Clinical trial NCT05737069
Conditions: Pain
Sponsor: HALEON
Start date: 2023-04-19; Completion date: 2023-05-15
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The primary purpose of this study is to demonstrate the bioequivalence of two ibuprofen arginine granules 400 milligram (mg) formulations under fasting and fed conditions in Chinese healthy adult participants. The secondary purpose of this study is to assess the pharmacokinetic and safety profile of the test and reference preparations.

Detailed description:
The bioequivalence study adopts a single-center, randomized, open-label, single-dose, two-treatment, two-sequence, two-period, two-cohort, two-way crossover design with at least 2-day washout period, under both fasting and fed conditions in Chinese healthy adult participants. It will be planned to enroll approximately 84 participants out of which the first 34 participants for the fasted cohort and the subsequent 50 participants for the fed cohort receiving ibuprofen arginine granules 400 mg. Participants will be randomly assigned to either one of the 2 treatment (Test or Reference product) sequences in a 1:1 ratio within fasted cohort and fed cohort.

Arms: arm 1: Participants will be randomly assigned as per cross-over design to receive one sachet of Ibuprofen arginine granules 400 mg (test product) on day 1 of period 1 and will receive one sachet of Ibuprofen arginine granules 400 mg (Spedifen) (reference product) on day 1 of period 2 with at least 2 days washout period. Participants will be instructed to consume the product orally by dissolving it in 240 mL of warm water. arm 2: Participants will be randomly assigned as per cross-over design to receive one sachet of Ibuprofen arginine granules 400 mg (Spedifen) (reference product) on day 1 of period 1 and will receive one sachet of Ibuprofen arginine granules 400 mg (test product) on day 1 of period 2 with at least 2 days washout period. Participants will be instructed to consume the product orally by dissolving it in 240 mL of warm water.
Interventions: intervention 1: Ibuprofen arginine granules 400 mg intervention 2: Ibuprofen arginine granules 400 mg (Spedifen)
Intervention descriptions: intervention 1: Experimental- Ibuprofen arginine granules 400 mg, one sachet administration containing 400 mg ibuprofen granules. intervention 2: Marketed drug- Ibuprofen arginine granules 400 mg (Spedifen), one sachet administration containing 400 mg ibuprofen granules.

Protocol documents:
Prot_000.pdf: 
GSK Consumer Healthcare 
Clinical Protocol 
Protocol Number: 218552  
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Protocol Template v8.0 
Page 1 of 63 
CLINICAL PROTOCOL 
A Randomized, Open-label, Single-center, Single-dose, Two-
treatment, Two-sequence, Two-period, Two-cohort, Two-way 
Crossover Bioequivalence Study of Two Ibuprofen Arginine 
Granules 400 mg Formulations Under Fasting and Fed Conditions 
in Chinese Healthy Adult Subjects 
Protocol Number: 
218552 
Compound/Product Name: 
Ibuprofen Arginine Granules 
United States (US) Investigational 
New Drug (IND) Number: 
N/A 
European Clinical Trials Database 
(EudraCT) Number: 
N/A 
Other Regulatory Agency Identified 
Number: 
N/A 
Phase: 
I 
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Protocol Template v8.0 
Page 2 of 63 
Sponsor Information 
Sponsor Name & Legal 
Registered Address 
 
Wyeth Pharmaceutical Co., Ltd. 
(hereinafter referred to as “GSK CH”)  
No. 4 West Baodai Road, Suzhou, Jiangsu, China. 
Sponsor Contact Details 
GlaxoSmithKline Consumer Healthcare (China) 
Co, Ltd (GSK CH) 
25/F and 26/F, No.90 Qirong Road, Pudong New 
Area, Shanghai, China, 200124 
Tel: +86 21-2301 9366  
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Protocol Template v8.0 
Page 3 of 63 
Document History 
 
Document 
Version 
Summary of Changes  
Original 
protocol 
1.0 
Not applicable 
Revised 
protocol 
2.0 
Change 
Version 1.0 
Version 2.0 
P13: short title 
A bioequivalence study of 
Fenbid Flash ibuprofen 
arginine granules 400 mg 
compared to the currently 
marketed ibuprofen arginine 
granules 400 mg (Spedifen) in 
healthy adult subjects 
A bioequivalence study of two 
ibuprofen arginine granules 400 
mg under fasting and fed 
conditions in Chinese healthy 
adult subjects. 
P18: Table1-1 
footnote f;  
P41: 9.2.11 
Electrocardio-
gram 
12-lead ECGs will be 
performed with the subject in a 
supine or semi-supine position 
having rested in this position 
for at least 5 minutes before 
the exam. 
12-lead ECGs will be performed 
with the subject in a sitting 
position having rested in this 
position for at least 5 minutes 
before the exam.  
P18: Table1-1 
footnote k; 
P42: 9.2.12 
COVID-19 test 
COVID-19 test: At any time 
during residential period in 
study, when subjects report 
symptoms suggestive of 
COVID-19.  
COVID-19 test: At any time 
during residential period in 
study, when subjects report 
symptoms suggestive of 
COVID-19 as defined by World 
Health Organization (WHO) or 
local guidance. In addition, 
added the abbreviation of WHO 
to Table 15-1.  
P18: Table 1-1 
footnote n; 
P25: 5.5.1 
Meals and 
Dietary 
Restrictions 
 A high-fat/high-calorie 
breakfast contains about 800-
1000 kcal, including about 500-
600 kcal from fat (more than 
50% of total calories), 150 kcal 
from protein, 250 kcal from 
carbohydrates.  
A high-fat/high-calorie breakfast 
contains about 800-1000 kcal, 
including about 500-600 kcal 
from fat (more than 50% of total 
calories), about 150 kcal from 
protein, about 250 kcal from 
carbohydrates.  
P23: 5.3 
Exclusion 
Criteria #11 
Those who have blood 
donation (including component 
donation) or blood loss ≥ 400 
mL within 3 months before the 
study, or have blood 
transfusion; those who have 
blood donation (including 
component donation) or blood 
loss ≥ 200 mL within 1 month 
before the study. 
Those who have blood donation 
(including component donation) 
or blood loss ≥ 400 mL within 3 
months before the study, or 
have blood transfusion; those 
who have blood donation 
(including component donation) 
or blood loss ≥ 200 mL within 1 
month before the study (except 
female physiological blood 
loss). 
P25: 5.5.3 
Activity 
Subjects will not be permitted 
to assume a fully recumbent 
position for 4 hours following 
dosing.  
Subjects will not be permitted to 
assume a fully recumbent 
position for 4 hours following 
dosing (except when AE 
requires medical treatment).  
P31: 6.5 
Blinding & 
Allocation/ 
Randomization 
Randomization number 
consists of one letter R+3 
digits number.  
Randomization number consists 
of one letter K+3 digits number 
in the fasted cohort, and C+3 
digits number in the fed cohort. 
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Protocol Template v8.0 
Page 4 of 63 
P41: 9.2.8 
Blood 
Pressure and 
Pulse Rate 
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.  
<text deleted>  
Amended 
protocol 
3.0 
Change 
Version 2.0 
Version 3.0 
P2: Sponsor 
Information 
GlaxoSmithKline Consumer 
Healthcare (China) Co, Ltd 
(GSK CH) 
8F, The Headquarters building, 
No. 168 Tibet Road (M), 
Shanghai, China, 200001 
Tel: +86 21 2301 9800 
GlaxoSmithKline Consumer 
Healthcare (China) Co, Ltd 
(GSK CH) 
25/F and 26/F, No.90 Qirong 
Road, Pudong New Area, 
Shanghai, China, 200124 
Tel: +86 21-2301 9366  
P15: 
Bioequivalence 
analysis;  
P54: 12.3.2-
Bioequivalence 
Analysis 
The log-transformed primary 
PK endpoints….will be 
analyzed with an analysis of 
variance (ANOVA) model with 
treatment, period, sequence 
and subject within sequence, 
as fixed effects to calculate the 
least squares means 
(LSMs)…. back-transformed 
values.  
The log-transformed primary PK 
endpoints….will be analyzed 
with an analysis of variance 
(ANOVA) model with treatment, 
period and sequence, as fixed 
effects to calculate the least 
squares means (LSMs)…. 
back-transformed values.  
P18: Table1-1 
footnote h; 
P24: 5.3 
Exclusion 
criteria #20; 
P39:Table 9-1; 
P40: 9.2.2 
Serology 
Serology includes HBsAg, 
HBcAb, HCV Ab and HIV 
antibody  
Revised Serology including 
HBsAg, HBcAb, HCV Ab, HIV 
antibody and Syphilis  
P18: Table 1-1 
(footnote k)  
COVID-19 tests are to be 
performed as follows: 
screening; Day -1; Day 4 or 
early termination; and at any 
time during residential period 
in study, when subjects report 
symptoms suggestive of 
COVID-19 as defined by World 
Health Organization (WHO) or 
local guidance. And the 2 
consecutive tests before the 
first dose should be separated 
by > 24 hours. 
COVID-19 tests are to be 
performed as follows: Day -1; 
and at any time during 
residential period in study, when 
subjects report symptoms 
suggestive of COVID-19 as 
defined by World Health 
Organization (WHO) or local 
guidance.  
P18: Table 1-1 
(footnote c)  
The subjects will complete a 
follow-up visit 2 days after last 
dose of medication, as their 
end-of-study (EOS) visit. The 
follow-up visit can be done via 
telephone if the subject does 
not need to receive any 
examination, as judged by the 
investigator.  
The subjects will complete a 
follow-up visit 2 days after last 
dose of medication, as their 
end-of-study (EOS) visit. Due to 
any unforeseen circumstances 
if follow-up visit is not 
completed on day 5, this can be 
rescheduled and completed in 
next 2 days i.e., till day 7. The 
follow-up visit can be done via 
telephone if the subject does 
not need to receive any 
examination, as judged by the 
investigator.  
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Protocol Template v8.0 
Page 5 of 63 
P22: 5.2-
Inclusion 
Criteria #7  
Subject with two negative 
polymerase chain reaction 
(PCR) tests (one at screening 
and one on Day-1) for active 
COVID-19, separated by > 24 
hours.  
Subject with one negative 
polymerase chain reaction 
(PCR) or antigen test (on Day-
1) for active COVID-19.  
P25: 5.5.1 
Meals and 
Dietary 
Restrictions; 
P28: 6.2 
Administration 
The study drug granules must 
be mixed and stirred with 240 
mL of hot but not boiling water 
to be completely dissolved  
The study drug granules must 
be mixed and stirred with 240 
mL of warm water to be 
completely dissolved  
P34: 8.1.5-
Screening 
procedures  
The following…COVID-19 test 
and AEs, prior/concomitant 
medications/treatments 
collection.  
The following…and AEs, 
prior/concomitant 
medications/treatments 
collection.  
P37: 8.2.3-
Period 2 [Day 
4 (Period 2)]  
COVID-19 test  
<deleted>  
P38: 8.2.4-End 
of study  
The subjects will 
complete…medication (Day 5). 
Subjects will be contacted by 
telephone by the investigator 
or his/her authorized staff to 
complete the following 
procedures after discharge 
from the study ward: 
The subjects will 
complete…medication (Day 5). 
Due to any unforeseen 
circumstances if follow-up visit 
is not completed on day 5, this 
can be rescheduled and 
completed in next 2 days i.e., till 
day 7. The follow-up visit can be 
done via telephone if the 
subject does not need to 
receive any examination, as 
judged by the investigator. The 
investigator or his/her 
authorized staff shall complete 
the following procedures after 
discharge from the study ward: 
P42: 9.2.12-
COVID-19 test  
Nasal/nasopharyngeal swab 
will be collected to test for 
COVID-19 using PCR test, at 
times specified in the STUDY 
PROCEDURES 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 during screening 
and one test will be done on 
Day -1. 
For detection of COVID-19, 
tests are to be performed as 
follows: 
• 
Screening 
• 
At check-in (Day -1) 
• 
At discharge from Period 2 
(Day 4) or early 
discontinuation  
• 
At any time during 
residential period in study, 
when subjects report 
symptoms suggestive of 
COVID-19 as defined by 
WHO or local guidance 
Nasal/nasopharyngeal swab will 
be collected to test for COVID-
19 using PCR or antigen test, at 
times specified in the STUDY 
PROCEDURES section. For 
detection of COVID-19, tests 
are to be performed as follows: 
• 
At check-in (Day -1) 
• 
At any time during 
residential period in study, 
when subjects report 
symptoms suggestive of 
COVID-19 as defined by 
WHO or local guidance  
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CCI


GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Protocol Template v8.0 
Page 6 of 63 
P42: 9.3.1-
Plasma for 
Analysis of 
ibuprofen  
The actual blood sample 
requirements for PK analysis 
shall be dependent on the 
laboratory manual.  
The actual blood sample 
requirements for PK analysis 
shall be dependent on the 
laboratory manual 
or other 
contracted central lab etc.).  
P47: 10.4.2 
Reporting of a 
Serious 
Adverse Event; 
P48: 10.6 
Follow-up of 
AEs and 
SAEs; P49: 
10.9.2 Action 
to be Taken if 
Pregnancy 
Occurs 
Change of safety reporting 
email box: 
Change of safety reporting 
email box:  
P52: 12.1-
Sample Size 
Determination  
This estimates to 78 subjects 
overall completing the study.  
This estimates to overall 78 
completer and evaluable 
subjects. Due to the 
unpredictability of the adverse 
covid situation the enrolment of 
subjects may be higher than 
specified in the protocol to meet 
the number of completer and 
evaluable subjects required for 
this study. 
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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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Protocol Template v8.0 
Page 7 of 63 
Principal Investigator Protocol Agreement Page 
x I confirm agreement to conduct the study in compliance with the protocol and any 
amendments according to the current International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) guidelines. 
x I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
x I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure site staff 
receives all appropriate information throughout the study. 
x I agree to conduct this study in full conformance with the laws and regulations of the 
country in which the research is conducted and the Declaration of Helsinki. 
 
