-Roger 
degrees of freedom approximation. a  Bioequivalence will be declared for a given 
parameter/analyte if the 90% 2-sided CI for the ratio is between 80% and 125% for ibuprofen 
and diphenhydramine. 
The SAS code for the analysis model will follow the format given below (The input variables (or 
datasets) are depicted in slanted red text and have been given generic names). 
If all study subjects are not recruited from the same enrollment pool and the study doses in more 
than one group, the statistical model will be modified to reflect the multigroup nature of the 
study. If the group effect is determined to be necessary, the following fixed effect terms will be 
included in the model: group, sequence, sequence by group, period within group, treatment, and 
treatment by group. Subject within sequence by group will be entered in the statistical model as a 
random effect. If the term of treatment by group is found to be not statistically significant (i.e., p 
>0.05), then the treatment by group term specified in the previous model will be removed. The 
ratio and 90% CI will be calculated for AUC0-t, AUC0-inf, and Cmax as applicable.  
The SAS code for the analysis model with group terms will follow the format given below (The 
input variables (or datasets) are depicted in slanted red text and have been given generic names). 
 
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Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 21 of 28 
The bioequivalence between Advil PM Liqui-Gels Minis (test) and Advil PM Liqui-Gels 
(reference) under fasted conditions will be declared as per FDA requirements: 
if the 90% CIs for the ratio of the geometric means of the primary PK parameters Cmax, 
AUC0-t, and AUC0-inf is between 80% and 125% for ibuprofen and diphenhydramine.  
 
10. Safety 
Safety analysis will be performed for all subjects in the safety population.  
10.1 Adverse Events (AEs) 
The assessment of safety will be based on the frequency and severity of treatment emergent AEs 
(TEAEs) i.e. AEs that are emergent or that worsen after the first study product (Test or 
Reference) administration. AEs without an onset date or time, or AEs with an onset date of the 
date of study drug administration but without an onset time, will be defined as treatment-
emergent, unless an incomplete date (e.g., month and year) clearly indicates that the event started 
prior to administration of study drug, or the AE stop date indicates that the event started and 
stopped prior to administration of study drug. 
Treatment-emergent AEs (TEAEs) and non-TEAEs will be listed by subject and treatment. The 
latest version of the MedDRA will be used to classify all AEs by SOC and PT. Output data will 
include the MedDRA version used in the study. 
TEAEs will be assigned to the treatment administered immediately prior to the onset. AEs 
continuing after dosing in the next treatment period will be evaluated on a case-by-case basis. 
The incidence of TEAEs will be summarized by presenting, for each treatment, the number and 
percentage of subjects having any AE, any AE in each MedDRA System Organ Class (SOC) and 
having each individual AE. The subset of AEs suspected of a relationship to study drug 
(probable, possible or remote) will be presented in a similar manner. All TEAEs will be also 
tabulated by severity (mild, moderate, and severe). Any other information collected (e.g. action 
taken, duration, outcome) will be listed. AEs due to COVID-19, if any, will be listed separately. 
The number and percentage of subjects experiencing TEAEs and the number of TEAEs will be 
tabulated. Subjects who experience the same TEAE (in terms of MedDRA PT) more than once 
will only be counted once for that event, however, the total number of events will be counted per 
category. This also applies to sub-categories displayed in the summaries. 
The following summaries will be presented by treatment: 
Overall summary of TEAEs 
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Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 22 of 28 
TEAEs by SOC  
TEAEs by SOC and PT 
TEAEs by SOC, PT, and severity 
TEAEs by SOC, PT, and relationship to study drug 
Related TEAEs by SOC and PT. 
10.2 Clinical Laboratory Evaluations 
Clinical laboratory testing (hematology, chemistry, and urinalysis) will be performed at 
screening and at the End of Study visit. 
The following clinical laboratory assessments will be performed: 
Hematology: 
Standard blood Hematology will be collected. These include: 
  
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelet count, RBC count, 
WBC count and differential (Basophils, Eosinophils, Lymphocytes, 
Monocytes, and Neutrophils). 
Chemistry: 
Standard serum chemistry will be collected. These include: 
 
Albumin, ALP, ALT, AST, Calcium, Chloride, Creatine kinase, Creatinine, 
GGT, Glucose, Phosphorus, Potassium, Sodium, Total bilirubin, Total 
protein, Urea (BUN). 
Urinalysis: 
Standard Urinalysis will be collected. This includes: 
 
Bilirubin, Blood (occult), Color and appearance, Glucose, Ketones, 
Leukocyte esterase, Nitrite, pH, Protein, Specific gravity, and Urobilinogen. 
 
