Conditions: Hypertension
Keywords: Cross-over Hydrochlorothiazide Amiloride hydrochloride Phase I GSK3542503 Bioequivalence FTIH
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 42
Healthy volunteers: yes

Brief summary:
The combination of the diuretics amiloride hydrochloride (HCl) and hydrochlorothiazide (HCTZ) (GSK3542503) is indicated for the treatment of hypertension, congestive heart failure and hepatic cirrhosis with ascites and edema. This first time in human (FTIH) study is aimed to determine whether the test product GSK3542503 is bioequivalent to the reference (ref) hydrochlorothiazide 50 milligram (mg)/amiloride hydrochlorothiazide 5 mg in healthy adult participants under fasting conditions based on pharmacokinetic (PK) endpoints. This is a phase I, open label, balanced, randomized, single dose, two-way crossover study, enroling approximately 42 healthy participants at a single center. Study participants will be randomized to one of two treatment sequences (A-B or B-A) in accordance with the randomization schedule. A single dose of one of the two treatments A (Test: GSK3542503, a hydrochlorothiazide 50 mg and amiloride hydrochloride 5 mg fixed dose combination) or B (Reference: Moduretic, a hydrochlorothiazide 50 mg and amiloride hydrochloride 5 mg fixed dose combination), will be administered on Day 1, in each treatment period. Each participant will participate in both treatment periods and receive a single dose of each treatment. The treatment periods will be separated by a washout period of at least 7 days and no more than 14 days. The total duration in the study for each participant is expected to be 5 to 7 weeks, from screening to his or her last visit. A maximum of 42 participants will be randomized such that at least 32 evaluable participants complete the study.

Detailed description:

Arms:
arm 1: Eligible participants following an overnight fast of at least 10 hours, will be administered the study drug orally with 240 mL (8 fluid ounces) of water. No food will be allowed for at least 4 hours post-dose. Water will be allowed as desired except for one hour before and after drug administration. arm 2: Eligible participants following an overnight fast of at least 10 hours, will be administered the study drug orally with 240 mL (8 fluid ounces) of water. No food will be allowed for at least 4 hours post-dose. Water will be allowed as desired except for one hour before and after drug administration.

Interventions: intervention 1: GSK3542503 (HCTZ 50mg/Amiloride HCl 5mg tablets) intervention 2: Moduretic (HCTZ 50mg/Amiloride HCl 5mg tablets)
Intervention descriptions: intervention 1: GSK3542503 (HCTZ 50mg/Amiloride HCl 5mg tablets) are cream-colored, circular, flat faced uncoated tablets with beveled edges having break line on one side and "BD" embossed on the other side. intervention 2: Moduretic (HCTZ 50mg/Amiloride HCl 5mg tablets) tablets are peach-colored, half scored, diamond shaped tablets marked "MSD917".

Protocol document:
Prot_SAP_000.pdf: 
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TITLE PAGE
Protocol Title: An open-label, randomised, single-dose, two-period cross-over study to 
evaluate bioequivalence of GSK3542503 hydrochlorothiazide + amiloride hydrochloride 
50mg: 5mg fixed dose combination tablets versus reference product in healthy adult 
participants under fasting conditions
Protocol Amendment Number: 01
Short Title: Bioequivalence study between  GSK3542503 hydrochlorothiazide + 
amiloride hydrochloride 50 mg: 5 mg tablets and reference product in healthy adult 
participants under fasting conditions.
Compound Number:
GSK3542503
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information
Dr. 
Senior Medical Advisor
Medical & Regulatory Affairs
Emerging Markets & Asia Pac
GSK Pharmaceuticals Ltd
Dr Annie Besant Road, Worli, Mumbai - 400030, 
India
Email:  
Regulatory Agency Identifying Number(s):
N/A
Approval Date: 12-JAN-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
2016N288797_01
12-JAN-2017
2016N288797_00
12-DEC-2016
Amendment 01 [12-JAN-2017]
Overall Rationale for the Amendment: This protocol amendment is to correct the asset 
number for the hydrochlorothiazide and amiloride hydrochloride fixed dose combination. 
The asset number in the original protocol, GR77494 is amiloride. The asset number for 
the fixed dose combination of hydrochlorothiazide and amiloride hydrochloride, is 
GSK3542503. All references to asset GR77494 have been replaced with GSK3542503 
throughout the protocol. There are no other changes.