Investigator Name: 
Investigator Qualifications: 
Investigator Signature: 
Date of Signature/Agreement: 
 
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Protocol Template v8.0 
Page 8 of 63 
Table of Contents 
Sponsor Information ............................................................................................................ 2 
Document History ............................................................................................................... 3 
Principal Investigator Protocol Agreement Page ................................................................ 7 
Table of Contents ................................................................................................................ 8 
1 
PROTOCOL SUMMARY ................................................................................................ 13 
1.1 
Synopsis ................................................................................................................. 13 
1.2 
Schedule of Activities ............................................................................................ 17 
2 
INTRODUCTION ............................................................................................................. 19 
2.1 
Study Rationale ...................................................................................................... 19 
2.2 
Background ............................................................................................................ 19 
2.3 
Benefit/Risk Assessment ....................................................................................... 19 
2.4 
Mechanism of Action/Indication ........................................................................... 20 
3 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 20 
4 
STUDY DESIGN .............................................................................................................. 21 
4.1 
Overall Design ....................................................................................................... 21 
4.2 
Scientific Rationale for Study Design ................................................................... 21 
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 ................................................................................................... 22 
5.3 
Exclusion Criteria .................................................................................................. 22 
5.4 
Randomization Criteria .......................................................................................... 24 
5.5 
Lifestyle Considerations ........................................................................................ 25 
5.5.1 
Meals and Dietary Restrictions ............................................................. 25 
5.5.2 
Alcohol, Caffeine and Tobacco............................................................. 25 
5.5.3 
Activity .................................................................................................. 25 
5.5.4 
Contraception ........................................................................................ 26 
5.6 
Screen Failures....................................................................................................... 26 
5.7 
Sponsor’s Qualified Medical Personnel ................................................................ 27 
5.8 
Rater/Clinical Assessor Qualifications .................................................................. 27 
6 
INVESTIGATIONAL/STUDY PRODUCTS................................................................... 27 
6.1 
Study Product Supplies .......................................................................................... 27 
6.1.1 
Dosage Form and Packaging ................................................................. 28 
6.1.2 
Preparation and Dispensing................................................................... 28 
6.2 
Administration ....................................................................................................... 28 
6.2.1 
Medication/Dosing Errors ..................................................................... 29 
6.2.2 
Overdose ............................................................................................... 29 
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
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6.3 
Study Product Storage ........................................................................................... 29 
6.4 
Study Product Accountability ................................................................................ 30 
6.5 
Blinding and Allocation/Randomization ............................................................... 31 
6.6 
Breaking the Blind ................................................................................................. 31 
6.7 
Compliance ............................................................................................................ 31 
6.8 
Concomitant Medication/Treatment(s) .................................................................. 31 
7 
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ......................................................................... 31 
7.1 
Subject Discontinuation/Withdrawal ..................................................................... 31 
7.2 
Lost to Follow up ................................................................................................... 32 
8 
STUDY PROCEDURES ................................................................................................... 32 
8.1 
Screening ............................................................................................................... 33 
8.1.1 
Informed Consent .................................................................................. 33 
8.1.2 
Demographics ....................................................................................... 34 
8.1.3 
Inclusion/Exclusion Criteria ................................................................. 34 
8.1.4 
Medical History and Prior Medication/Treatment ................................ 34 
8.1.5 
Screening procedures ............................................................................ 34 
8.2 
Study Period .......................................................................................................... 34 
8.2.1 
Period 1 ................................................................................................. 34 
8.2.2 
Interval .................................................................................................. 36 
8.2.3 
Period 2 ................................................................................................. 36 
8.2.4 
End of study .......................................................................................... 38 
8.3 
Study Conclusion ................................................................................................... 38 
9 
STUDY ASSESSMENTS ................................................................................................. 38 
9.1 
Screening Assessments .......................................................................................... 39 
9.2 
Safety and Other Assessments ............................................................................... 39 
9.2.1 
Laboratory Tests.................................................................................... 39 
9.2.2 
Serology ................................................................................................ 40 
9.2.3 
Urine Drug Abuse Screening ................................................................ 40 
9.2.4 
Alcohol Breath Test .............................................................................. 40 
9.2.5 
Pregnancy Testing ................................................................................. 40 
9.2.6 
Physical Examinations .......................................................................... 40 
9.2.7 
Height and Weight ................................................................................ 41 
9.2.8 
Blood Pressure and Pulse Rate .............................................................. 41 
9.2.9 
Respiratory Rate .................................................................................... 41 
9.2.10 
Temperature .......................................................................................... 41 
9.2.11 
Electrocardiogram ................................................................................. 41 
9.2.12 
COVID-19 test ...................................................................................... 42 
9.3 
Pharmacokinetics (PK) .......................................................................................... 42 
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Clinical Protocol 
 
 
Protocol Number: 218552  
 
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Protocol Template v8.0 
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9.3.1 
Plasma for Analysis of ibuprofen .......................................................... 42 
9.3.2 
Shipment of Pharmacokinetic Samples ................................................. 43 
9.4 
Blood Volume ........................................................................................................ 43 
10 ADVERSE EVENT AND SERIOUS ADVERSE EVENTS ........................................... 43 
10.1 
Definition of an Adverse Event (AE) .................................................................... 44 
10.2 
Definition of a Serious Adverse Event (SAE) ....................................................... 44 
10.3 
Time Period and Frequency for Collecting AE and SAE Information .................. 45 
10.4 
Reporting Procedures............................................................................................. 46 
10.4.1 
Reporting of an Adverse Event ............................................................. 46 
10.4.2 
Reporting of a Serious Adverse Event .................................................. 47 
10.5 
Evaluating Adverse Events .................................................................................... 47 
10.5.1 
Assessment of Intensity/Severity .......................................................... 47 
10.5.2 
Assessment of Causality ....................................................................... 48 
10.6 
Follow-up of AEs and SAEs.................................................................................. 48 
10.7 
Withdrawal Due to an Adverse Event ................................................................... 49 
10.8 
Regulatory Reporting Requirements for SAEs...................................................... 49 
10.9 
Pregnancy .............................................................................................................. 49 
10.9.1 
Time Period for Collecting Pregnancy Information.............................. 49 
10.9.2 
Action to be Taken if Pregnancy Occurs .............................................. 49 
11 DATA MANAGEMENT .................................................................................................. 50 
11.1 
Case Report Form .................................................................................................. 50 
11.2 
Data Handling ........................................................................................................ 51 
11.3 
Data Queries .......................................................................................................... 51 
11.4 
External Data ......................................................................................................... 51 
12 STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................. 52 
12.1 
Sample Size Determination ................................................................................... 52 
12.2 
Populations for Analysis ........................................................................................ 53 
12.3 
Statistical Analyses ................................................................................................ 53 
12.3.1 
Pharmacokinetic Analysis ..................................................................... 53 
12.3.2 
Bioequivalence Analysis ....................................................................... 54 
12.3.3 
Safety Analysis ..................................................................................... 55 
12.3.4 
Exclusion of Data from Analysis .......................................................... 56 
12.3.5 
Subject Disposition ............................................................................... 56 
12.3.6 
Demographic and Baseline Characteristics ........................................... 56 
12.3.7 
Study Product Compliance and Use of Other Therapies ...................... 56 
12.3.8 
Handling of Dropouts and Missing Data .............................................. 57 
12.3.9 
Interim Analysis .................................................................................... 57 
13 STUDY GOVERNANCE CONSIDERATIONS.............................................................. 57 
13.1 
Quality Control ...................................................................................................... 57 
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
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13.2 
Quality Assurance .................................................................................................. 57 
13.3 
Regulatory and Ethical Considerations ................................................................. 58 
13.3.1 
Institutional Review Board/ Ethics Committee..................................... 58 
13.3.2 
Ethical Conduct of the Study ................................................................ 58 
13.3.3 
Subject Information and Consent .......................................................... 58 
13.3.4 
Subject Recruitment .............................................................................. 59 
13.3.5 
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP ............................................................................................... 59 
13.4 
Posting of Information on Publicly Available Clinical Study Registers ............... 59 
13.5 
Provision of Study Results to Investigators ........................................................... 59 
13.6 
Records Retention .................................................................................................. 60 
13.7 
Conditions for Terminating the Study ................................................................... 60 
14 REFERENCES .................................................................................................................. 61 
15 APPENDICIES.................................................................................................................. 62 
15.1 
ABBREVIATIONS ............................................................................................... 62 
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List of in text tables 
Table 1-1 
Schedule of Activities ........................................................................... 17 
Table 3-1 
Study Objectives and Endpoints ........................................................... 20 
Table 6-1 
Study Product Supplies ......................................................................... 27 
Figure 1 
Study Schematic .................................................................................... 33 
Table 9-1 
Laboratory Tests.................................................................................... 39 
Table 9-2 
Table of Permissible Deviation for Blood Collection Time ................. 42 
Table 9-3 
Blood Volume ....................................................................................... 43 
Table 15-1 
Abbreviations ........................................................................................ 62 
 List of in text figures 
Figure 1 
Study Schematic .................................................................................................... 33 
 
 
 
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1 
PROTOCOL SUMMARY  
1.1 
Synopsis 
Title: A Randomized, Open-label, Single-center, Single-dose, Two-treatment, Two-sequence, 
Two-period, Two-cohort, Two-way Crossover Bioequivalence Study of Two Ibuprofen 
Arginine Granules 400 mg Formulations Under Fasting and Fed Conditions in Chinese Healthy 
Adult Subjects. 
Short Title: 
A bioequivalence study of two ibuprofen arginine granules 400 mg under fasting and fed 
conditions in Chinese healthy adult subjects.  
Background and Rationale: 
Ibuprofen arginine granules (Spedifen) was approved in China by the National Medical 
Products Administration (NMPA) in 2005 (200 mg, H20058759; 400 mg, H20058760; 600 mg, 
H20058761). A new ibuprofen arginine granules formulation will be investigated in this study 
to support the generic registration in China. This randomized crossover study is now being 
conducted to demonstrate the bioequivalence of ibuprofen arginine granules manufactured by 
the sponsor (test product) and Spedifen (reference product), under fasting and fed conditions. 
Objectives and Endpoints: 
Objective(s) 
Endpoint(s) 
Primary 
The objective of this study is to demonstrate the 
bioequivalence of 400 mg new ibuprofen 
arginine granules compared to 400mg ibuprofen 
arginine granules (Spedifen) in two separate 
conditions (fed cohort and fasted cohort) 
• Primary pharmacokinetic (PK) endpoints in 
fed cohort: AUC0-t, AUC0-∞ and Cmax 
• Primary PK endpoints in fasted cohort: AUC0-
t, AUC0-∞ and Cmax 
Secondary 
Pharmacokinetics 
 
To assess the PK profile of test and reference 
product 
x Secondary PK endpoints in fed cohort: Tmax, 
t1/2, λz, and %AUCex 
x Secondary PK endpoints in fasted cohort: 
Tmax, t1/2, λz, and %AUCex 
Safety 
 
To assess the safety profile of test and reference 
product  
Ь Frequency and nature of adverse events 
Ь Physical examination 
Ь Vital signs 
Ь Laboratory tests 
Ь 12-lead electrocardiogram  
Study Design: 
The bioequivalence study adopts a single-center, randomized, open-label, single-dose, two-
treatment, two-sequence, two-period, two-way crossover design with at least 2-day washout 
period, in two cohorts under fasting and fed conditions respectively  
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For this study, it is planned to enroll approximately 84 subjects (the first 34 subjects for the 
fasted cohort and the subsequent 50 subjects for the fed cohort). Within fasted cohort and fed 
cohort, subjects will be randomly assigned to either one of the 2 treatment sequences in a 1:1 
ratio, according to the following table.  
Fasted cohort 
Sequence 
Period 1 
Period 2 
TR  
Test product (T) 
Reference product (R) 
RT  
Reference product (R) 
Test product (T) 
 
 
 
Fed cohort 
 
 
Sequence 
Period 1 
Period 2 
TR  
Test product (T) 
Reference product (R) 
RT  
Reference product (R) 
Test product (T) 
Study Products: 
x Test product 
Ibuprofen arginine granules 400 mg, - one sachet administration containing 400 mg ibuprofen 
granules 
x Reference product 
Reference listed drug, ibuprofen arginine granules 400 mg, Spedifen, from
 - one sachet administration containing 400 mg ibuprofen granules 
Study Procedure: 
For this study, it is planned to enroll approximately 84 subjects (the first 34 subjects for the 
fasted cohort and the subsequent 50 subjects for the fed cohort). 
The fasted/fed cohort will consist of an ambulant screening day within 7 days prior to first 
product administration and two study periods. When screening results are qualified and are 
reviewed and confirmed for eligibility by the investigator, the subject will be admitted to the 
study ward on 1 day prior to first administration (Day -1). The first product administration will 
be on Day 1, and the second product administration on Day 3. Carry-over effects will be avoided 
by a wash-out interval of at least 2 days between investigational product administrations. 
The drug will be administered as follows: 
Fasted cohort: After an overnight fasting (water is allowed) of at least 10 hours, subjects will 
take 1 sachet (400 mg ibuprofen) of test (T) or reference (R) product with 240 mL of water in 
the morning on Day 1 under fasting condition, and cross-over 2 days later. 
Fed cohort: After an overnight fasting (water is allowed) of at least 10 hours, subjects will firstly 
take a high-fat/high-calorie breakfast exactly 30 minutes prior to dosing in the morning and 
finish eating within 30 minutes, then take 1 sachet (400 mg ibuprofen) of test (T) or reference 
(R) product with 240 mL of water under fed condition on Day 1, and cross-over 2 days later.  
The Pharmacokinetic (PK) blood samples will be collected as follows: 
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Fasted cohort: PK blood samples will be obtained prior to dosing (pre-dose) and 5, 10, 15, 20, 
30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 h after test or reference product 
administration.  
Fed cohort: PK blood samples will be obtained prior to dosing (pre-dose) and 10, 30, 45, 60, 
75, 90, 120 min, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 h after test or reference product 
administration. 
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. No food is allowed within 
4 hours after administration. Lunch will be provided approximately 4 hours after dosing. Dinner 
will be provided approximately 10 hours after dosing. 
For each subject the duration of study participation is up to 12 days of which up to 4 days 
confined. 
Type and Planned Number of Subjects: 
For this study, it is planned to enroll approximately 84 subjects (34 subjects for the fasted cohort 
and 50 subjects for the fed cohort) to achieve 32 subjects completing in the fasted cohort and 
46 subjects completing in the fed cohort respectively. This estimates to 78 subjects overall 
completing the study. 
In the fasted cohort, at least 17 subjects will be assigned to either TR or RT sequence and 
similarly in the fed cohort at least 25 subjects will be assigned to either TR or RT sequence. 
Statistical methods 
The fasted cohort and fed cohort will be summarized and analyzed separately.  
Pharmacokinetic analysis: 
Descriptive statistical analysis will be conducted to summarize drug plasma concentration data 
by treatment groups at each planned sampling time point. Descriptive statistics for plasma 
concentration will include arithmetic mean, standard deviation (SD), coefficient of variation 
(CV%), median, maximum, minimum, geometric mean, etc. The individual and average 
concentration-time curve, semi logarithmic concentration-time curve of ibuprofen will be 
displayed by treatment.  
The non-compartmental analysis modeling in software 
 will be used to calculate the PK parameters of ibuprofen according to actual sampling 
time points. Descriptive statistical analysis will be conducted for all PK parameters by treatment. 
Descriptive statistics for the PK parameters will include arithmetic mean, SD, CV%, median, 
maximum, minimum, geometric mean and geometric CV, etc. 
Bioequivalence analysis: 
The log-transformed primary PK endpoints (area under the plasma concentration-time curve 
from time zero to time infinity [AUC0-∞], area under the plasma concentration-time curve from 
time zero to last observed concentration at time t [AUC0-t], and observed maximum plasma 
concentration [Cmax]) will be analyzed with an analysis of variance (ANOVA) model with 
treatment, period and sequence, as fixed effects to calculate the least squares means (LSMs) 
between the test product and the reference product, and the geometric mean ratio (GMR) and 
its 90% confidence interval (CI) will be calculated using back-transformed values. The test and 
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reference products can be considered equivalent if the 90% CIs of the GMR (T/R) for AUC0-∞, 
AUC0-t, and Cmax are each between 80.00% and 125.00%. Non-parametric analysis will be 
performed for the secondary PK parameters without logarithmic transformation. For time to 
reach maximum concentration (Tmax), terminal half-life (t1/2) and terminal elimination rate 
constant (λz), the paired Hodges-Lehmann test (Hodges-Lehmann 's median analysis) will be 
used. The median of the difference between the test product and the reference product and 
corresponding 90% CI will be calculated. 
Safety analysis: 
Adverse events (AEs) will be coded using the preferred terms (PTs) from Medical Dictionary 
for Regulatory Activities (MedDRA) of the most recent version at the time of database lock and 
grouped by system organ class (SOC). The severity of AEs will be graded. The number and 
percentage of subjects will be summarized for all treatment-emergent adverse events (TEAEs, 
defined as any AE occurring from the start of dosing to the end of the study), serious adverse 
event (SAEs), investigational product-related TEAEs, investigational product-related SAEs, 
and TEAEs leading to study discontinuation by medication (T/R) and sequence (TR/RT) based 
on PT and SOC. In addition, the severity of TEAEs and their relationship to investigational 
product will also be summarized by medication (T/R) and sequence (TR/RT) based on PT and 
SOC. 
Descriptive statistical analyses will be performed for the baseline values, post-dose values, and 
changes from baseline for vital signs, physical examinations, laboratory tests, and 12-lead 
electrocardiogram (ECG). 
Criteria for Evaluation 
The test product is considered to be equivalent to the reference product if the 90% CI for the 
GMR (T/R), based on log-transformed data, is completely contained within the acceptance 
interval of 0.8000 to 1.2500 for the primary PK parameters (AUC0-t, AUC0-∞, and Cmax) in both 
fasted cohort and fed cohort. 
 