Microscopic examination will be performed only in the event of abnormal 
findings. 
Clinical laboratory data, including hematology, biochemistry, and urinalysis will be listed. 
Reference ranges provided by clinical laboratories for each laboratory parameter will be given. If 
a result falls outside of a provided range, it will be flagged 
, 
along with a determination of clinical significance  
not clinically significant). 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 23 of 28 
10.3 Vital Signs  
Vital sign measurements will include systolic and diastolic blood pressures, pulse rate, 
respiratory rate, and oral body temperature (OT). Vital sign measurements will be performed at 
screening, on Day 1 (within 1 hour before drug administration) of each treatment period, and at 
the End of Study visit. Additionally, OT will be obtained on Day -1, Day 2 and Day 3 of each 
treatment period (note: OT performed on Day 3 of Period 2 can be used as the oral body 
temperature required at End of Study). 
Vital sign measurements will be listed, and summarized for each timepoint by treatment or 
overall as appropriate. Abnormal results will be flagged in the listing (either 
, along with a determination of clinical significance  
).  
10.4 Physical Examination  
A full physical examination will be performed at screening and a brief physical examination will 
be performed on Day -1 in each treatment period and at End of Study. 
The results of physical examinations will be listed. Abnormal results will be flagged in the 
listings. 
 
11. Acceptability 
On Day 1 of each period, immediately after dosing, the assessment of 
ease of 
swallowing  will be done via one question with a categorical response (
Do you agree or 
disagree that the product is Easy to swallow?
) and one question with an ordinal response 
(
Rank the 
ease of swallowing
of the product on the following scale from 1 to 5
).  
The results of the ease of swallowing questionnaires will be listed and tabulated by treatment for 
the safety population. 
Frequency counts and percentages will be presented for the categorical response to 
agree or disagree that the product is e
. The scale ranges from 1 = not easy to 
 will be summarized by a frequency distribution of 
response by treatment. Additionally, 
ordinal response (ranks) will be 
summarized for each treatment using descriptive statistics (n, mean, SD, min, median, and max). 
 