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................8
3.
INTRODUCTION....................................................................................................13
3.1.
Study Rationale ..........................................................................................13
3.2.
Background ................................................................................................13
3.3.
Benefit/Risk Assessment ............................................................................14
3.3.1.
Risk Assessment .........................................................................15
3.3.2.
Benefit Assessment.....................................................................18
3.3.3.
Overall Benefit: Risk Conclusion..................................................18
4.
OBJECTIVES AND ENDPOINTS...........................................................................18
5.
STUDY DESIGN ....................................................................................................19
5.1.
Overall Design ............................................................................................19
5.2.
Number of Participants ...............................................................................20
5.3.
Participant and Study Completion...............................................................20
5.4.
Scientific Rationale for Study Design ..........................................................20
5.5.
Dose Justification........................................................................................20
6.
STUDY POPULATION...........................................................................................21
6.1.
Inclusion Criteria.........................................................................................21
6.2.
Exclusion Criteria........................................................................................22
6.3.
Lifestyle Restrictions...................................................................................24
6.3.1.
Meals and Dietary Restrictions ....................................................24
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................24
6.3.3.
Activity .........................................................................................24
6.4.
Screen Failures...........................................................................................24
7.
TREATMENTS.......................................................................................................25
7.1.
Treatments Administered............................................................................25
7.2.
Dose Modification .......................................................................................25
7.3.
Method of Treatment Assignment ...............................................................26
7.4.
Blinding.......................................................................................................26
7.5.
Preparation/Handling/Storage/Accountability..............................................26
7.6.
Treatment Compliance................................................................................27
7.7.
Concomitant Therapy..................................................................................27
7.8.
Treatment after the End of the Study ..........................................................28
8.
DISCONTINUATION CRITERIA.............................................................................28
8.1.
Discontinuation of Study Treatment ............................................................28
8.1.1.
Liver Chemistry Stopping Criteria ................................................28
8.1.2.
QTc Stopping Criteria ..................................................................29
8.1.3.
Temporary Discontinuation ..........................................................30
8.2.
Withdrawal from the Study..........................................................................30
8.3.
Lost to Follow Up........................................................................................30


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9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................31
9.1.
Efficacy Assessments.................................................................................31
9.2.
Adverse Events...........................................................................................31
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................32
9.2.2.
Method of Detecting AEs and SAEs.............................................32
9.2.3.
Follow-up of AEs and SAEs.........................................................32
9.2.4.
Regulatory Reporting Requirements for SAEs .............................32
9.2.5.
Pregnancy ...................................................................................33
9.3.
Treatment of Overdose...............................................................................33
9.4.
Safety Assessments ...................................................................................34
9.4.1.
Physical Examinations.................................................................34
9.4.2.
Vital Signs....................................................................................34
9.4.3.
Electrocardiograms......................................................................34
9.4.4.
Clinical Safety Laboratory Assessments ......................................35
9.5.
Pharmacokinetics .......................................................................................35
9.6.
Pharmacodynamics ....................................................................................36
9.7.
Genetics .....................................................................................................36
9.8.
Biomarkers .................................................................................................36
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................36
10. STATISTICAL CONSIDERATIONS........................................................................37
10.1.
Sample Size Determination ........................................................................37
10.2.
Populations for Analyses ............................................................................38
10.3.
Statistical Analyses.....................................................................................38
10.3.1.
PK Analyses ................................................................................39
10.3.2.
Protocol Deviations and Changes to Planned Analyses...............39
10.3.3.
PK Parameters ............................................................................39
10.3.3.1.
Primary Pharmacokinetic Parameters for 
hydrochlorothiazide and amiloride ..............................40
10.3.3.2.
Secondary Pharmacokinetic Parameters for 
hydrochlorothiazide and amiloride ..............................40
10.3.4.
Analysis of Bioequivalence ..........................................................40
10.3.5.
Safety Analyses...........................................................................41
10.3.6.
Other Analyses ............................................................................41
10.3.7.
Interim Analyses ..........................................................................41
11. REFERENCES.......................................................................................................42
12. APPENDICES........................................................................................................43
12.1.
Appendix 1: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................43
12.2.
Appendix 2: Study Governance Considerations..........................................47
12.3.
Appendix 3: Liver Safety: Required Actions and Follow-up 
Assessments. .............................................................................................51
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................53
12.5.
Appendix 5: Clinical Laboratory Tests.........................................................58
12.6.
Appendix 6:  Analysis Plan .........................................................................60
12.7.
Appendix 7: Abbreviations and Trademarks................................................66