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1.2 
Schedule of Activities 
The schedule of activities table provides an overview of the subject visits and study procedures. 
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 
Period 1 
Interval a 
Period 2 
End of 
study c 
Early 
termination b 
Within 7 
days 
prior to 
first dose  
Day -1 
Day 
1 
Day 2 
Day 
3 
Day 
4 
Day 5 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusio
n Criteria 
X 
X 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
Smoking history 
and alcohol 
consumption 
history 
X 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications/treatm
ents review 
X 
X 
X 
X 
X 
X 
X 
X 
Height/weight 
X 
 
 
 
 
 
 
 
Physical 
examination d 
X 
X 
 
X 
 
X 
 
X 
Vital signs e 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECG f 
X 
 
 
X 
 
X 
 
X 
Laboratory tests g 
X 
 
 
X 
 
X 
 
X 
Alcohol breath test 
X 
X 
 
 
 
 
 
 
Urine drug abuse 
screening 
X 
X 
 
 
 
 
 
 
Serology h 
X 
 
 
 
 
 
 
 
Blood pregnancy 
test i 
X 
X 
 
 
 
X 
 
X 
Hormone test j 
X 
 
 
 
 
 
 
 
COVID-19 test k 
 
X 
 
 
 
 
 
 
Admission to study 
ward 
 
X 
 
 
 
 
 
 
Randomization l 
 
X 
 
 
 
 
 
 
Investigational 
product 
administration m 
 
 
X 
 
X 
 
 
 
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Procedure 
/Assessment 
Screening 
Period 1 
Interval a 
Period 2 
End of 
study c 
Early 
termination b 
Within 7 
days 
prior to 
first dose  
Day -1 
Day 
1 
Day 2 
Day 
3 
Day 
4 
Day 5 
 
High-fat/high-
calorie meal n 
 
 
X 
 
X 
 
 
 
AE Collection o 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic 
blood sampling p 
 
 
X 
 
X 
 
 
 
Leave study ward 
 
 
 
 
 
X 
 
 
Abbreviations: AE= Adverse Events; ECG= electrocardiogram. 
Footnotes:  
a. The first dose will be in the morning of Day 1 and the second dose in the morning of Day 3, with a washout 
period of 2 days. 
b. If a subject who has received the investigational product discontinues the study prematurely, an early termination 
safety assessment is required, while pharmacokinetic blood sampling will no longer be performed. If the subject 
who discontinues study has completed randomization but has not received the investigational product, safety 
assessments may be performed as the investigator deems appropriate. 
c. The subjects will complete a follow-up visit 2 days after last dose of medication, as their end-of-study (EOS) 
visit. Due to any unforeseen circumstances if follow-up visit is not completed on day 5, this can be rescheduled 
and completed in next 2 days i.e., till day 7. The follow-up visit can be done via telephone if the subject does 
not need to receive any examination, as judged by the investigator.  
d. A full physical examination will be required at screening, and an abbreviated physical exam will be performed 
for all the other visits.  
e. Vital signs (blood pressure, pulse, body temperature, respiratory rate) in a sitting position need to be measured. 
f. 12-lead ECG parameters include heart rate, PR interval, QRS interval, QT interval and QTcF interval. 12-lead 
ECGs will be performed with the subject in a sitting position having rested in this position for at least 5 minutes 
before the exam. 
g. Laboratory tests include blood chemistry, hematology, urinalysis, coagulation. 
h. Serology: including hepatitis B surface antigen (HBsAg), HBcAb, hepatitis C virus antibody (HCV), human 
immunodeficiency virus (HIV) antibody and syphilis. 
i. Females of childbearing potential should complete the blood pregnancy test at screening, 1 day before dosing 
in period 1, and Day 4/ early termination. 
j. Follicle-stimulating hormone done only in females who have been consecutively amenorrhoeic for 12 months. 
k. COVID-19 tests are to be performed as follows: Day -1; and at any time during residential period in study, when 
subjects report symptoms suggestive of COVID-19 as defined by World Health Organization (WHO) or local 
guidance. 
l. Randomization: After confirmation of subject enrollment on Day -1. 
m. In fasted/fed cohort, subjects randomized to TR sequence will receive test product on Day1 and reference 
product on Day3; subjects randomized to RT sequence will receive reference product on Day1 and test product 
on Day3. 
n. Applicable to fed cohort only. The temporal order should be: vital signs > blood sampling before dosing > high-
fat and high-calorie meal > drug administration. A high-fat/high-calorie breakfast contains about 800-1000 kcal, 
including about 500-600 kcal from fat (more than 50% of total calories), about 150 kcal from protein, and about 
250 kcal from carbohydrates. 
o. The AEs will be collected from time of informed consent. 
p. Fasted cohort: PK samples for determination of ibuprofen in plasma will be taken prior dose, and at 5, 10, 15, 
20, 30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 h after oral administration of test product or reference 
product. 
Fed cohort: PK blood samples will be obtained prior to dosing (pre-dose) and 10, 30, 45, 60, 75, 90, 120 min, 
2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 h after test or reference product administration. 
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2 
INTRODUCTION 
2.1 
Study Rationale 
A new ibuprofen arginine granules formulation developed by Wyeth Pharmaceutical Co., Ltd 
(hereinafter referred to as “GSK CH”), is intended to be registered in China. In order to ensure 
that this new formulation is clinically equivalent to the original reference product, GSK CH will 
conduct this bioequivalence study. This study is required to determine whether the test product 
is bioequivalent to the reference ibuprofen arginine granules under fasting and fed conditions 
in Chinese healthy adult subjects.  
2.2 
Background  
Ibuprofen, (±)-(R, S)-2-(4-isobutylphenyl)-propionic acid, is a chiral 2-arylpropionic acid 
derivative nonsteroidal anti-inflammatory drug (NSAID) widely used in the management of 
mild to moderate pain, fever and inflammation since early seventies [2]. Ibuprofen is a non-
selective inhibitor of cycloxygenase-1 and -2 derived prostaglandin biosynthesis [3]. In the 
clinical practice the drug is usually given by oral route, and the commonest adverse events (AEs) 
occurring during therapy with ibuprofen include gastrointestinal discomfort, nausea and 
diarrhea. Nevertheless, systematic review of controlled epidemiological studies have 
consistently shown that ibuprofen is associated with the lowest relative risk of serious 
gastrointestinal complications compared with other NSAIDs [4]. 
Currently, different ibuprofen formulations are available on the market [5]. These formulations 
differ in terms of pharmaceutical composition that influences the pharmacokinetic (PK) profile 
and eventually the onset of action of ibuprofen. The formulation of ibuprofen has a significant 
effect on its rate of absorption and subsequent time to reach maximum concentrations (Tmax). 
Ibuprofen is a Biopharmaceutics Classification System (BCS) class II drug (BCS II = low 
solubility, high permeability) [6]. The ibuprofen acid has low solubility at pH 1.2 and 4.5 and 
high solubility at pH 6.8. Ibuprofen is highly permeable and is rapidly absorbed as soon as it 
dissolves. Formulations that aid ibuprofen’s rate of dissolution (soluble salt forms) or provide 
ibuprofen in a ‘dissolved’ form (gel capsules or effervescent tablets) speed time to maximal 
concentrations [2],[3],[7],[8].There is one such formulation, ibuprofen arginine, specifically 
designed to improve the absorption of ibuprofen. Ibuprofen arginine was firstly introduced on 
the market in 1994 in Spain [9], and is now commercially available in several other European 
Countries as Spedifen
  
Ibuprofen arginine granules (Spedifen) was approved in China by the National Medical 
Products Administration (NMPA) in 2005 (200 mg, H20058759; 400 mg, H20058760; 600 mg, 
H20058761). A new ibuprofen arginine granules formulation developed by GSK CH will be 
investigated in this study to support the generic registration in China. This randomized 
crossover study is now being conducted to evaluate the bioequivalence of ibuprofen arginine 
granules manufactured by the sponsor and Spedifen manufactured by
 under fasting 
and fed conditions. 
2.3 
Benefit/Risk Assessment  
The investigational drug may cause adverse reactions as described in instructions [10], and blood 
samples drawn during the study procedures may cause some pain, discomfort, bruising and 
redness/irritation at the site of drawing. Participants will be monitored closely by the site staff 
during the site visits. If any discomfort occurs during the study, appropriate measures will be 
taken promptly by investigator.  
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Participants enrolled into this study are healthy participants. There will be no direct benefits 
gained from participation in this study. The participants’ involvement will be contributing to 
the PK analysis and safety profile of the ibuprofen arginine granules manufactured by GSK CH 
compared to reference product (Spedifen). 
Complete information for this product may be found in the single reference safety document, 
which for this study is the Investigator Brochure (IB). 
2.4 
Mechanism of Action/Indication 
Ibuprofen by inhibiting the synthesis of prostaglandin produces analgesic, antipyretic and anti-
inflammatory effects. Ibuprofen arginine is an arginine salt of ibuprofen, which can improve 
the solubility of ibuprofen, and thus leads to more rapid absorption [10],[11]. The analgesic effect 
is achieved within 15-30 minutes after administration [10],[12]. 
This product is indicated for the following symptoms: Toothache, dysmenorrhea, pain caused 
by trauma (such as sports injury), arthralgia and desmalgia, dorsalgia, encephalalgia, neuralgia 
and fever caused by flu. 
The recommended oral dosage for adults aged 12 years old and above is one sachet (400 mg) 
twice daily. Place this product into a glass, add an appropriate amount of warm water, and take 
it after the product completely is dissolved. This product takes effect more quickly being taken 
on an empty stomach. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
Table 3-1 
Study Objectives and Endpoints 
Objective(s) 
Endpoint(s) 
Primary 
Primary 
The objective of this study is to demonstrate the 
bioequivalence of 400 mg new ibuprofen 
arginine granules compared to 400mg ibuprofen 
arginine granules (Spedifen) in two separate 
conditions (fed cohort and fasted cohort) 
• Primary PK endpoints in fed cohort: AUC0-t, 
AUC0-∞, and Cmax 
y Primary PK endpoints in fasted cohort: AUC0-
t, AUC0-∞ and Cmax 
Secondary 
Pharmacokinetics 
To assess the PK profile of test and reference 
product 
y Secondary PK endpoints in fed cohort: Tmax, 
t1/2, λz, and %AUCex 
y Secondary PK endpoints in fasted cohort: 
Tmax, t1/2, λz, and %AUCex 
Safety 
 