12. Changes from Analysis Planned in the Protocol 
No changes were made to planned analyses. 
  
13. Programming Considerations 
All TFLs and statistical analyses will be generated using SAS for Windows, release 9.4 
(SAS Institute Inc., Cary, NC, USA) software in accordance with FDA guidelines. Phoenix 
WinNonlin, version 8.3.4 (Certara USA, Inc., Princeton, NJ) will be used for all PK analyses. 
This software was validated by 
 in compliance with US 21 CFR Part 11 regulation. 
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Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 24 of 28 
13.1 General Considerations 
One SAS program can create several outputs. 
Each output will be stored in a separate file. 
Output files will be delivered in rich text format that can be manipulated in MS Word. 
Numbering of TFLs will follow International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guideline E3.b  
13.2 Table, Listing, and Figure Format 
13.2.1 General 
TFLs will be produced in landscape format. The orientation may be changed to portrait, 
as necessary to allow additional rows to be presented. 
TFLs will be produced using the Times New Roman font, size 10. The font size may be 
reduced as necessary to allow additional columns to be presented, but not at the expense 
of clarity.  
The data displays for all TFLs will have a minimum blank 1-inch margin on all four 
sides. 
Unless otherwise specified, TFLs will be in black and white (no color). 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some 
occasions, superscripts 1, 2, or 3 may be used; see below. 
Standard keyboard characters will be used in the TFLs. Special characters, such as 
non-printable control characters, printer-specific, or font-specific characters, will not be 
used. Hexadecimal-derived characters will be used, where possible, if they are 
appropriate to help display math symbols (e.g.
(e.g., cm2, Cmax) will be employed on a case-by-case basis. 
TFLs will be produced using sentence case, unless otherwise specified. 
13.2.2 Headers and Footers 
Times New Roman font, size 10 will be used for TFL headers and footers. 
All outputs will have the following at the top left of each page: GSK 
CH Protocol 218677. 
All outputs will have page x of y at the top or bottom right corner of each page. TFLs are 
individually paginated in relation to total length (i.e., the page number appears 
sequentially as page x of y, where y is the total number of pages in the output). 
The date and time the output was generated will appear, along with the program name, at 
the bottom of each page. 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 25 of 28 
13.2.3 Display Titles 
Each display title includes the 
numeral, along with a descriptive name (e.g., Table 10.1-1 Subject Disposition). ICH E3 
numbering is strongly recommended, but Sponsor preferences are obtained for final 
determination. Display titles are left aligned, single spaced, and presented in title case. A solid 
line spanning the margins will separate display titles from column headings.  
13.2.4 Column and Row Headings 
Column and row headings are presented in title case, with the exception of complete 
sentences, which will be presented in sentence case.  
numeric variables, as appropriate. 
Column and row headings will include the number of subjects in the analysis population 
for each group, presented as (N=xx). This is different from the n  used in descriptive 
statistics, which represents the number of observations. 
The order of sequences in the tables and listings will be 
first, 
, followed 
lastly by Overall . 
13.2.5 Body of the Data Display 
13.2.5.1 General Conventions 
Data in columns of a table or listing are formatted as follows: 
Alphanumeric values are left aligned 
Whole numbers (e.g., counts) are right aligned 
13.2.5.2 Table Conventions 
Units will be included where available. 
If the categories of a parameter are ordered, then all categories between the maximum 
and minimum category are presented in the table, even if n=0 for all groups in a given 
category that is between the minimum and maximum level for that parameter. See the 
example for the frequency distribution for symptom severity below. 
Severity Rating
N
Severe 
0 
Moderate 
8 
Mild 
3 
Where percentages are presented in these tables, 0% will not be presented, therefore, 
counts of zero will be presented as 0
0 (0%) . 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from 
the Study, etc.), then only those categories for which there is at least one subject 
represented in one or more groups are included. 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 26 of 28 
If data for a given parameter is unavailable for one or more subjects, then an Unknown or 
Missing category is included. 
P-values are presented in the format: 0.xxxx, where xxxx is the value. If the p-values are 
less than 0.0001, then present as <0.0001. If the p-value is returned as >0.999, then 
present as >0.999. 
Percentage values are presented in parentheses with no spaces, one space after the count 
[e.g., 7 (12.8%), 13 (5.4%)]. Unless otherwise noted, for all percentages, the number of 
subjects in the analysis population for the group that has an observation will be the 
denominator. Percentages after zero counts are not displayed, and percentages equating to 
100% are presented as 100%
without decimal places).  
Tabular display of data for medical history, prior/concomitant medications, and all 
tabular displays of AE data are presented in alphabetical order.  
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant group (or overall) for the analysis population presented. 
However, careful consideration is required in many instances, due to the complicated 
nature of selecting the denominator, usually the appropriate number of subjects exposed. 
Describe details of this in footnotes or programming notes. 
For categorical summaries (number and percentage of subjects) where a subject can be 
included in more than one category, describe in a footnote or programming note if the 
subject is included in the summary statistics for all relevant categories or just one 
category and the criteria for selecting the criteria. 
Where a category with a subheading (such as SOC) must be split over more than one 
page, present 
The overall summary statistics for the subheading will only be presented on the first 
relevant page. 
13.2.5.3 Listing Conventions 
Listings will be sorted for presentation in order of subject number, visit/collection day, 
and visit/collection time. 
portions of dates are represented on subject listings as dashes (--JUL2000). Dates that are 
missing because they are not applic
otherwise specified. 
All observed time values are to be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
Units will be included where available. 


Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 27 of 28 
13.2.5.4 Figure Conventions 
For safety figures, study visits will be displayed on the X-axis and endpoint (e.g., 
treatment mean change from baseline) values will be displayed on the Y-axis, unless 
otherwise specified. 
Legends will be used for all figures with more than one variable, group, or item 
displayed. 
Units will be included where available. 
13.2.6 Footnotes 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
All footnotes will be left aligned, with single spacing, immediately below the solid line 
beneath the data display. 
Informational footnotes 
. Reference footnotes begin with a reference 
number or letter (e.g., 1, 2, 3 or a, b, c).  
Each new footnote starts on a new line, where possible. 
Subject-specific footnotes are avoided, where possible. 
Footnotes will be used sparingly and add value to the table, figure, or data listing. If more 
than six lines of footnotes are planned, then a cover page may be used to display 
footnotes, and only those essential to comprehension of the data will be repeated on each 
page.  
 