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1.
SYNOPSIS
Protocol Title: An open-label, randomised, single-dose, two-period cross-over study to 
evaluate bioequivalence of GSK3542503 hydrochlorothiazide + amiloride hydrochloride 
50 mg: 5 mg fixed dose combination tablets versus reference product in healthy adult 
participants under fasting conditions. 
Short Title: Bioequivalence study between GSK3542503 hydrochlorothiazide + 
amiloride hydrochloride 50 mg: 5 mg tablets and reference product in healthy adult 
participants under fasting conditions. 
Rationale:
This study will determine if GSK3542503 (marketed as BIDURETTM), manufactured by 
Panacea Biotec Ltd, India is bioequivalent to reference product, Moduretic , 
manufactured by Merck Sharpe and Dome Limited, United Kingdom (UK).  Both 
products are combination diuretics of hydrochlorothiazide and amiloride hydrochloride, 
50 milligrams (mg): 5 mg.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To determine if 50 mg HCTZ/5 mg 
amiloride hydrochloride (GSK3542503) 
tablets are bioequivalent to reference 
50 mg HCTZ/5 mg amiloride 
hydrochloride tablets in healthy adult 
participants under fasting conditions. 

Plasma PK parameters: AUC(0-t) and 
Cmax, for hydrochlorothiazide and 
amiloride in relevant treatments. 
Secondary

To measure secondary PK parameters 
of 50 mg HCTZ/5 mg amiloride 
hydrochloride tablets (GSK3542503) 
relative to reference 50 mg HCTZ/5 mg 
amiloride hydrochloride in healthy adult 
participants under fasting conditions. 

To compare the safety and tolerability 
of GSK3542503 with reference 
product 50 mg HCTZ/5 mg amiloride 
hydrochloride, , in healthy adult  
participants under fasting conditions.

Plasma PK parameters: AUC(0-), tmax, 
%AUCex and t½ for hydrochlorothiazide and 
amiloride  in relevant treatments.

Adverse events (AE), clinical laboratory 
values (Biochemistry) and vital signs 


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AUC(0-) =  Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time; %AUCex= 
Percentage of AUC(0-) obtained by extrapolation; AUC(0-t)= Area under the concentration-time curve from time zero 
(pre-dose) to last time of quantifiable concentration within a participant across all; Cmax= Maximum observed 
concentration; HCTZ= Hydrochlorothiazide; Pk= Pharmacokinetic; t½= Terminal phase half-life; Tmax= Time of 
occurrence of Cmax
Overall Design:
This is a Phase I, open label, balanced, randomised, single dose, two-way crossover 
study, enrolling 42 healthy participants at a single centre. 
Each enrolled study participant will take part in two treatment periods in accordance with 
the randomisation schedule.  The treatment periods will be separated by a washout period 
of at least 7 days and no more than 14 days.  
Number of Participants:
A maximum of 42 participants will be randomized to yield at least 32 evaluable 
participants completing the study. 
Treatment Groups and Duration:
The total duration in the study for each participant is expected to be up to approximately 
5 - 7 weeks, from screening to their last visit.
Study treatments will be referred to as Test and Reference throughout the protocol:

Treatment A – Test: GSK3542503 (BIDURETTM), a hydrochlorothiazide 50 mg 
and amiloride hydrochloride 5 mg fixed dose combination.

Treatment B - Reference: Moduretic, a hydrochlorothiazide 50 mg and 
amiloride hydrochloride 5 mg fixed dose combination.
Treatment Groups and Sequences:

Participants will be randomised to one of two sequences, and administered a 
single oral dose of one of the two treatments (A or B) in each treatment period, 
such that each participant receives a dose of each treatment in the study.


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2.
SCHEDULE OF ACTIVITIES (SOA)
Details of study assessments and collection windows are given in Table 1.