To assess the safety profile of test and reference 
product  
Ь Frequency and nature of adverse events 
Ь Physical examination 
Ь Vital signs 
Ь Laboratory tests 
Ь 12-lead electrocardiogram  
This study will be considered successful, that is the test product will be considered equivalent 
to the reference product, if the 90% CI for the geometric mean ratio (GMR) (T/R), based on 
log-transformed data, is completely contained within the acceptance interval of 0.8000 to 
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1.2500 for the primary PK parameters (AUC0-t, AUC0-∞, and Cmax) in both fasted cohort and fed 
cohort.  
4 
STUDY DESIGN  
4.1 
Overall Design 
The bioequivalence study adopts a single-center, randomized, open-label, single-dose, two-
treatment, two-sequence, two-period, two-cohort, two-way crossover design with at least 2-day 
washout period, under fasting and fed conditions respectively. 
For this study, it is planned to enroll approximately 84 subjects (the first 34 subjects for the 
fasted cohort and the subsequent 50 subjects for the fed cohort). 
4.2 
Scientific Rationale for Study Design 
A single-center, randomized, open-label, single-dose, two-period, crossover-controlled design 
will be used. Healthy adult males and females subjects will be selected in accordance with 
Technical Guidelines for Human Bioequivalence Studies of Chemical Generics Taking 
Pharmacokinetic Parameters as Endpoint Evaluation Indicators [1] published by NMPA in 2016 
and as per Chinese Pharmacopoeia [13]. 
A crossover design, using the same subjects to test each product, will be used to reduce 
variability. The blood sampling time points and the washout interval have been chosen based 
on the information available particularly on Spedifen’s absorption, as well as its elimination.  
In accordance with the catalogue of reference preparations for generic drugs, the ibuprofen 
arginine granules, Spedifen, manufactured by
 is selected as the reference product. 
The mean terminal half-life (t1/2) of a single oral dose of ibuprofen arginine is approximately 
1.5~2 hours according to the instruction of Spedifen (200 mg), thus the washout period (dosing 
interval) between 2 doses in the study periods is set to 2 days, much greater than 7-fold t1/2. 
4.3 
Justification for Dose 
This is a study to assess the bioequivalence of the test product to a commercial reference product. 
In accordance with the Chinese guideline of the bioequivalence study, single dose will be used 
for both test and reference product. 
4.4 
End of Study Definition 
A subject is considered to have completed the study if he or she has completed all procedures 
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 to complete the 
study. 
5 
STUDY POPULATION 
5.1 
Type and Planned Number of Subjects 
For this study, it is planned to enroll approximately 84 subjects (34 subjects for the fasted cohort 
and 50 subjects for the fed cohort) to achieve 32 subjects completing in the fasted cohort and 
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46 subjects completing in the fed cohort respectively. This estimates to 78 subjects overall 
completing the study. 
In the fasted cohort, at least 17 subjects will be assigned to either TR or RT sequence and 
similarly in the fed cohort at least 25 subjects will be assigned to either TR or RT sequence. 
An enrolled subject is one who has agreed to participate in this 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 achieve its objectives only if appropriate subjects are enrolled. The following 
eligibility criteria are designed to select subjects for whom participation in this 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 study.  
Subject’s eligibility to participate in this 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 be included into the study: 
1. Subject provision of a signed and dated informed consent and/or assent document indicating 
that the subject has been informed of all pertinent aspects of the study before any assessment 
is performed. 
2. Subject is male or female. 
3. Subject is 18~50 years of age inclusive, at the signing of the informed consent. 
4. Subject who is willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, study restrictions, lifestyle considerations and other study procedures. 
5. Healthy subject, which is defined as in general good physical health, as judged by the 
investigator and no clinically significant relevant abnormalities identified by a detailed 
medical history, full physical examination, including vital signs, 12-lead electrocardiogram 
(ECG) and laboratory tests. 
6. A subject with a Body Mass Index (BMI) of 19~26 kg/m2 (including 19, excluding 26) 
[BMI = weight (kg)/height2 (m2)]; and a total body weight ≥ 50 kg for males, and ≥ 45 kg 
for females, at screening. 
7. Subject with one negative polymerase chain reaction (PCR) or antigen test (on Day-1) for 
active COVID-19. 
8. Female subject of childbearing potential and are sexually active 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 subjects who are not of 
childbearing potential must meet requirements in the Contraception section of protocol.  
5.3 
Exclusion Criteria 
An individual who meets any of the following exclusion criteria will be excluded from the study: 
1. Known or suspected intolerance or hypersensitivity or photosensitivity to the investigational 
products (or closely related compounds) or any of their stated ingredients. 
2. 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 candidate. 
3. Diagnosis of long QT syndrome or QTcF > 450 msec at screening. 
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4. Clinically significant vital sign abnormalities (systolic blood pressure lower than 90 or over 
140 mmHg, diastolic blood pressure lower than 60 or over 90 mmHg, or pulse rate less than 
50 or over 100 bpm). 
5. Use of any medication (including over-the-counter medications and Chinese herbal and 
traditional remedies) within 2 weeks before first scheduled study drug administration or 
within less than 10 times the elimination half-life of the concomitant medication (whichever 
is longer), 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 in 24 hours). 
6. Subject has a history of drug abuse or has positive urine drug abuse screening at screening 
or on Day-1. 
7. Subject reported regular consumption of > 5 cups (1 cup Ү 250 mL) of coffee or tea per day 
(or equivalent consumption of ≥ 500 mg caffeine per day using other products). Or 
consuming any beverages or food containing caffeine, such as coffee, tea, coke, chocolate, 
etc., within 48 hours prior to screening. 
8. Smoking or history of regular use of tobacco- or nicotine-containing products (e.g. 
nicotinepatch, electronic cigarette) within 6 months prior to screening. Or a subject who is 
unwilling to abstain from tobacco or nicotine containing product use during the study. 
9. Evidence, as reported by an alcohol breath testing, for current alcohol abuse or reports a 
regular average alcohol consumption exceeding 18 g (women) or 35 g (men) of pure alcohol 
per day, i.e. 1 drink/day for women or 2 drinks/day for men [1 drink = 5 ounces (150 mL) 
of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor] within 6 
months prior to screening. 
10. Participation in other clinical trials involving investigational drug(s) within 90 days prior to 
screening. 
11. Those who have blood donation (including component donation) or blood loss ≥ 400 mL 
within 3 months before the study, or have blood transfusion; those who have blood donation 
(including component donation) or blood loss ≥ 200 mL within 1 month before the study 
(except female physiological blood loss). 
12. Acute or chronic medical 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. Or 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. 
13. Evidence or history of clinically significant 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.  
14. Clinically relevant chronic or acute infectious illnesses or febrile infections within two 
weeks prior to start of the study. 
15. Subject with known COVID-19 positive contacts in the past 14 days. 
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Clinical Protocol 
 
 
Protocol Number: 218552  
 
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16. Subject with signs or symptoms highly suggestive of COVID-19 (including not limited to 
fever, cough, chills, new loss of taste or smell, etc.)* that also align with the clinical 
judgement of the investigator, within 14 days of inpatient admission. *as defined by World 
Health Organization (WHO) or local guidance.  
17. Any vaccination, including COVID-19 vaccine, within 14 days prior to the first dose of 
investigational products. 
18. 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; 
x History or current evidence of renal disease or impaired renal function at screening as 
indicated by abnormal levels of eGFR㸺90 mL/min/1.73m2 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 
deviations are found: 1) AST (≥ 1.2 ULN), ALT (≥ 1.2 ULN), 2) GGT (≥ 1.2 ULN), 
ALP (≥ 1.2 ULN), 3) bilirubin (≥ 1.5 ULN) or CK (≥ 3 ULN). A 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 or difficulty in voiding at screening; 
x History or clinical evidence at screening of pancreatic injury or pancreatitis. 
19. Pregnant or lactating women, or subjects intending to become pregnant over the duration of 
the study; 
20. Positive results (or out of normal range) any of the virology tests for hepatitis B surface 
antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C virus (HCV) antibody, 
human immunodeficiency virus (HIV) antibody or syphilis . 
21. 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 screening until admission to the unit. 
22. Performance of strenuous physical exercise (body building, high performance sports) from 
2 weeks prior to admission. 
23. Those who are not suitable for participation in this study as determined by the investigator. 
5.4 
Randomization Criteria 
In each cohort, subjects will be randomized into the study provided they have satisfied all 
subject selection criteria. Subjects are assigned to TR sequence or RT sequence in a 1:1 ratio 
according to the randomization schedule. 
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
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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. 
x In the fasted cohort, after an overnight fasting for at least 10 hours, the subjects will take 
the test product or the reference product according to the randomization schedule with 
240 mL of warm water under fasting condition on Day 1 during each period. The study drug 
granules must be mixed and stirred with 240 mL of warm water to be completely dissolved. 
The oral solution will then be left to cool down, to allow a rapid (less than 1 minute) and 
continuous ingestion by the subject. 
x In the fed cohort, after an overnight fasting for at least 10 hours, the subjects will take a 
high-fat/high-calorie breakfast (completed within 30 minutes) and then take the test product 
or the reference product according to the randomization schedule on Day 1 in each period. 
The study drug granules must be mixed and stirred with 240 mL of warm water to be 
completely dissolved. The oral solution will then be left to cool down, to allow a rapid (less 
than 1 minute) and continuous ingestion by the subject. 
A high-fat/high-calorie breakfast contains about 800-1000 kcal, including about 500-600 
kcal from fat (more than 50% of total calories), about 150 kcal from protein, and about 250 
kcal from carbohydrates. 
x Water consumption requirements: Water is prohibited from 1 hour before dosing to 1 hour 
after dosing on Day 1 in each cycle (except for water for dosing). Water is provided ad 
libitum at other times. 
x Food consumption requirements: No food is allowed within 4 hours after administration. 
x Lunch will be provided approximately 4 hours after dosing. 
x Dinner will be provided approximately 10 hours after dosing. 
x Non-caffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices ̽ see below) 
may be consumed with meals. 
x Subjects will not be allowed to eat or drink beverages or food supplements (e.g. broccoli, 
Brussels sprouts, grapefruit or grapefruit-related citrus fruits (e.g. Seville oranges, pomelos, 
papaw, dragon fruit, kiwi fruit, mango, passion fruit, pomegranate, rambutan, star fruit or 
products that contain these fruits and St. John’s Wort etc.) from admission to the clinic site 
until collection of the final PK blood sample. 
x Meals intake during the study will also be standardized. 
5.5.2 
Alcohol, Caffeine and Tobacco 
x Subjects will be prohibited from consuming alcohol and consuming any beverages or food 
containing caffeine, such as coffee, tea, coke, chocolate, etc., from screening until collection 
of the final PK blood sample.  
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 (except when any AE(s) require(s) medical treatment). 
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Clinical Protocol 
 
 
Protocol Number: 218552  
 
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x Subjects will abstain from strenuous exercise (e.g., heavy lifting, weight training, 
calisthenics, aerobics) for the duration of the study. Walking at a normal pace will be 
permitted. 
5.5.4 
Contraception 
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 
investigational product. The investigator or his or her designee will educate the subjects about 
highly effective methods of contraception (see below) and requirements about contraception 
during the informed consent process, admission education and during the study. Subjects need 
to affirm that they meet the criteria for the correct use of at least 1 of the selected methods of 
contraception. 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 sterilization with absence of sperm in the post-vasectomy ejaculate; 
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label); 
6. Female who meets the criteria for non-childbearing potential as described below: 
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-stimulating hormone (FSH) level ≥ 40 mIU/mL; 
x Have undergone a documented hysterectomy and/or bilateral oophorectomy. 
All other female subjects (including females with tubal ligations) will be considered to be of 
childbearing potential. 
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.  
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Clinical Protocol 
 
 
Protocol Number: 218552  
 
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 Clinical Protocol Template v8.0 
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Individuals who do not meet the criteria for participation in this study (screen failure) will not 
be re-screened. 
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 investigator study master file held at the 
study site. 
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 for the sponsor's appropriately qualified medical personnel 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 investigator’s 
contacts in the informed consent form (ICF). 
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 Harmonisation (ICH) guidelines, 
and GSK CH 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. 
6.1 
Study Product Supplies 
The selection of the batches of Test and Reference product will be based on assay content to 
ensure that the products do not differ by more than 5%. 
The following study products will be supplied by the Clinical Supplies Department, GSK CH: 
Table 6-1 
Study Product Supplies 
 
Test Product 
Reference Product 
Product Name 
Ibuprofen Arginine Granules 
Ibuprofen Arginine Granules 
(Spedifen) 
Pack Design  
Sachet 
Sachet 
Dispensing Details 
Period 1- one sachet 
Period 2- one sachet 
Period 1- one sachet 
Period 2- one sachet 
Strength 
400 mg (calculated with 
ibuprofen) 
400 mg (calculated with 
ibuprofen) 
Product Master 
Formulation Code (MFC) 
Commercial Product 
Route of Administration 
Oral 
Oral 
Manufacturer 
Wyeth Pharmaceutical Co., Ltd. 
Storage 
This product is sealed and stored 
at ambient temperature (10-30Ԩ). 
This product is sealed and stored 
at ambient temperature (10-30Ԩ). 
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Return Requirements 
Unused (excluding samples 
retained by the study site) 
Unused (excluding samples 
retained by the study site) 
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. 
6.1.1 
Dosage Form and Packaging 
Granules will be supplied to the clinical site as packaged carton 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 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 an approved GSK CH vendor, prior to the start of the study, using validated software. 
Study product will be dispensed by qualified site personnel. 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. 
In the fasted cohort, after an overnight fasting for at least 10 hours, subjects will take one sachet 
of either the test product (400 mg ibuprofen) or one sachet of the reference product (400 mg 
ibuprofen) according to the randomization schedule. The study drug granules must be mixed 
and stirred with 240 mL of warm water to be completely dissolved. The oral solution will then 
be left to cool down, to allow a rapid (less than 1 minute) and continuous ingestion by the 
subject. 
In the fed cohort, after an overnight fasting for at least 10 hours, subjects will take a high-
fat/high-calorie breakfast (completed within 30 minutes) 30 minutes exactly before 
administration and then take either one-sachet of the test product (400 mg ibuprofen) or one-
sachet of the reference product (400 mg ibuprofen) according to the randomization schedule 
under fed condition on Day 1 during each period. The study drug granules must be mixed and 
stirred with 240 mL of warm water to be completely dissolved. The oral solution will then be 
left to cool down, to allow a rapid (less than 1 minute) and continuous ingestion by the subject.  
After administration, the study personnel will examine the subject's oral cavity to ensure the 
subject's compliance with the dosing. 
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6.2.1 
Medication/Dosing Errors 
Dosing errors may result, in this study, from the administration or consumption:  
x of the wrong product, 
x by the wrong subject,  
x at the wrong time,  
x or at the wrong dosage.  
Such dosing errors occurring to a study subject are to be captured in the case report form (CRF). 
In the event of medication dosing error, the sponsor should be notified immediately and under 
no circumstance should this exceed 24 hours from its first knowledge. 
Dosing errors are reportable irrespective of the presence of an associated AE, including: 
x Dosing errors involving subject exposure to any of the study products; 
x Potential dosing errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating subject. 
If a dosing error is accompanied by an AE, as determined by the investigator, the dosing error 
and, any associated AE(s) 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. Limited quantities of the study product(s) will be 
supplied, and closely monitored by the site for each subject. 
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 
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.  
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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, must be documented as a 
protocol deviation and reported to the Sponsor. 
Once an excursion is identified, the affected products must be quarantined and not used until 
the sponsor provides documentation of permission to use. Use of any of the affected products 
prior to sponsor approval will be considered a protocol deviation. 
6.4 
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.  
In accordance with Chinese Good Clinical Practice (GCP) [14] and Technical Guidelines for 
Human Bioequivalence Studies of Chemical Generic Drugs Using Pharmacokinetic Parameters 
as Endpoint Evaluation Indicators [1], the study site should retain samples of the test and 
reference products in accordance with relevant requirements. The retained sample shall be from 
the same batch as the drug administered in the study, and the quantity of the retained drugs shall 
be adequate for 5 full inspections according to the specifications. Retained samples will be 
stored by the study site until least 2 years after the product is marketed. The study site may 
entrust a qualified independent third party to store the retained samples, but the samples may 
not be returned to the sponsor or a third party with related interests. 
At the end of the study, the principal investigator or an appropriate designee, and a 
representative of GSK CH (study monitor) will inventory all used and unused study products. 
The study product accountability record for returned study products (excluding samples 
retained by the study site) will then be completed. All unused study product for this clinical 
study, excluding samples retained by the study site, 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. 
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
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6.5 
Blinding and Allocation/Randomization 
This clinical study is an open-label study, in which all personnel (except bio-analysis and testing 
personnel), such as clinical investigator, Project Manager, project monitor, data management 
personnel, will not be blinded. Blind analysis techniques will be used by the analysis and testing 
personnel, who does not know which investigational product the subjects are given in each 
period during the analysis. Also personnel involved in any data analysis (data management, 
statisticians etc.) should be using anonymised subject data. 
Subjects will be assigned to TR sequence or RT sequence in a 1:1 ratio by randomization 
number at the site in fasted and fed cohorts. Randomization number consists of one letter K+3 
digits number in the fasted cohort, and C+3 digits number in the fed cohort. Randomization will 
be based on the randomization scheme taking the lowest available number when assigning a 
subject. 
6.6 
Breaking the Blind 
Not applicable. 
6.7 
Compliance 
Study products will be administered under the supervision of investigator site personnel. A 
mouth check will be performed to ensure consumption of the medication.  
6.8 
Concomitant Medication/Treatment(s) 
No therapeutic medications are allowed during the study 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. Any medications, 
treatments or vaccine (including over-the-counter 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.  
Prohibited medications: barbiturates, benzodiazepines ,cocaine, methadone, phencyclidine. 
Medication/treatments taken within 90 days of signing the ICF and finished before the first dose 
will be documented as prior medication/treatments. 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 for safety, behavioral reasons, 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 
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
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x Positive test for COVID-19, conducted during the study, at times deemed necessary by 
investigator 
x Withdrawal of informed consent 
x Subject lost to follow-up 
x Pregnancy  
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 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, request 
that the subject return for a final visit and follow-up with the subject regarding any unresolved 
AEs. 
Early termination safety assessments may be carried out when the subject returns to the study 
site, at the investigator’s discretion, which could include the following: vital signs, physical 
examination, 12-lead ECG, laboratory tests, blood pregnancy test (women of childbearing 
potential), COVID-19 test, and collection of concomitant medications/treatments and AE(s). 
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 as 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. 
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 of protocol. 
Adherence to the study design requirements, including all procedures are essential and required 
for study conduct. 
The study visit plan includes: 
Ь 
Screening (within 7 days prior to first dose); 
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Ь 
Period 1 (Day -1 and Day 1); 
Ь 
Interval (Day 2) If the interval between 2 doses exceeds 2 days, the second dose and 
subsequent visits will be postponed accordingly; 
Ь 
Period 2 (Day 3 to 4); 
Ь 
End of study (Day 5). 
Figure 1 
Study Schematic 
 