14. Quality Control 
SAS programs are developed to produce outputs such as analysis data sets, summary tables, data 
listings, figures, and statistical analyses. These are developed and undergo quality control in 
accordance with the latest versions of 
c and 
d 
 
 
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Statistical Analysis Plan for Interventional Studies (Early Phase) 
Sponsor: GSK CH; Protocol: 218677 
This document is confidential. 
SAP Version: Final 1.0 22-Mar-2023 
Controlled Document ID: 2805A.00, Effective Date 29-Jul-2019 
Filing requirements: TMF 
Page 28 of 28 
15. Reference List 
 
aKenward, M. G., & Roger, J. H. (1997). Small Sample Inference for Fixed Effects from 
Restricted Maximum Likelihood. Biometrics, 53(3), 983-997. doi:10.2307/2533558  
bInternational Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use (ICH). (1996). Guideline for Industry, Structure and Content of Clinical Study 
Reports (ICH E3). 
. Standard Operating Procedure, Developing Statistical Programming 
Specifications for Early Phase Studies 
. 
. Standard Operating Procedure, Developing Statistical Programs for Early 
Phase Studies 
.  
End of document 
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GSK Consumer Healthcare 
 
Clinical Study Report 
 
 
Study Protocol Number: 218677 
 
 
Property of GSK Consumer Healthcare Confidential 
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Study Report Template v4.0 
Page 3 of 16 
 
Table/Figure/Listing Shells Version Final 1.0 dated 22-MAR-2023
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Statistical Analysis Plan (Table/Figure/Listing Shells)  
GSK CH Protocol 218677
 
 
 
 
22-Mar-2023 (Final 1.0)
Page 1 of 72
 
 
 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
 
 
Sponsor Name: GlaxoSmithKline Consumer Healthcare (GSK CH) 
 
Protocol Number: 218677 
 
Protocol Title: A Randomized, Open label, Single Center, Single Dose, Two Treatment, Two 
Period, Two Sequence Crossover Bioequivalence Study of Advil PM Liqui-Gels Minis 
(ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg) To Advil PM Liqui-Gels 
(ibuprofen/diphenhydramine hydrochloride 200 mg/25 mg) in Healthy Adult Subjects Under 
Fasted Conditions 
 
Protocol Version and Date: Amendment 2, 30-Nov-2022 
 
 Project Code: 222003 
 
Authors: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to GSK CH. Acceptance of this 
document constitutes agreement by the recipient that no information contained herein will be published or 
disclosed without prior written authorization from an official of GSK CH. However, this document may be 
disclosed to appropriate Institutional Review Board and ethics committees or duly authorized 
representatives of a national regulatory authority under the condition that they are requested to keep it 
confidential. In the event of an actual or suspected breach of this obligation, 
 should be 
notified promptly. 
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Statistical Analysis Plan (Table/Figure/Listing Shells) 
GSK CH Protocol 218677
22-Mar-2023 (Final 1.0)
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Signature Approvals
I confirm that I have reviewed this document and agree with the content.
Approval
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Date 
(DD-Mmm-YYYY)
 
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Name, Title
Sponsor Contact
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Statistical Analysis Plan (Table/Figure/Listing Shells)  
GSK CH Protocol 218677
 
 
 