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Table 1
Schedule of Activities
Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 7 days 
post last dose 
or at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Day 3
Informed consent
X
Inclusion and exclusion criteria
X
X
Refer to Section 6. Recheck clinical status before 
randomization and/or 1st dose of study medication.
Admission to the Unit (domiciled)
X
X
X
Participants to be admitted on Day -1 of each treatment 
period, and discharged after the 24 hour PK sample, on Day 
2.
Outpatient Visits
X
X
At the end of treatment period 2, participants will have a brief 
medical exam, vital signs (VS) and lab assessments taken at 
48 hours post dose .
Discharge
X
Participants will be discharged from the unit following the 
collection of the 24 hour PK samples and following review by 
a doctor to assess participant safety. Participants who have 
normal safety assessment results on discharge do not require 
a follow up.
Phone Call
X
If a participant’s safety assessments (medical exam, VS, Lab 
assessments) are abnormal and clinically significant at 
Treatment Period 2 discharge, then a follow up phone call is 
required within 7 days. An outpatient clinic visit may be
required. Enquiries on the participant’s general health, 
including any AEs/SAEs/concomitant medication should be 
recorded in the medical notes.


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Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 7 days 
post last dose 
or at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Day 3
Demography and Medical history (includes 
substance usage)
X
Substances: Drugs, Alcohol, tobacco and caffeine
Full physical examination including height 
and weight
X
X
Abbreviated physical exam (excluding height and weight) can 
be performed at Day -1
Past and current medical conditions  
X
X
Pregnancy test (WOCBP only)
X
X
Serum -hCG at screening. At Day-1, urine -hCG
HIV, Hepatitis B and C screening
X
Testing for Hepatitis B (HBsAg) and Hepatitis C (HepC 
antibody) at screening is not required if this was performed 
within 3 months prior to first dose of study treatment. 
Participants who are positive for Hepatitis C antibody due to 
prior resolved disease, must have a confirmatory negative 
Hepatitis C RNA test. 
1.
Laboratory assessments (include liver 
chemistries) 
X
X
X
  
Screening: Participants are required to fast at least 10 hours 
prior to the Screening Laboratory assessment. Haematology, 
Biochemistry, Coagulation profile (PT and aPTT)and 
Urinalysis are assessed.
Day -1: Haematology, Biochemistry and Urinalysis are 
assessed.
Day 3: Biochemistry is assessed 48 hours post dose. 
Additional safety labs must be collected as deemed 
necessary at the Investigator’s discretion.
Urine Drug/Urine Cotinine/Breath alcohol
X
X


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Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 7 days 
post last dose 
or at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Day 3
12-lead ECG
X
Vital signs
X
X
X
X
X
Vitals will be taken at screening, Day -1, pre-dose (Day 1) and 
at , 1.00, 2.00, 4.00, 6.00, 8.00 ,24.00 and 48 hours post-
dose. Post dose vitals to be taken 30min of each timepoint.
Randomization
X
Day -1 of treatment period 1 only. 
Study treatment
X
Day -1 results must be reviewed by physician prior to 
randomisation and dosing. Participants to be fasted 
10.00hours prior and 4.00 hours post dose. Dosing between 
Treatment periods will be separated by a washout of 7 -14 
days. Participants will remain in a sitting or semi-supine 
position for at least 4 hours after dosing on Day 1 of each 
treatment period. 
AE Review
===========================
Collected from the start dosing to the participant’s final 
discharge from study at the end of Treatment Period 2, follow 
up call or last outpatient visit, whichever is the latest. 
SAE review
================================================
Any SAEs assessed as related to study participation (e.g. 
investigational product, protocol-mandated procedures, 
invasive tests) or related to a GSK concomitant medication 
will be recorded from the time a participant consents to 
participate in the study up to and including any follow up 
contact.
Concomitant medication review
X
============================


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Procedure
Screening 
(Day -21  
to Day -1)
Treatment Periods 1 and 2
Follow-up
(within 7 days 
post last dose 
or at 
discontinuation)
Notes
Day –1
Day 1
Day 2
Day 3
Pharmacokinetics
X
X
X
Day 1: Pre-dose, 0.33, 0.67, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 
4.5, 5.0, 6.0, 7.0, 8.0, 10.0, 12.0,14.0, 16.0, 
Day 2: 24.0 and 36.0 hours post dose
Day 3: 48.0 hours post dose, 
Pre-dose sample will be taken within 15 minutes before dose. 
Post dose samples for 0.33 -24 hours will be taken 2 min. 
Post dose samples for 36 and 48 hours will be taken 2 
hours

Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by 
the relevant study team member and then archived in the sponsor and site study files, but will not constitute a protocol 
amendment. The Institutional review board (IRB)/ Independent ethics committee (IEC)  and regulatory authority will be 
informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the informed consent form
(ICF).