8.1 
Screening 
Screening procedures will be conducted by the Investigator, or suitably qualified designee. 
Subjects will be screened within 7 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. Two copies of the ICF will be signed and dated by the subject, the subject will retain 
one copy and the other will be kept at site. 
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.  
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 ICF 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. 
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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. 
8.1.2 
Demographics 
The following demographic information will be recorded in the CRF: gender, year of birth, 
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, 2016. 
8.1.3 
Inclusion/Exclusion Criteria 
The investigator and/or medically qualified designee will review inclusion/exclusion criteria as 
specified in STUDY POPULATION, medical history, smoking history and alcohol 
consumption history, prior/concomitant medications/treatments to confirm subject eligibility to 
participate in the clinical study. This will be documented in the CRF. 
8.1.4 
Medical History and Prior Medication/Treatment 
Details of relevant medical history (in the last 5 years), transfusion/blood donation history (in 
the last 3 months), allergy history, surgical history, childbearing history, family history, 
menstrual history female), drug abuse history, smoking history, alcohol consumption history, 
COVID-19 history and COVID-19 positive contact history (in the past 14 days) will be 
documented in the electronic CRF (eCRF). 
Prior medications/treatments, including prescription and non-prescription drugs, dietary 
supplements and herbal remedies, taken in the 90 days prior to signing the ICF and finished 
before the first dose, will be documented in the eCRF. 
8.1.5 
Screening procedures 
The following screening procedures should be completed 7 days prior to first administration: 
Height/weight measurement, full physical examination, vital signs examination, 12-lead ECG, 
laboratory tests (blood chemistry, hematology, urinalysis, coagulation), alcohol breath test, 
urine drug abuse screening, serology, blood pregnancy test (only in females of childbearing 
potential), hormone test (only in females who have been consecutively amenorrhoeic for 12 
months), and AEs, prior/concomitant medications/treatments collection. 
8.2 
Study Period  
8.2.1 
Period 1 
Day -1 (Period 1) 
The fasted and fed cohorts will follow the same procedures on Day -1. 
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On Day -1, subjects will be admitted to the study ward, the following procedures will be 
performed: concomitant medications/treatments review, abbreviated physical examination, 
vital signs examination, alcohol breath test, urine drug abuse screening, blood pregnancy test 
(only in females of childbearing potential), COVID-19 test, and collect AEs. The 
inclusion/exclusion criteria will be reviewed again. Enrolled subject will be randomized on Day 
-1. 
Day 1 (Period 1) 
The fasted and fed cohorts have different procedures on Day 1. 
Fasted cohort: 
Within 2 hours before dosing: 
Ь 
Vital signs (blood pressure, pulse, body temperature, and respiratory rate); 
Ь 
PK blood sampling, completed within 2 hours prior to investigational product 
administration. 
Administration of investigational product: 
Ь 
See Administration for details. 
Post-dose: 
Ь 
A standard lunch will be provided approximately 4 hours after dosing, a uniform standard 
dinner will be provided approximately 10 hours after dosing, and water is not allowed 
until 1 hour after dosing; 
Ь 
PK blood sampling (5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 h 
after oral administration, the blood collection window is detailed in Table 9-2); 
Ь 
Collection of concomitant medications/treatments; 
Ь 
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; 
Ь 
Vital signs (3 [± 0.5], 6 [± 0.5] hours post-dose); 
Ь 
Subjects will be remained in the study ward. 
Fed cohort: 
Within 2 hours before dosing: 
Ь 
Vital signs (blood pressure, pulse, body temperature, and respiratory rate); 
Ь 
PK blood sampling, completed within 2 hours prior to investigational product 
administration; 
Ь 
High-fat/high-calorie breakfast (started exactly 30 minutes before dosing and completed 
within 30 minutes); 
Administration of investigational product: 
Ь 
See Administration for details. 
Post-dose: 
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Ь 
A standard lunch will be provided approximately 4 hours after dosing, a uniform standard 
dinner will be provided approximately 10 hours after dosing, and water is not allowed until 
1 hour after dosing; 
Ь 
PK blood sampling (10, 30, 45, 60, 75, 90, 120 min, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 h 
after oral administration, the blood collection window is detailed in Table 9-2); 
Ь 
Collection of concomitant medications/treatments; 
Ь 
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; 
Ь 
Vital signs (3 [± 0.5], 6 [± 0.5] hours post-dose); 
Ь 
Subjects will be remained in the study ward. 
8.2.2 
Interval 
Day 2 
The fasted and fed cohorts will follow the same procedures on Day 2. 
Subjects will remain in the study ward on Day 2. They will be received the following 
examinations: 
Ь 
Abbreviated physical examination; 
Ь 
Vital signs (blood pressure, pulse,body temperature, respiratory rate); 
Ь 
Laboratory tests (see Table 9-1 for specific tests); 
Ь 
12-lead ECG; 
Ь 
Collection of concomitant medications/treatments; 
Ь 
AE monitoring, and 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 
Period 2  
Day 3 (Period 2) 
The fasted and fed cohorts have different procedures on Day 3. 
Fasted cohort: 
Within 2 hours before dosing: 
Ь 
Vital signs (blood pressure, pulse, body temperature, and respiratory rate); 
Ь 
PK blood sampling, completed within 2 hours prior to investigational product 
administration. 
Administration of investigational product: 
Ь 
See Administration for details. 
Post-dose: 
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Ь 
A standard lunch will be provided approximately 4 hours after dosing, a uniform standard 
dinner will be provided approximately 10 hours after dosing, and water is not allowed until 
1 hour after dosing; 
Ь 
PK blood sampling (5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 h 
after oral administration, the blood collection window is detailed in Table 9-2); 
Ь 
Collection of concomitant medications/treatments; 
Ь 
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; 
Ь 
Vital signs (3 [± 0.5], 6 [± 0.5] hours post-dose); 
Ь 
Subjects will be remained in the study ward. 
Fed cohort: 
Within 2 hours before dosing: 
Ь 
Vital signs (blood pressure, pulse, body temperature, and respiratory rate); 
Ь 
PK blood sampling, completed within 2 hours prior to investigational product 
administration; 
Ь 
High-fat/high-calorie breakfast (started exactly 30 minutes before dosing and completed 
within 30 minutes); 
Administration of investigational product: 
Ь 
See Administration for details. 
Post-dose: 
Ь 
A standard lunch will be provided approximately 4 hours after dosing, a uniform standard 
dinner will be provided approximately 10 hours after dosing, and water is not allowed until 
1 hour after dosing; 
Ь 
PK blood sampling (10, 30, 45, 60, 75, 90, 120 min, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 h 
after oral administration, the blood collection window is detailed in Table 9-2); 
Ь 
Collection of concomitant medications/treatments; 
Ь 
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; 
Ь 
Vital signs (3 [± 0.5], 6 [± 0.5] hours post-dose); 
Ь 
Subjects will be remained in the study ward. 
Day 4 (Period 2) 
The fasted and fed cohorts will follow the same procedures on Day 4. 
On Day 4, subjects can leave the study ward after completing the following examinations: 
Ь 
Abbreviated physical examination; 
Ь 
Vital signs (blood pressure, pulse,body temperature, respiratory rate); 
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Ь 
12-lead ECG; 
Ь 
Laboratory tests (see Table 9-1 for specific tests); 
Ь 
Blood pregnancy test (female subjects of childbearing potential only); 
Ь 
Collection of concomitant medications/treatments; 
Ь 
AE monitoring, and 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. 
8.2.4 
End of study 
The subjects will complete an end-of-study (EOS) visit 2 days after last dose of study 
medication (Day 5). Due to any unforeseen circumstances if follow-up visit is not completed 
on day 5, this can be rescheduled and completed in next 2 days i.e., till day 7. The follow-up 
visit can be done via telephone if the subject does not need to receive any examination, as judged 
by the investigator. The investigator or his/her authorized staff shall complete the following 
procedures after discharge from the study ward:  
Ь 
Concomitant medications/treatments; 
Ь 
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. 
Subjects may be asked to return to the ward for follow-up if deemed necessary by the 
investigator. 
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. And efforts should be made to complete the early 
termination safety assessment as described in Lost to Follow up of protocol. 
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.  
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 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 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. Specific clinical laboratory tests are detailed in Table 9-1. 
Table 9-1 
Laboratory Tests  
Blood chemistry 
Creatine kinase 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Gamma-glutamyl transpeptidase 
Total protein 
Albumin 
Total bilirubin 
Direct bilirubin 
Urea 
Creatinine 
Total cholesterol 
Triglycerides 
Serum calcium 
Phosphorous 
Sodium, potassium, chlorine 
Fasting glucose 
Hematology 
Red blood cell count (RBC) 
Hematocrit 
Hemoglobin 
White blood cell count (WBC) 
Differential white blood cell count (including 
percentages and absolute counts of neutrophils, 
eosinophils, 
basophils, 
monocytes, 
and 
lymphocytes) 
Platelet count 
Blood Pregnancy test (for women of childbearing 
potential only) 
Hormone test (postmenopausal women only) 
Follicle stimulating hormone (FSH) 
Urinalysis 
Urine white blood cells (dry chemistry) 
Nitrite 
Urine pH 
Urine specific gravity 
Urine protein 
Urine glucose 
Urine ketones 
Urobilinogen 
Urine bilirubin 
Urine occult blood 
White blood cells (sediment) 
Red blood cells (sediment) 
Routine coagulation test 
Plasma prothrombin time 
Activated partial thromboplastin time (APTT) 
International normalized ratio (INR) 
Fibrinogen (FIB) 
Serology 
HBsAg 
HBcAb 
HCV Ab 
HIV antibody 
Syphilis  
Urine drug abuse screening 
Alcohol breath test 
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Morphine 
Amphetamines/methamphetamine 
Ketamine 
Methylene dioxymetham-phetamine 
Tetrahydrocannabinolic acid 
breath alcohol concentration 
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 or results would not require additional collection of blood. 
Unscheduled clinical lab tests may be obtained at any time during the study to assess any 
perceived safety concerns. 
9.2.2 
Serology 
The following serology tests will be performed by appropriately trained staff/clinical examiners, 
at the times and in the order defined in STUDY PROCEDURES of this protocol: HBsAg, 
HBcAb, HCV antibody, HIV antibody and Syphilis. In case of a positive (or out of normal 
range) finding in virus serology screen, the subject must be excluded from trial participation. 
9.2.3 
Urine Drug Abuse Screening 
The following drugs will be screened by appropriately trained staff/clinical examiners, at the 
times and in the order defined in STUDY PROCEDURES of this protocol: morphine, 
amphetamines/methamphetamine, 
ketamine, 
methylene 
dioxymetham-phetamine, 
tetrahydrocannabinolic acid. 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 Breath Test 
The alcohol breath test will be performed by appropriately trained staff/clinical examiners, at 
the times and in the order defined in STUDY PROCEDURES of this protocol. In case of the 
result in the alcohol test is out of the negative range, the subject must be discontinued from the 
trial. 
9.2.5 
Pregnancy Testing 
For female subjects of childbearing potential, a blood pregnancy test, will be performed on 
screening, Days -1 and 4/ early termination.  
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 institutional review boards/ethics committees (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, and study termination procedures 
will be followed. 
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 be 
required at screening, and an abbreviated physical examination will be acceptable for all the 
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other visits. A full physical examination will include head, ears, eyes, nose, mouth, skin, heart 
and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, cardiovascular and 
neurological systems. An abbreviated physical examination will include, at a minimum, 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). 
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 meters and body weight in kilograms (kg) to the nearest 0.1 kg 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 can be calculated by a calibrated device directly. The unit of BMI is kg/m2. 
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. 
Sitting blood pressure will be measured with the subject’s arm supported at the level of the heart 
and recorded to the nearest mmHg after a minimum 5 minutes of rest. The same arm (preferably 
the dominant arm) will be used throughout the study. 
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.  
9.2.9 
Respiratory Rate 
Respiratory rate will be measured after approximately 5 minutes rest in sitting 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 during the 
5 minutes of rest and before blood pressure measurement. 
9.2.10 
Temperature 
Body temperature will measure the ear temperature.  
9.2.11 
Electrocardiogram 
A standard 12-lead ECG will be performed at screening. 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 
abnormalities should also be recorded on the Adverse Event CRF. 12-lead ECG parameters 
include heart rate, PR interval, QRS interval, QT interval and QTcF interval. 12-lead ECGs will 
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be performed with the subject in a sitting position having rested in this position for at least 5 
minutes before the exam.  
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 PROCEDURES section. For detection of COVID-19, tests are 
to be performed as follows: 
Ь 
At check-in (Day -1) 
Ь 
At any time during residential period in study, when subjects report symptoms suggestive 
of COVID-19 as defined by WHO or local guidance  
If transportation is required then to provide transportation reimbursement to subjects to and 
from the unit to avoid public transportation. 
9.3 
Pharmacokinetics (PK) 
Fasted cohort: 18 blood samples will be collected for PK analysis, within 2 hours prior to dosing 
(pre-dose), and at 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, 120 min, 2.5, 3, 4, 6, 8, and 12 h 
following dosing in each treatment period. Therefore 36 blood samples will be collected for 
each subject. 
Fed cohort: 18 blood samples will be collected for PK analysis, within 2 hours prior to dosing 
(pre-dose), and at 10, 30, 45, 60, 75, 90, 120 min, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10 and 12 h following 
dosing in each treatment period. Therefore 36 blood samples will be collected for each subject. 
Time zero ("0") as reference for post-dose PK samplings is defined as the time of drug 
administration. All PK blood sampling collection times 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 
During all study periods, blood samples (3 mL) to provide approximately 1.5 mL plasma for 
PK analysis will be collected into appropriately labeled tubes containing dipotassium ethylene 
diamine tetraacetic acid (K2EDTA) at times specified in the protocol. All centrifuged plasma 
samples will be divided into 2 parts and stored in a freezer at the test facility for PK analysis. 
The actual blood sample requirements for PK analysis shall be dependent on the laboratory 
manual 
 or other contracted central lab 
etc.).  
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. However, 
samples obtained within allowable time windows will not be captured as a protocol deviation, 
as long as the exact time of the sample collection is noted on the source document and data 
collection tool (e.g. CRF). 
Table 9-2 
Table of Permissible Deviation for Blood Collection Time 
Planned sampling time point 
Time window 
0 h (pre-dose) 
- 120 minutes 
> 0 h and ≤ 60 min post-dose 
± 1 minute 
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Planned sampling time point 
Time window 
> 60 min and ≤ 4 h post-dose 
± 2 minutes 
> 4 h and ≤ 12 h post-dose 
± 5 minutes 
The specific biological sample handling procedures shall be detailed in the laboratory manual.  
9.3.2 
Shipment of Pharmacokinetic Samples 
The actual shipment of blood sample requirements shall be dependent on the laboratory manual. 
All PK samples will be stored until they are properly disposed of at the end of its retention 
period (i.e., 2 years after clinical 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 after clinical 
studyreport. 
9.4 
Blood Volume 
The total blood sampling volume for each subject in this study is up to 159 mL. The table below 
reflects approximate sample volumes needed for each measured endpoint. Additional blood 
samples may be taken for safety assessments at the discretion of the investigator. 
Table 9-3 
Blood Volume 
Sample Type 
Sample 
Volume 
(mL) 
Number of Sampling Times 
Total Volume (mL) 
Screening 
Study Period 
Follow-Up 
Safety Labs 
9 
1 
2 
- 
27 
Serology 
8 
1 
- 
- 
8 
Blood pregnancy 
testa 
4 
2 
1 
- 
12 
Hormone testa 
4 
1 
- 
- 
4 
PK 
3 
- 
36 
- 
108 
TOTAL 
 