 
22-Mar-2023 (Final 1.0)
Page 3 of 72
 
Table of Contents 
Signature Approvals ...................................................................................................................................................... 2 
Table of Contents........................................................................................................................................................... 3 
1. 
CSR In-text Tables ................................................................................................................................................. 5 
Table 10.1-1 Subject Enrollment and Disposition (Screened Population) .................................................................... 6 
Table 11.4.1-1 Summary of Ibuprofen Pharmacokinetic Parameters by Treatment (PK Analysis Set) ........................ 8 
Table 11.4.1-2 Summary of Diphenhydramine Pharmacokinetic Parameters by Treatment (PK Analysis Set) ........... 9 
Table 11.4.1-3 Assessment of Bioequivalence (PK Analysis Set) .............................................................................. 10 
Table 12.2.3-1 TEAEs by Severity and Relationship to the Study Drug (Safety Population) ..................................... 11 
2. 
Summary Tables ................................................................................................................................................... 12 
Table 14.1-1 Subject Enrollment and Disposition (Screened Population)................................................................... 13 
Table 14.1-2 Summary of Major Protocol Deviations (Randomized Population) ....................................................... 15 
Table 14.1.3-1 Demographics and Baseline Body Measurements (Safety Population)............................................... 16 
Table 14.2.1-1 PK Concentrations (PK Analysis Set) ................................................................................................. 18 
Table 14.2.1-2 PK Parameters (PK Analysis Set) ....................................................................................................... 20 
Table 14.2.1-3 Assessment of Bioequivalence (PK Analysis Set) .............................................................................. 22 
Table 14.3.1-1 Overall Summary of TEAEs (Safety Population) ............................................................................... 23 
Table 14.3.1-2 TEAEs by SOC (Safety Population) ................................................................................................... 24 
Table 14.3.1-3 TEAEs by SOC and PT (Safety Population) ....................................................................................... 25 
Table 14.3.1-4 TEAEs by SOC, PT, and Severity (Safety Population) ....................................................................... 26 
Table 14.3.1-5 TEAEs by SOC, PT, and Relationship to the Study Drug (Safety Population) ................................... 27 
Table 14.3.1-6 Related TEAEs by SOC and PT (Safety Population) .......................................................................... 28 
Table 14.3.4-1 Vital Signs (Safety Population) ........................................................................................................... 29 
Table 14.3.4-2 Acceptability (Safety Population) ....................................................................................................... 30 
3. 
Figures .................................................................................................................................................................. 31 
Figure 14.2.1-4 PK Concentrations by Subject - Linear Scale (PK Population)   ....................................................... 32 
Figure 14.2.1-5 PK Concentrations by Subject  Semi-Log Scale (PK Population)   ................................................. 33 
Figure 14.2.1-6 Mean PK Concentrations - Linear Scale (PK Analysis Set) .............................................................. 34 
Figure 14.2.1-7 Mean PK Concentrations - Semi-Log Scale (PK Analysis Set) ......................................................... 35 
4. 
Listings ................................................................................................................................................................. 36 
Listing 14.3.2-1 Deaths Occurring After Treatment Administration (Safety Population) ........................................... 37 
Listing 14.3.2-2 Non-Fatal Serious Adverse Events Occurring After Treatment Administration (Safety Population)
 ..................................................................................................................................................................................... 38 
Listing 14.3.2-3 Adverse Events Causing Discontinuation of Study Treatment (Safety Population) ......................... 39 
Listing 16.1.9-1 Linear Mixed Effects Model Output for the Assessment of Bioequivalence - Ibuprofen (PK 
Analysis Set) ................................................................................................................................................................ 40 
Listing 16.1.9-2 Linear Mixed Effects Model Output for the Assessment of Bioequivalence - Diphenhydramine (PK 
Analysis Set) ................................................................................................................................................................ 42 
Listing 16.2.1-1 Subject Disposition (Screened Population) ....................................................................................... 44 
Listing 16.2.2-1 Protocol Deviations (Randomized Population) ................................................................................. 45 
Listing 16.2.3-1 Inclusion and Exclusion Criteria (Screened Population) ................................................................... 46 
Listing 16.2.3-2 Assignment to Analysis Populations (Screened Population) ............................................................ 47 
Listing 16.2.4-1 Demographics (Safety Population) ................................................................................................... 48 
Listing 16.2.4-2 Body Measurements (Safety Population) .......................................................................................... 49 
Listing 16.2.4-3 Medical History (Safety Population) ................................................................................................. 50 
Listing 16.2.4-4 Prior and Concomitant Medications (Safety Population) .................................................................. 51 
Listing 16.2.4-5 Drug Screen (Safety Population) ....................................................................................................... 52 
Listing 16.2.4-6 Alcohol Breath Test (Safety Population) .......................................................................................... 53 
Listing 16.2.4-7 Cotinine Test (Safety Population) ..................................................................................................... 54 
Listing 16.2.4-8 ECGs (Safety Population) ................................................................................................................. 55 
Listing 16.2.5-1 Study Drug Administration (Safety Population) ............................................................................... 56 
Listing 16.2.5-2 Subject Randomization (Screened Population) ................................................................................. 57 
Listing 16.2.5-3 Acceptability (Safety Population) ..................................................................................................... 58 
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22-Mar-2023 (Final 1.0)
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Listing 16.2.6-1 PK Concentrations (PK Population).................................................................................................. 59 
Listing 16.2.6-2 PK Parameters (PK Population) ........................................................................................................ 60 
Listing 16.2.7-1 TEAEs (Safety Population) ............................................................................................................... 61 
Listing 16.2.7-2 Non-TEAEs (Screening Population) ................................................................................................. 62 
Listing 16.2.8-1 Biochemistry (Safety Population) ..................................................................................................... 63 
Listing 16.2.8-2 Hematology (Safety Population) ....................................................................................................... 64 
Listing 16.2.8-3 Urinalysis: Quantitative (Safety Population)..................................................................................... 65 
Listing 16.2.8-4 Urinalysis: Categorical (Safety Population) ...................................................................................... 66 
Listing 16.2.8-5 Pregnancy Test (Safety Population) .................................................................................................. 67 
Listing 16.2.8-6 Follicle Stimulating Hormone Test (Safety Population) ................................................................... 68 
Listing 16.2.8-7 Serology (Safety Population) ............................................................................................................ 69 
Listing 16.2.8-8 COVID-19 Test (Safety Population) ................................................................................................. 70 
Listing 16.2.8-9 Vital Signs (Safety Population) ......................................................................................................... 71 
Listing 16.2.8-10 Physical Examination (Safety Population) ...................................................................................... 72 
 