AE= Adverse Event; aPTT= Activated Partial Thromboplastin Time; ECG= Electrocardiogram; GSK= GlaxoSmithKline; HIV= 
Human Immunodeficiency Virus;  hr= Hour; IP= Investigational Product; PK= Pharmacokinetic; PT= Prothrombin Time; SAE= 
Serious adverse event(s);


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3.
INTRODUCTION
3.1.
Study Rationale
GSK Product, GSK3542503 (containing hydrochlorothiazide 50 milligrams (mg) and 
amiloride hydrochloride 5 mg) tablets are marketed in India as BIDURETTM.  This study 
is required to determine whether the test product GSK3542503/BIDURETTM is 
bioequivalent to the reference hydrochlorothiazide 50 mg/amiloride hydrochlorothiazide 
5 mg in healthy adult participants.  Bioequivalence (BE) will be declared if the 90%  
confidence interval  (CI ) for the true ratio of test to reference geometric means falls 
entirely within the range of 0.80 to 1.25 for all primary PK parameters.
3.2.
Background
The cardiovascular disease hypertension is defined as the elevation of systolic and /or 
diastolic blood pressures (BP) to140/90 mm Hg.  Although asymptomatic, “benign” 
hypertension is a major risk factor for stroke, congestive heart failure and coronary artery 
disease.  Thiazide diuretics and related pthalimidine derivatives have become the 
mainstay of antihypertensive regimens owing to their antihypertensive effects when used 
alone and their ability to enhance the efficacy of virtually all other antihypertensive drugs 
when used in combination [Gerber JG, 1990].  
The combination of the diuretics Amiloride hydrochloride and hydrochlorothiazide 
(GSK3542503), are indicated for the treatment of hypertension, congestive heart failure 
and hepatic cirrhosis with ascites and oedema [MODURETIC Package Insert, 2015].
Amiloride Hydrochloride
Amiloride hydrochlorothiazide is a potassium-conserving (antikaliuretic) drug with mild 
(compared to thiazide diuretics) naturetic, diuretic and antihypertensive activity. [Weiner
IM, 1990].
These activities may be additive to the effects of thiazides or other saluretic-diuretic 
agents.  The principle use of amiloride hydrochloride is to conserve potassium in selected 
patients receiving kaliuretic diuretic agents.  The drug acts directly on the distal portion 
of the nephron inhibiting the reabsorption of sodium [Willem H. Birkenhager, 1990].  
Amiloride hydrochloride usually begins to act within 2 hrs after an oral dose.  Its effect 
on electrolyte excretion reaches a peak between 6 and 10 hrs and lasts about 24 hrs.  Peak 
plasma levels are obtained in 3 to 4 hrs and the plasma half life varies from 6 to 9 hrs 
[APO-AMILIZIDE Package Insert, 2013].  Amiloride hydrochloride does not undergo 
metabolic transformation, and is not bound to serum proteins [DG Vidt, 1981].
Hydrochlorothiazide (HCTZ) 
Hydrochlorothiazide (HCTZ) is a diuretic and antihypertensive agent.  It affects the renal 
tubular mechanism of electrolyte re-absorption [APO-AMILIZIDE Package Insert, 
2013].  The exact mechanism of the antihypertensive effect of thiazides is unknown.  
HCTZ does not usually affect normal BP.  