 
 
 
143 (minimum) 
159 (maximum) 
This total volume does not include discarded blood from pre-draws used to remove fluid from flushed catheters, if applicable. 
Footnotes:  
a. Females of childbearing potential should complete the blood pregnancy test. Follicle-stimulating hormone (FSH) done 
only in females who have been consecutively amenorrhoeic for 12 months. 
b. In the event of early termination or reexamination due to abnormal laboratory parameters, the total approximately blood 
volume should be calculated separately. The blood sample volume required for each examination is the same as the above 
table. 
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 investigational product or the study, or that 
caused the subject to discontinue the study product or study. 
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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 definition of an AE include: 
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. 
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 that do not meeting the definition of an AE include:  
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 expected progression of or death due to the pre-existing disease or the disease 
under study, unless more severe than expected). 
A SAE is any untoward medical occurrence at any dose that: 
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x Results in death 
x Is life-threatening  
Note: The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to 
an event, which hypothetically might have caused death, if it were more severe. 
x Requires inpatient hospitalization or prolongation of existing hospitalization  
Note: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or 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 
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which 
may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
x Is a congenital anomaly/birth defect 
x Other situations: 
Note: 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. 
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 30 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.  
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours from its first knowledge. The investigator will submit 
any updated SAE data to the sponsor within 24 hours of it being available. 
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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 original records 
or 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. 
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 
documented as the AE/SAE when 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 
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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 
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 sent to contract research organization 
(CRO),
immediately and under 
no circumstance should this exceed 24 hours of first awareness. CRO will then email the 
SAE 
form 
to 
the 
Case 
Management 
Group, 
Global 
Safety 
at 
GSK 
CH 
 with copy to the appropriate GSK CH Study Manager as 
soon as possible, but not later than one business day after receiving the SAE form from the 
study site. The GSK CH Study Manager will be responsible for forwarding the SAE form to 
other GSK CH personnel as appropriate. 
10.5 
Evaluating Adverse Events  
10.5.1 
Assessment of Intensity/Severity 
The investigator or medically qualified designee will make an assessment of intensity/severity 
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. 
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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/severity 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. 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 degree of certainty about causality will be graded 
using the categories below.  
y 
Reasonable Possibility that AE is related -Yes: The AE is known to occur with the study 
product, there is a reasonable possibility that the study product caused the AE, or there is a 
temporal relationship between the study product and event. 
y 
Reasonable Possibility that AE is related -No: There is not a reasonable possibility that 
the administration of the study product caused the event, there is no temporal relationship 
between the study product and event onset, and an alternate etiology is likely. 
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. The 
investigator will use clinical judgment to determine the relationship and will also consult the 
IB, Safety Statement and/or Product Information, for marketed products, 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. Generally, the facts (evidence) or arguments to suggest a causal 
relationship should be provided. 
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. There may be situations when an 
SAE has occurred, and the investigator has minimal information to include in the initial report 
to GSK CH. 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 to elucidate as fully as possible the nature and/or causality of 
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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). 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 
GSK CH Clinical Operations Safety Reporting email box 
 