All Tables and Listings marked with an * are to be included as part of the topline report. 
 
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Statistical Analysis Plan (Table/Figure/Listing Shells)  
GSK CH Protocol 218677
 
 
 
 
22-Mar-2023 (Final 1.0)
Page 5 of 72
 
1. CSR In-text Tables 
 
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Statistical Analysis Plan (Table/Figure/Listing Shells) 
GSK CH Protocol 218677
 
 
 
 
22-Mar-2023 (Final 1.0)
Page 12 of 72
 
2. Summary Tables  
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Statistical Analysis Plan (Table/Figure/Listing Shells)  
GSK CH Protocol 218677
 
 
 
 
22-Mar-2023 (Final 1.0)
Page 31 of 72
 
3.  
Figures
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Statistical Analysis Plan (Table/Figure/Listing Shells) 
GSK CH Protocol 218677
 
 
 
 
22-Mar-2023 (Final 1.0)
Page 36 of 72
 
4. Listings 
 
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GSK Consumer Healthcare 
 
Clinical Study Report 
 
 
Study Protocol Number: 218677 
 
 
Property of GSK Consumer Healthcare Confidential 
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Study Report Template v4.0 
Page 4 of 16 
 
 
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Sponsor: GlaxoSmithKline Consumer Healthcare (GSK CH), Protocol No.: 218677 
 
 
This document is confidential. 
Controlled Document ID: 1600A.01, Effective Date 29-Nov-2018 
Page 2 of 2 
Filing requirement: TMF/PMF 
Created by : 
  
 
 
Printed Name, Title 
 
 
Signature 
 
Date  
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Reviewed by: 
 
 
 
 
Printed Name, Title 
 
 
Signature 
 
Date  
(DD-Mmm-YYYY) 
 
 
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GSK Consumer Healthcare 
 
Clinical Study Report 
 
 
Study Protocol Number: 218677 
 
Property of GSK Consumer Healthcare Confidential 
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Study Report Template v4.0 
Page 5 of 16 
 
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GlaxoSmithKline Consumer Healthcare 
Confidential 
Protocol: GSK-218677 
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GlaxoSmithKline Consumer Healthcare 
Confidential 
Protocol: GSK-218677 
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GlaxoSmithKline Consumer Healthcare 
Confidential 
Protocol: GSK-218677 
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GlaxoSmithKline Consumer Healthcare 
Confidential 
Protocol: GSK-218677 
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GSK Consumer Healthcare 
 
Clinical Study Report 
 
 
Study Protocol Number: 218677 
 
 
 
Property of GSK Consumer Healthcare Confidential 
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Study Report Template v4.0 
Page 10 of 16 
 
 
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GlaxoSmithKline Consumer Healthcare 
Confidential 
Protocol: GSK-218677 
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GlaxoSmithKline Consumer Healthcare 
Confidential 
Protocol: GSK-218677 
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GlaxoSmithKline Consumer Healthcare 
Confidential 
Protocol: GSK-218677 
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GlaxoSmithKline Consumer Healthcare 
Confidential 
Protocol: GSK-218677 
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GlaxoSmithKline Consumer Healthcare 
Confidential 
Protocol: GSK-218677 
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GlaxoSmithKline Consumer Healthcare 
Confidential 
Protocol: GSK-218677 
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