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The PK properties of hydrochlorothiazide show that 70% of an oral dose is absorbed and 
it is excreted unchanged in the urine.  It has a plasma half life of 5.6 to 14.8 hrs 
[MODURETIC Package Insert, 2015]. Time of occurrence of Cmax (Tmax) is reached at 
2.1 hrs, and maximum observed concentration (Cmax) is 280 ng/ milliliter (mL) after a 
50 mg dose[Welling, 1986]  Hydrochlorothiazide is bound to plasma proteins to about 
40% and accumulates in erythrocytes.  The absorption in patients with hypertension is 
similar to healthy individuals, but decreased in patients with heart failure [Beermann, 
1984].
Hydrochlorothiazide and amiloride combination
The combination of HCTZ/ amiloride provides diuretic and antihypertensive activity 
(principally due to the HCTZ component) while acting through the amiloride component 
to prevent excessive potassium loss that may occur in patients receiving a thiazide 
diuretic.  The onset of action of the combination is within 1 to 2 hrs and this action 
appears to be sustained for approximately 24 hrs [APO-AMILIZIDE Package Insert, 
2013]. 
The optimal dosage should be established by the individual titration of the components.  
For hypertension the usual maintenance dose is 1 or 2 tablets of HCTZ 50 mg/amiloride 
5 mg given once a day in divided doses.  The dosage should not exceed 4 tablets a day 
[APO-AMILIZIDE Package Insert, 2013]. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of Amiloride 
hydrochloride and hydrochlorothiazide is provided in the package insert for Moduretic.
3.3.
Benefit/Risk Assessment
Hydrochlorothiazide/ amiloride hydrochloride fixed dose combination was first approved 
in 1986 for the treatment of hypertension, congestive heart failure and hepatic cirrhosis 
with ascites and oedema, by the Medicines and Healthcare Product Regulatory Agency 
(MHRA), in the United Kingdom (UK).
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of HCTZ/amiloride hydrochloride can be 
found in the Summary of Product Characteristics (SmPC) [MODURETIC Package 
Insert, 2015].  HCTZ/amiloride hydrochloride fixed dose combination has a well 
established safety profile.
The following section outlines the risk assessment and mitigation strategy for this 
protocol.


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3.3.1.
Risk Assessment
The potential risks of clinical significance for this study are derived from the prescribing information from marketed formulations of 
HCTZ/amiloride hydrochloride tablets.  Risks associated with chronic use or in patient types (e.g. patients with renal failure) are not 
included as this is an acute dose study in healthy participants.
Table 2
Summary of Risks and Mitigation Strategies for Investigational Products
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study treatment GSK3542503 and reference HCTZ/amiloride hydrochloride
Allergic reaction to the active substances or to 
any of the excipients
Contraindication : Urticaria or anaphylactic 
reactions may occur if a volunteer has 
hypersensitivity to HCTZ/amiloride or excipients.
Exclude participants with known hypersensitivity 
to HCTZ or amiloride hydrochloride or other 
sulphonamide derived drugs, or excipients 
including but not limited to lactose, guar gum and 
sunset yellow. .
Hyperkalaemia 
Warning: Rapid increases in plasma potassium 
may lead to the development of acidosis.
Exclude participants taking potassium 
supplements. All study participants will undergo
laboratory testing for renal function, in order to 
exclude patients with a creatinine clearance level 
below 30ml/min, and those with existing 
hyperkalaemia where the serum potassium level 
is > ULN. Study participants will be warned 
against consuming potassium rich foods and 
taking potassium supplements during 
participation the study. 
Laboratory tests will be used to monitor 
potassium levels, and creatinine level, during the 
study


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Electrolyte imbalance
Warning:Signs or symptoms of electrolyte 
imbalance could include dryness of the mouth, 
weakness, lethargy, drowsiness, restlessness, 
seizures, confusion, muscle pain or cramps, 
hypotension, oligouria, tachycardia, nausea or 
vomiting. 
Study participants will undergo laboratory testing 
for sodium, chloride, potassium and magnesium 
for detection of electrolyte imbalance which may 
need to be treated. Patients will also be 
assessed for clinical signs of electrolyte 
imbalance through the collection of  AEs during 
the study period.
Metabolic abnormalities
Warnings. Metabolic abnormalities such as gout, 
or diabetes may be precipitated. 
A standard panel of chemistry laboratory 
assessments, will be performed prior to dosing 
and after each dose of study medication  and 
reviewed for  metabolic abnormalities. 
Sensitivity reactions
Warning. Thiazides may activate or exacerbate 
Systemic lupus erythematosus .
Participants with a history of systemic lupus 
erythematosus will be excluded.
Opthalmologic reactions
Warning: increased intra-ocular pressure, has 
been reported in patients using amiloride 
hydrochloride; and transient blurred vision and 
xanthopsia have been reported in patients taking 
HCTZ . Visual disturbances have been reported 
in patients taking the HCTZ/amiloride 
hydrochloride fixed dose combination.
Exclude participants with a history of 
sulphonamide or penicillin allergy which are risk 
factors for developing acute angle-closure 
glaucoma. Immediately discontinue study 
medication if participants present with any ocular 
complaints.
Hepatic disease
Thiazides should be used with caution in patients 
with impaired hepatic function or progressive 
liver disease, since minor alterations of fluid and 
electrolyte balance may precipitate hepatic coma
Exclude participants with active hepatic disease.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Blood sampling
An intravenous cannula will be inserted into 
participants to obtain blood samples for testing. 
This may cause some pain, discomfort, bruising 
and redness/irritation at the site of injection.
Participants will be monitored closely by the site 
staff during the visits. The cannula will be 
removed if this is causing pain and discomfort.  If 
the cannula is removed, the subsequent blood 
samples will be collected by venepuncture or the 
cannula will be replaced.
Other 
Not applicable
Not applicable