The GSK CH Study Manager or designee will be responsible for forwarding the information to 
the 
Case 
Management 
Group, 
Global 
Safety 
mailbox 
at 
GSK 
CH 
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 applicable 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. 
10.9 
Pregnancy 
10.9.1 
Time Period for Collecting Pregnancy Information 
Pregnancy information will be collected on all pregnancies of a female subject reported while 
subjects are participating in the study from the signing of informed consent until 30 days after 
last administration of study product. 
10.9.2 
Action to be Taken if Pregnancy Occurs 
The investigator will collect pregnancy information on female subject while participating in the 
study after administration of the study product. The investigator will record pregnancy 
information on the appropriate form and submit it to CRO within 24 hours of learning of the 
female subject becoming pregnant.  
If a female subject becomes pregnant, she must stop the study product immediately and 
withdrawn from the study. The female 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 to CRO. Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. 
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If the outcome of the pregnancy meets the criteria of SAEs (e.g., spontaneous abortion, stillbirth, 
death of newborn or congenital anomaly, including aborted fetus, stillbirth, or death of 
newborn), the investigator needs to follow the procedures for reporting SAEs. 
CRO will scan and email the pregnancy form to the Case Management Group, Global Safety 
mailbox at GSK CH
with copy to the appropriate GSK CH 
Study Manager. 
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 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, evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, 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 and or diary can be used as a source 
document at the discretion of data management. 
Subjects will be sequentially assigned randomization numbers in the order of screening 
numbers. 
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 study 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 Third Party Vendor 
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 Personal Information (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. 
Refer to the appropriate vendor CRO handbook and study-specific CRF specifications as 
needed for the study. 
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.  
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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 a validated medication dictionary, 
WHODrug. 
11.3 
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. The Clinical Dictionary Development and Management Group will 
raise queries as needed on safety data to code the terms (AEs and Drugs or concomitant 
medication) appropriately.  
The study monitor will perform ongoing review the 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, rights and well-being 
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. 
11.4 
External Data  
External Data are subject data obtained externally to the CRF and other sources such as patient 
reported outcome. 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.  
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. 
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12 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
12.1 
Sample Size Determination 
For this study, it is planned to enroll approximately 84 subjects (34 subjects for the fasted cohort 
and 50 subjects for the fed cohort) to achieve 32 subjects completing in the fasted cohort and 
46 subjects completing in the fed cohort respectively. This estimates to overall 78 completer 
and evaluable subjects. Due to the unpredictability of the adverse covid situation the enrolment 
of subjects may be higher than specified in the protocol to meet the number of completer and 
evaluable subjects required for this study.  
In the fasted cohort, at least 17 subjects will be assigned to either TR or RT sequence and 
similarly in the fed cohort at least 25 subjects will be assigned to either TR or RT sequence. 
The study will be deemed successful if the test product is equivalent to the reference product 
defined as the 90% confidence interval (CI) for the GMR (T/R), based on log-transformed data, 
being completely contained within the acceptance interval of 0.8000 to 1.2500 for the primary 
PK parameters (AUC0-t, AUC0-Ğ, and Cmax) in both fasted cohort and fed cohort respectively. 
Considering a 2  2 crossover study design and using the information from the literature most 
similar to this study (refer to literature data of fasting condition [15]), the following estimates 
were used to calculate the intra-coefficient of variation (CV) of ibuprofen: GMR = 0.95, alpha 
= 0.05, power = 80%, N = 22 and the upper and lower limit range for determining the 
bioequivalence: 80.00 ~ 125.00%. The intra-CV was estimated to be 22.1%.  
In this literature, since the 90% CI for Cmax was outside the acceptance internal of 0.8000 to 
1.2500 the data was calculated for parameters AUC0-t, AUC0-Ğ. No data on fed status was 
reported in this literature however it seems that some factors will increase the variability after 
meal consumption. 
Another reference that was considered for making intra-CV assumptions was public assessment 
report [16]. The intra-CV for Cmax was back calculated using the following estimates: GMR = 
0.95, alpha = 0.05, power = 80%, N = 24 and the upper and lower limit range for determining 
the bioequivalence: 80.00 ~ 125.00 %. The intra-CV for Cmax was estimated to be 23.2%. From 
experience on previous studies, it is also believed that Cmax intra-CV would be typically higher 
than AUC.  
From above references and discussion and the likely impact of food on the CV, this protocol 
assumes a higher intra-CV estimate of 28% for the fed cohort and 23% intra-CV for the fasted 
cohort, for the calculation of sample size for this study.  
For the fasted cohort, to calculate the sample size for this study the following estimates were 
then used: GMR = 0.95, alpha = 0.05, power = 90%, intra-CV = 23% and the upper and lower 
limit range for determining the bioequivalence: 80.00 ~ 125.00% which calculates 32 subjects 
per cohort. 
Similarly for the fed cohort, to calculate the sample size for this study the following estimates 
were then used: GMR = 0.95, alpha = 0.05, power = 90%, intra-CV = 28% and the upper and 
lower limit range for determining the bioequivalence: 80.00 ~ 125.00% which calculates 46 
subjects per cohort. 
As the cohorts are independent, the overall power of the study was estimated to be 80% (0.9*0.9) 
which meets the minimum threshold requirement as per ICH guidelines.  
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12.2 
Populations for Analysis 
Analysis Populations: Analysis populations includes randomized population, safety analysis 
population, pharmacokinetic concentration set, pharmacokinetic parameter set, and 
bioequivalence set.  
Randomized Population: Randomized population includes all randomized subjects. This will 
be the population used for analysis of dropout rate, demography and baseline characteristics. 
Safety Analysis Population (SS): Safety analysis population is defined as all subjects who 
received at least one dose of study drug after randomization and who have safety evaluation. 
This will be the population used for safety analyses. Analysis will be performed according to 
the actual treatment received. 
Pharmacokinetic Concentration Set (PKCS): PKCS includes all randomized subjects who 
have received at least one dose of investigational product with available data of concentration 
for at least one component tested after administration. This is to provide descriptive statistics of 
the PK concentration data of subjects. 
Pharmacokinetic Parameter Set (PKPS): PKPS is defined as the evaluable PK parameter 
data set obtained from subjects randomized who received at least one dose of investigational 
product. This is to provide descriptive statistics of the evaluable PK parameter data of subjects. 
Bioequivalence Set (BES): BES will include subjects who receive at least one study period 
and have at least one evaluable PK parameter for ibuprofen. BES will be used in bioequivalence 
analysis for ibuprofen. 
However, the subject or subject’s period will be excluded from BES, if one of the following is 
true for the specific period. 
1. The pre-dose concentration is greater than 5% of observed maximum plasma concentration 
(Cmax); 
2. Vomiting occurs at or before 2 times median Tmax of subjects in the same treatment group;  
3. With major PD which will affect PK results. 
12.3 
Statistical Analyses 
Additional details of the proposed statistical analysis will be documented in the statistical 
reporting and Vtatistical analysis plan (SAP), which will be written following finalization of the 
protocol and prior to study unblinding/analysis (as appropriate). SAS Version 9.4 or above 
version will be applied for statistical analysis. For quantitate data, descriptive summary 
including the number of evaluable volunteers, mean, standard deviation (SD), median, 
maximum and minimum values will be performed. For categorical variables, number of 
volunteers and proportions will be summarized. Throughout the statistical methods the fasted 
cohort and fed cohort will be summarized and analyzed separately. 
12.3.1 
Pharmacokinetic Analysis 
12.3.1.1 Concentration Analysis 
Plasma concentration analysis of ibuprofen will be based on PKCS. Descriptive statistical 
analysis will be conducted to summarize drug plasma concentration data by treatment groups 
at each planned sampling time point. Descriptive statistics for plasma concentration will include 
arithmetic mean, SD, CV%, median, maximum (observed), minimum (observed), geometric 
mean, etc. The mean, SD, and CV% will be calculated only if at least two-thirds of the 
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individual data meet or exceed the lower limit of quantification (LLOQ) at a specific sampling 
time point, otherwise only the minimum and maximum will be reported (these rules do not 
apply to pre-dose time points). Only mean, minimum and maximum will be reported for the 
pre-dose time points. 
Plasma concentration-time curves will be plotted by blood sampling time points and mean 
concentrations or individual concentrations. The actual blood collection time will be used in the 
individual plasma concentration-time curves, and the scheduled blood collection time for mean 
plasma concentration-time curves. Individual or mean plasma concentration-time curves will 
be plotted linearly and semi-logarithmically. The plasma concentration-time curves for both 
dose formulations should be graphically displayed in an overlay. 
12.3.1.2 Parameter Analysis 
The PK parameter analysis of ibuprofen will be based on PKPS. The non-compartmental 
analysis modeling in software 
will be used to 
calculate the PK parameters of ibuprofen according to actual sampling time points. Descriptive 
statistical analysis will be conducted for all PK parameters by treatment. Descriptive statistics 
for the PK parameters will include arithmetic mean, SD, CV%, median, maximum, minimum, 
geometric mean and geometric CV%, etc. 
The PK parameters will be calculated as follows: 
Cmax: observed maximum plasma concentration 
Tmax: time to reach Cmax 
AUC0-t: area under the plasma concentration-time curve from time zero to last observed 
concentration at time t, will be calculated by the linear up log down trapezoidal rule. 
AUC0-∞: area under the plasma concentration-time curve from time zero to time infinity, 
calculated as below: 
AUC0-∞ = AUC 0-t + Ct/λz (Ct is the plasma concentration at the last measurable time point) 
t1/2: elimination half-life, calculated as below:  
t1/2 = ln(2)/λz. 
λz: terminal elimination rate constant. It will be estimated by log-linear regression of the 
terminal part of the plasma concentration versus time curve. 
%AUCex : percentage of extrapolated area of AUC0-∞, calculated as below: 
%AUCex = (1- AUC0-t AUC0-ɱ)× 100% 
For handling of values below the lower limit of quantification (BLQ):  
When calculating individual or average plasma concentration or PK parameters, if one or 
more BLQs appear in the same subject before the Cmax, it will be set to 0; if one or more 
BLQs appear in the same subject after the Cmax, it will be set to missing.  
12.3.2 
Bioequivalence Analysis 
The ln-transformed PK parameters Cmax, AUC0-t, and AUC0-f for Ibuprofen will be analyzed 
by analysis of variance (ANOVA) with treatment, period and sequence as fixed effects using 
PROC MIXED. 
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For both fasted and fed cohorts, the general approach average bioequivalence (ABE) is 
constructing a 90% CI for the quantity ߤ்െߤோ. If this CI is contained in the interval (80%, 
125%), ABE is concluded. 
The ABE hypothesis tests are: 
ܪ଴ଵǣ ߤ்െߤோ൑݈݊ͲǤͺǡܪ஺ଵǣ ߤ்െߤோ൐݈݊ͲǤͺ 
and 
ܪ଴ଶǣ ߤ்െߤோ൒݈݊ͳǤʹͷǡܪ஺ଶǣ ߤ்െߤோ൏݈݊ͳǤʹͷ 
By rejecting the null hypothesis, we conclude ABE. 
The point estimates (test/reference GMR) will be calculated for Cmax, AUC0-t, and AUC0-f for 
Ibuprofen. 
90% CIs for the difference between least square means of test and reference formulations will 
be obtained in ANOVA for ln-transformed PK parameters Cmax, AUC0-t, and AUC0-f for 
Ibuprofen. 90% CI for the geometric least squares mean (LSM) ratio will be obtained by taking 
the exponent of lower and upper limits of 90% CI, obtained for the least square mean difference. 
For Ibuprofen, based on the statistical results of 90% CIs for the GMR of (T/R) for the PK 
parameters Cmax, AUC0-t, and AUC0-f, conclusions will be drawn whether test formulation is 
bioequivalent to reference formulation. Acceptance range for bioequivalence is 80.00%-125.00% 
for 90% CIs of the geometric means ratio for Cmax, AUC0-t, and AUC0-f. 
Hodges-Lehmann testing model will be used to perform the non-parameter analysis for the 
secondary PK parameters including t1/2 and Tmax. The median of the difference between the test 
product and the reference product and the corresponding 90% CI will be calculated. 
12.3.3 
Safety Analysis 
Safety analyses will be performed based on SS. 
12.3.3.1 Adverse event 
AEs will be coded using the preferred terms (PTs) from the ICH MedDRA of the most recent 
version at the time of database lock, and grouped by system organ class (SOC). The severity of 
AEs will be graded as mild, moderate, and severe. The number and percentage of subjects will 
be summarized for all treatment-emergent adverse events (TEAEs), SAEs, investigational 
product-related TEAEs, investigational product-related SAEs, and TEAEs leading to study 
discontinuation by medication (T/R) and sequence (TR/RT) based on PT and SOC. In addition, 
the severity of TEAEs and their relationship to investigational product will also be summarized 
by medication (T/R) and sequence (TR/RT) based on PT and SOC. AEs due to COVID-19, if 
any, will be listed and tabulated separately. 
12.3.3.2 Laboratory Tests 
Descriptive statistical analysis of all laboratory results and changes from baseline will be 
performed by scheduled time point and group, and laboratory abnormalities (mainly focusing 
on the occurrence of normal or abnormal results before treatment but abnormal values after 
treatment) will be summarized by time-point and treatment. Summary statistics will include 
mean, SD, minimum, median, and maximum. No inferential statistics will be presented. Data 
will be listed with abnormal values flagged. 
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12.3.3.3 12-lead ECG 
Descriptive statistical analysis of results of 12-lead ECGs and changes from baseline will be 
performed by scheduled time point and group, and ECG abnormalities (mainly focusing on the 
occurrence of normal or abnormal results before treatment but abnormal values after treatment) 
will be summarized by time-point and treatment. Summary statistics will include mean, SD, 
minimum, median, and maximum. No inferential statistics will be presented. Data will be listed 
with abnormal values flagged. 
12.3.3.4 Vital Sign, Physical Examination 
The vital sign, physical examination, and other safety-related abnormalities (mainly focusing 
on the occurrence of normal or abnormal results before treatment but abnormal values with 
clinical significance after treatment) will be summarized by time-point and treatment. Summary 
statistics will include mean, SD, minimum, median, and maximum. No inferential statistics will 
be presented. Data will be listed with abnormal values flagged. 
12.3.4 
Exclusion of Data from Analysis  
The subjects with protocol deviation will be reviewed at the data review meeting prior to 
database lock. Exclusion of any data from the analyses will be determined after discussion by 
biostatisticians, investigator or designee. Any reasons for exclusion from an analysis population 
will be recorded.  
12.3.5 
Subject Disposition 
The total number of subjects screened, and the number of screening failures will be listed. The 
number and percentage of subjects who complete the study, and dropout and the main reasons 
for dropout (lost to follow-up, AEs, poor compliance, etc.) will be calculated by group. 
The number and percentage for subject distribution in each analysis population will be 
calculated by group. 
12.3.6 
Demographic and Baseline Characteristics 
Descriptive statistical analysis will be performed on demographic characteristics such as age, 
height, sex, weight, and other baseline characteristics such as disease history for all randomized 
population 
12.3.7 
Study Product Compliance and Use of Other Therapies 
12.3.7.1 Study Product Compliance 
Exposure to study medication during the study period will be presented for the SS. Number 
and percentage of subjects who administered the investigational product will be summarized 
by group and study period.  
12.3.7.2 Prior and Concomitant Medications 
Prior and concomitant medications will be listed for the SS. 
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12.3.8 
Handling of Dropouts and Missing Data  
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.  
For handling of values BLQ, will refer to Section 12.3.1. 
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. 
x Safety, rights and well-being 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 
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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 and/or assent documents, IB/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. 
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), NMPA GCP (2020), 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 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 OR assent documents must be in compliance with GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws. 
The informed consent OR assent 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. 
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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.  
13.3.4 
Subject Recruitment  
Advertisements approved by IRBs/ECs and investigator databases may be used as recruitment 
procedures.  
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, rights and well-being 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 Study 
Registers 
Study information from this protocol will be posted on publicly available clinical study registers 
before enrollment of subjects begins in accordance with applicable GSK CH processes. 
GSK CH intends to make anonymized subject-level data from this study 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 study 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. 
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. 
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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 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. 
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 test product 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 authorities and 
the investigator should promptly inform the IRB/EC and provide the IRB/EC a detailed written 
explanation of the termination or suspension.  
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If the IRB/EC terminates or suspends its approval/favorable opinion of a study, 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]. Technical Guidelines for Human Bioequivalence Studies of Chemical Generic Drugs 
Using Pharmacokinetic Parameters as End-point Evaluation Indicators. National Medical 
Products Administration. 2016.  
[2]. Davies NM. Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin 
Pharmacokinet. 1998 Feb;34(2):101-54. 
[3]. Rainsford KD. Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacology. 
2009 Dec;17(6):275-342. 
[4]. Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal 
complications with individual non-steroidal anti-inflammatory drugs: results of a 
collaborative meta-analysis. BMJ. 1996 Jun 22;312(7046):1563-6. 
[5]. Cattaneo D, Clementi E. Clinical pharmacokinetics of ibuprofen arginine. Curr Clin 
Pharmacol. 2010 Nov;5(4):239-45.  
[6]. Álvarez, C, Nunez I, Torrado J, et al. Investigation on the possibility of biowaivers for 
ibuprofen. Journal of pharmaceutical sciences. 2011 Jun;100(6):2343-9. 
[7]. Packman B, Packman E, Doyle G, et al. Solubilized ibuprofen: evaluation of onset, relief, 
and safety of a novel formulation in the treatment of episodic tension-type headache. 
Headache. 2000 Jul-Aug;40(7):561-7. 
[8]. Moore RA, Derry S, Straube S, Ireson-Paine J, Wiffen PJ. Validating speed of onset as a 
key component of good analgesic response in acute pain. Eur J Pain. 2015 Feb;19(2):187-
92.  
[9]. Cajaraville JP. Ibuprofen Arginate for Rapid-Onset Pain Relief in Daily Practice: A 
Review of Its Use in Different Pain Conditions. J Pain Res. 2021 Jan 25;14:117-26. 
[10]. Ibuprofen Arginine Granules 0.4 g (Spedifen),
㸪Instruction Revision Date: November 23, 2018. 
[11]. Hamid S. Alghurabi. Solubility enhancement of ibuprofen in oral liquid preparations 
using basic amino acids as counter ions. Kerbala journal of pharmaceutical sciences. 
2017, 13: 337-348.  
[12]. Castelo-Branco C, Casals G, Haya J, et al. Efficacy and safety of Ibuprofen arginine in 
the treatment of primary dysmenorrhoea. Clin Drug Investig. 2004;24(7):385-93. 
[13]. Chinese Pharmacopoeia. Chinese Pharmacopoeia Commission. 2015. 
[14]. Good Clinical Practice. National Medical Products Administration. 2020. 
[15]. Public Assessment Report-Scientific discussion, Ibuprofen 400 mg/100 ml solution for 
infusion & Ibuprofen 600 mg/100 mL solution for infusion, ibuprofen arginine, Medicine 
Online Information Center of AEMPS, January 2017. 
[16]. Sádaba B, Campanero MA, Muñoz-Juarez MJ, et al. A comparative study of the 
pharmacokinetics of ibuprofen arginate versus dexibuprofen in healthy volunteers. Eur J 
Clin Pharmacol. 2006 Oct;62(10):849-54. 
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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 
ABE 
average bioequivalence 
AE 
adverse event 
ALT 
alanine transaminase 
ANOVA 
analysis of variance 
AST 
aspartate transaminase 
AUC 
area under the curve 
AUC0-∞ 
area under the plasma concentration-time curve from time zero to time infinity 
AUC0-t 
area under the plasma concentration-time curve from time zero to last observed 
concentration at time t 
BCS 
biopharmaceutics classification system 
BES 
bioequivalence set 
BLQ 
below the lower limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
observed maximum plasma concentration 
CRF 
case report form 
CRO 
contract research organization 
CV 
coefficient of variation 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOS 
End of study 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GMR 
geometric mean ratio 
GSK CH 
GlaxoSmithKline Consumer Healthcare 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
investigator brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
institutional review board 
K2EDTA 
dipotassium ethylene diamine tetraacetic acid 
LLOQ 
lower limit of quantification 
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GSK Consumer Healthcare 
 
Clinical Protocol 
 
 
Protocol Number: 218552  
 
Property of GSK Consumer Healthcare - Confidential  
May not be used, divulged, published or otherwise disclosed without the consent of GSKCH 
 Clinical Protocol Template v8.0 
Page 63 of 63 
Abbreviation 
Term 
LSM 
least squares mean 
MedDRA 
medical Dictionary for Regulatory Activities 
NMPA 
National Medical Products Administration 
NSAID 
nonsteroidal anti-inflammatory drug 
PCR 
polymerase chain reaction 
PK 
pharmacokinetics 
PKCS 
pharmacokinetic concentration set 
PKPS 
pharmacokinetic parameter set 
PT 
preferred term 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum concentration 
WBC 
white blood cell 
WHO 
World Health Organization  
λz 
terminal elimination rate constant 
%AUCex 
percentage of extrapolated area of AUC0-∞ 
 
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SAP_001.pdf: 
Compound/Product Name:     Ibuprofen Arginine Granules
     Wyeth Pharmaceutical Co., Ltd
CRO:   
 
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1. Introduction 
 
 
 
 
2. Study Objectives 
 
 
 
 
 
 
3. Study Design 
3.1 Overall Study Design 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.2 Sample Size Determination 
 
 
 
 


 
 
 
 
 
 
3.3 Randomization and Blinding 
 
 


 
 
4. Study Endpoints 
4.1  Pharmacokinetics Endpoints 
1
Primary PK Endpoints 
 Cmax
observed maximum plasma concentration. 
 AUC0-t
area under the plasma concentration-time curve from time zero to last 
observed concentration at t. 
 AUC0-
area under the plasma concentration-time curve from time zero to time 
infinity. 
2
Secondary PK Endpoints 
 Tmax:  time to reach maximum concentration 
 t1/2:   terminal half-life 
 z:  
terminal elimination rate constant 
 %AUCex: percentage of extrapolated area of AUC0- , calculated as below: 
%AUCex = (1 - AUC0-t / AUC0- ) × 100% 
4.2  Safety Analysis Endpoints 
 Frequency and nature of adverse events 
 Physical examination 
 Vital signs 
 Laboratory tests 
 12-lead electrocardiogram 
 


5. Definition 
5.1 Baseline 
Baseline (the first period baseline) is defined as the last non-missing measurement prior 
to first dose of investigational drug in the first period. The second period baseline is defined 
as the last non-missing measurement prior to first dose of investigational drug in the second 
period. 
5.2 Change from Baseline 
Change from baseline will be calculated as follows: 
 
 
 
5.3 Study Day 
Study day
Study day will be calculated from the date of the first administration of 
study drug, the date of the first administration of study drug is referred to as Day 1. 
If the date of any event during the study is on or after the date of the first administration 
of study drug:  
 
 
 
 
If the date of event is prior to the date of the first administration of study drug:  
 
 
6. Populations for Analysis 
 
Analysis Population: Analysis populations include randomized population, safety 
analysis population, pharmacokinetic concentration set, and bioequivalence set. 
Randomized Population: Randomized population includes all randomized subjects. 
This will be the population used for analysis of dropout rate, demography, and baseline 
characteristics. 


Safety Analysis Population (SS): Safety analysis population is defined as all subjects 
who received at least one dose of study drug after randomization and who have safety 
evaluation. This will be the population used for safety analysis. Analysis will be performed 
according to the actual treatment received. 
Pharmacokinetic Concentration Set (PKCS): PKCS includes all randomized subjects 
who have received at least one dose of investigational product with available data of 
concentration for at least one component tested after administration. This is to provide 
descriptive statistics of the PK concentration data of subjects.  
Pharmacokinetic Parameter Set (PKPS): PKPS is defined as the evaluable PK 
parameter data set obtained from subjects randomized who received at least one dose of 
investigational product. This is to provide descriptive statistics of the evaluable PK parameter 
data of subjects. 
Bioequivalence Set (BES): BES will include subjects who receive at least one study 
period and have at least one evaluable PK parameter for ibuprofen. BES will be used in 
bioequivalence analysis for ibuprofen. 
H
following is true for the specific period. 
1. The pre-dose concentration is greater than 5% of observed maximum plasma 
concentration (Cmax) 
2. Vomiting occurs at or before 2 times median Tmax of subjects in the same treatment 
group 
3. With major PD which will affect PK results. 
 
7. Interim Analysis 
 
 
8. Data Review 


 
8.1 Data Handling and Transfer 
The data from eCRF will be exported from EDC system and delivered to statistical 
programming team as SAS datasets by data management team. The PK analysis data will be 
provided for the PK analyst by the data management team. The PK parameters calculated by 
PK analyst will be sent to the statistical programming team in EXCEL for further statistical 
analysis. 
8.2 Data Screening 
Beyond the data screening based on the
Data Management Plan, the
programming of analysis datasets, tables, figures, and listings (TFL) provides additional 
data screening. Any data issues 
 will be output into SAS logs  and 
extracted from the logs by a SAS macro and sent to Data Management for validation. 
Prior to the database lock, further data screening will be provided for the TFLs which is 
generated by analysis dataset after data cleaning. The TFLs will be discussed with the 
sponsor in a data review meeting to identify any data issues and implement corrections prior 
to the database lock.
9. Statistical Methods 
9.1 General Considerations for Statistical Analyses 
9.1.1 
General Principles 
SAS Version 9.4 or above will be used for statistical analyses. 
For quantitative data, descriptive summary will include the number of subjects, mean, 
standard deviation (SD), median, first quartile (Q1), third quartile (Q3), maximum, minimum, 
geometric mean, CV% and geometric CV% where geometric mean, CV% and geometric 
CV% are summarized for PK parameters only. Unless otherwise specified, the number of 
decimal places for the minimum and maximum will be the same as the original data recorded 
in the database. The mean, geometric mean and median (Q1, Q3) will retain one decimal 
place more than original data recorded in the database. The SD will retain two decimal places 
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more than original data recorded in the database. The CV% and geometric CV% will retain 
one decimal place. All statistics contain a maximum of four decimal places. 
 
 
9.1.2 
Handling of Missing Data 
Handling of missing values: The missing value will not be filled in or imputed and the 
outliers will be checked. 
Handling of missing dates: Due to the short study period, missing date in adverse events 
will be checked but not be filled in or imputed. For missing dates in medical history and 
medication history, they will also not be filled in or imputed. The dates in the listing will be 
presented as they are in the CRF. 
9.1.3 
Output of Statistical Results 
All statistical results will be output using SAS 9.4 or above. TFL templates are presented 
in a separate document. The templates will be used to direct statistical programme
work. 
For any modifications in templates that will not have essential effects on this plan, the SAP 
will not require modification and approval. 
9.2  Subject Disposition 
The summary of subject disposition is based on all subjects. Total number of subjects 
screened, subjects enrolled, subjects screened failure, and main reasons for screen failures 
 and/or did meet exclusion criteria, withdrawal of informed 
consent or other reasons) will be listed. The number and percentage of subjects who complete 
the study, subjects who withdraw the trial and the main reasons for withdrawal from the trial 
(protocol violation that may impact the subject s safety, withdrawal of informed consent, 
etc.) will be calculated by sequence group (TR: Test product  Reference product, RT: 


Reference product  Test product). The number and percentage for subject distribution in 
each analysis population will also be calculated by sequence group (TR/RT). 
The listing of subject disposition sorted by sequence group and subject screening 
number will be provided. 
9.3  Demographic and Baseline Characteristics 
The summary of demographic and other baseline characteristics is based on randomized 
population. 
9.3.1 
Demographic 
Demographic and baseline characteristics will be summarized with descriptive statistics 
by sequence group (TR/RT). The following information will be included in the table: 
 Age (years)  
 Gender 
 Race 
 Ethnicity 
 Height (cm) 
 Weight (kg) 
 BMI (kg/m2) 
 Past history (Transfusion/blood donation history (in the last 3 months), Allergy 
history, Childbearing history, Family history, Drug abuse history, COVID-19 
history and COVID-19 positive contact history) 
 Smoking history 
 Alcohol consumption history 
The listing of demographic and baseline characteristics sorted by sequence group and 
subject randomization number will be provided. 
9.3.2  Protocol Deviation 
P
protocol and ICH GCP. PD can be classified into major PD or minor PD by severity. 
Major PD is the deviation from the protocol that may affect the subject s rights, safety, 
or wellbeing and/or the completeness, accuracy, and reliability of the study data. This may 
also be defined in the study plans, as agreed upon by the sponsor.  


Minor PD is the deviation from accepted procedures that will not adversely affect 
subjects or data integrity but should be dealt with appropriately. This may also be defined in 
the study plans, as agreed upon by the sponsor. 
The number and percentage of subjects with at least one major or minor PD will be 
summarized by sequence group (TR/RT). The listing of protocol deviations sorted by subject 
randomization number will be provided. 
All protocol deviations will be finally reviewed prior to the database lock. 
9.3.3  Medical/Surgery History 
The medical and surgery history will be coded using the preferred terms (PTs) according 
to the ICH Medical Dictionary for Regulatory Activities (MedDRA, V26.0 or above) and 
grouped by system organ class (SOC). All medical and surgery history will be summarized 
by sequence group (TR/RT). 
The listing of medical history and surgery history sorted by sequence group and subject 
randomization number will be provided. 
9.4  Pharmacokinetic Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.4.1 Plasma Concentration Analysis 
 


 
 
 
9.4.2 Pharmacokinetic Parameter Analysis 
 
 
 
PK parameter Calculation method 
Cmax 
Observed maximum plasma concentration. 
Tmax 
Time to reach Cmax. 
AUC0-t 
Area under the plasma concentration-time curve from time zero to 
last observed concentration at time t, will be calculated by the linear 
up log down trapezoidal rule. 
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AUC0-  
Area under the plasma concentration-time curve from time zero to 
time infinity, calculated as: 
AUC0-  = AUC0-t + Ct/ z, (Ct is the plasma concentration at the last 
measurable time point). 
t1/2  
Elimination half-life, calculated as below: 
t1/2 = Ln 
z. 
z 
Terminal elimination rate constant. It will be estimated by log-linear 
regression of the terminal part of the plasma concentration versus 
time curve. 
%AUCex 
Percentage of extrapolated area of AUC0- , calculated as below: 
%AUCex = (1- AUC0-t /AUC0- ) × 100%. 
 
 
 
9.5 Bioequivalence Analysis 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
9.6 Safety Analysis 
 
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9.6.1 Study Product Exposure 
The number and percentage of subjects who administered the investigational product 
will be summarized by treatment group (T/R) and period. The listing of exposure to study 
product sorted by sequence group and subject randomization number will be provided.  
 
9.6.2 Prior/Concomitant Medications 
No therapeutic medications are allowed during the study except for contraceptives and 
hormone replacement therapy, and those used for the treatment of AEs unless they jeopardize 
the integrity of the study. 
Prior medications are defined as non-investigational medications taken within 90 days of 
signing the ICF and finished before the first dose administered. 
Concomitant medications are defined as non-investigational medications taken after the 
first dose administered. 
Prior and concomitant medications will be coded by anatomical therapeutic chemical 
(ATC) classification system using WHODrug Global (Mar, 2023 or above). Prior and 
concomitant medications will be summarized by ATC, PT and sequence group (TR/RT).  
The listing of prior and concomitant medications sorted by subject randomization 
number will be provided. 
9.6.3 Prior/Concomitant Non-Drug Therapies  
Prior non-drug therapies are defined as non-drug therapies taken within 90 days of 
signing the ICF and finished before the first dose administered. 
Concomitant non-drug therapies are defined as non-drug therapies taken after the first 
dose administered. 
Prior and concomitant non-drug therapies will be coded by SOC and PT using ICH 
MedDRA (V26.0 or above). The listing of prior and concomitant non-drug therapies sorted 
by subject randomization number will be provided. 
9.6.4 Adverse Events 
An adverse event (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). 


All AEs will be coded into SOC and PT using ICH MedDRA (V26.0 or above).  
The severity of AE will be graded as mild, moderate, and severe. The causality of AE 
will be divided as related and not related.  
In this study, treatment-emergent adverse events (TEAEs) are defined as AEs that occur 
on or after the first dose administered and before the end (or discontinuation) of the study. 
Besides, the period of AE should be specified as follows: 
 The first period AEs: AEs present after the first dose administered and before the 
dose administered in the second period. 
 The second period AEs: AEs present after the dose administered in the second 
period. 
In situations with missing AE start/end dates/times, available data will be used for 
TEAE classification and treatment assignment. If the TEAE classification is inconclusive, 
worst-case will be assumed and the AE will be classified as a TEAE. If the treatment 
assignment is inconclusive, the earliest of the possible treatments will be assigned. AEs will 
be summarized by sequence group (TR/RT) and treatment group (T/R). 
The number of events will be summarized with number and percentage of the subjects 
for all AEs, TEAEs, serious AEs (SAEs), investigational product-related TEAEs, 
investigational product-related SAEs, and TEAEs leading to study discontinuation. 
For TEAEs, SAEs, investigational product-related TEAEs, investigational product-
related SAEs, and TEAEs leading to study discontinuation, the number of events will be 
summarized with number and percentage of the subjects by treatment (T/R) and sequence 
(TR/RT) based on PT and SOC. In addition, the severity of TEAEs and the relationship to 
investigational product will also be summarized by treatment (T/R) and sequence (TR/RT) 
based on PT and SOC. Subjects with multiple occurrences of events for a given SOC, PT, or 
overall will only be counted once at the worst severity and strongest relationship to 
investigational drug. 
The listing of all AEs, TEAEs, serious AEs (SAEs), investigational product-related 
TEAEs, investigational product-related SAEs, and TEAEs leading to study discontinuation 
will be provided. 
9.6.5 Laboratory Tests 
Laboratory tests include blood chemistry, hematology, urinalysis, coagulation. 
Descriptive statistical analysis of all laboratory tests results and changes from baseline 
will be summarized by scheduled time point and sequence group (TR/RT). Summary 


statistics will include mean, SD, minimum, median (Q1, Q3), and maximum. Shift in clinical 
significance from baseline will be summarized by timepoint and treatment (T/R). Shift in 
clinical significance from baseline to the worst post-baseline result will also be summarized 
by sequence group (TR/RT). 
The listing of laboratory tests results and abnormal laboratory results (clinical 
) will be provided. 
9.6.6 Vital Signs 
Vital signs include systolic blood pressure, diastolic blood pressure, pulse, respiratory 
rate, and ear temperature. 
Descriptive statistical analysis of all vital signs results and changes from baseline will be 
summarized by scheduled time point and sequence group (TR/RT). Summary statistics will 
include mean, SD, minimum, median (Q1, Q3), and maximum. Shift in clinical significance 
from baseline will be summarized by timepoint and treatment (T/R). Shift in clinical 
significance from baseline to the worst post-baseline result will also be summarized by 
sequence group (TR/RT). The listing of vital signs results and abnormal vital signs results 
will be provided. 
9.6.7 Physical Examination 
Shift in clinical significance from baseline will be summarized by timepoint and 
treatment (T/R). Shift in clinical significance from baseline to the worst post-baseline result 
will also be summarized by sequence group (TR/RT). The listing of physical examination 
will be provided. 
9.6.8 12-lead ECG 
Descriptive statistical analysis of all 12-lead ECG results and changes from baseline will 
be summarized by scheduled time point and sequence group (TR/RT). Summary statistics 
will include mean, SD, minimum, median (Q1, Q3), and maximum. Shift in clinical 
significance from baseline will be summarized by timepoint and treatment (T/R). Shift in 
clinical significance from baseline to the worst post-baseline result will also be summarized 
by sequence group (TR/RT). 
The listing of 12-lead ECG results and abnormal laboratory results (clinical significance 
will be provided. 


9.6.9 Admission to/ Leaving Study Ward 
The listing of admission to/ leaving study ward sorted by sequence and subject 
randomization number will be provided. 
9.6.10 Other Examinations 
The listing of following examinations sorted by sequence and subject randomization 
number will be provided. 
 Urine drug abuse screening 
 Alcohol breath test 
 Serology 
 Blood pregnancy test (For female only) 
 Menstrual History (For female only) 
 Hormone test (Follicle-stimulating hormone done only in females who have been 
consecutively amenorrhoeic for 12 months) 
 COVID-19 test 
 Intake of high-fat/high-calorie breakfast (For fed cohort only) 
 Unscheduled visit (if applicable) 
 
10.   Quality Control 
To ensure that each delivery of TFL is of a high standard, the TFL quality control 
process will be documented in detail in the Quality Control Tracker. 
 


Appendix 1 Abbreviations 
 
Abbreviation 
Term 
ABE 
average bioequivalence 
AE 
adverse event 
ANOVA 
analysis of variance 
AUC 
area under the curve 
AUC0-  
area under the plasma concentration-time curve from time zero to time 
infinity 
AUC0-t 
area under the plasma concentration-time curve from time zero to last 
observed concentration at time t 
BES 
bioequivalence set 
BLQ 
below the lower limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
Cmax 
observed maximum plasma concentration 
CRF 
case report form 
CV 
coefficient of variation 
ECG 
electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
GMR 
geometric mean ratio 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
LLOQ 
lower limit of quantification 
LSM 
least squares mean 
MedDRA 
medical Dictionary for Regulatory Activities 
PK 
pharmacokinetics 
PKCS 
pharmacokinetic concentration set 
PKPS 
pharmacokinetic parameter set 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 


Abbreviation 
Term 
SOC 
system organ class 
t1/2 
terminal half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum concentration 
WHO 
World Health Organization  
z 
terminal elimination rate constant 
%AUCex 
percentage of extrapolated area of AUC0-  
 
 Appendix 2 References 
[1]. 
 
[2].