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3.3.2.
Benefit Assessment
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 GSK3542503 compared to reference 
HCTZ/amiloride hydrochloride.
3.3.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimise risk to participants in this study, the 
potential risks identified in association with GSK3542503 tablets are justified by the 
anticipated benefits that may be afforded to patients for the treatment of hypertension 
congestive heart failure and hepatic cirrhosis with ascites and oedema.
4.
OBJECTIVES AND ENDPOINTS
Table 3
Study Objectives and Endpoints
Objectives
Endpoints
Primary
To determine if 50 mg HCTZ/5 mg amiloride 
hydrochloride (GSK3542503) tablets are 
bioequivalent to reference 50 mg HCTZ/5 mg 
amiloride hydrochloride tablets in healthy adult 
participants under fasting conditions. 
Plasma PK parameters: AUC(0-t) and Cmax, for 
hydrochlorothiazide and amiloride  in relevant 
treatments. 
Secondary
To assess secondary PK parameters of 50 mg 
HCTZ/5 mg amiloride hydrochloride tablets
(GSK3542503) relative to reference 50 mg 
HCTZ/5 mg amiloride hydrochloride in healthy 
adult participants under fasting conditions . 
To compare the safety and tolerability of 
GSK3542503 with reference product50 mg 
HCTZ/5 mg amiloride hydrochloride,  in healthy 
adult  participants under fasting conditions.

Plasma PK parameters: AUC(0-), tmax, 
%AUCex and t½ for hydrochlorothiazide and 
amiloride in relevant treatments.

Adverse events (AE), clinical laboratory 
values (Biochemistry) and vital signs
AUC(0-) =  Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time; %AUCex= 
Percentage of AUC(0-) obtained by extrapolation; AUC(0-t)= Area under the concentration-time curve from time zero 
(pre-dose) to last time of quantifiable concentration within a participant across all treatments; t1/2= Terminal phase 
half-life 


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5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase I, open label, balanced, randomised, single dose, two-way crossover 
study, enrolling approximately 42 healthy participants at a single centre. 
Each enrolled study participant will participate in two treatment periods in accordance 
with the randomisation schedule. The treatment periods will be separated by a washout 
period of at least 7 days and no more than 14 days. 
Figure 1
Study Schematic
Treatments
A = Test– GSK3542503 Hydrochlorothiazide 50mg and Amiloride
hydrochloride 5mg  fixed dose combination 
B = Reference  - Hydrochlorothiazide 50mg and Amiloride hydrochloride 5mg 
fixed dose combination 
SCREENING
RANDOMISATION (n=42)
Treatment Sequences 1-2
Sequence 2:  B-A  (n=21)
Sequence 1:  A-B  (n=21)
21days 
prior to 
Day -1
7-14 days 
washout 
between 
Treatment 
Periods
FOLLOW-UP
(If required at the end of the last 
Treatment period)
Study participants will be randomised to one of two treatment sequences (A-B or B-A). A 
single dose of one of the two treatments A or B, will be administered on Day 1, in each 
treatment period.  Each participant will participate in both treatment periods and receive a 
single dose of each treatment.
Study treatments will be referred to as Test and Reference throughout the protocol:

Treatment A – Test: GSK3542503 (BIDURETTM), a hydrochlorothiazide 50mg 
and amiloride hydrochloride 5mg fixed dose combination.

Treatment B - Reference:Moduretic, a hydrochlorothiazide 50mg and amiloride 
hydrochloride 5mg fixed dose combination.
Treatment periods 1 and 2 will be separated by a washout period of 7 to 14 days. 


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The total duration in the study for each participant is expected to be 5 to 7 weeks, from 
screening to their last visit.
5.2.
Number of Participants
A maximum of 42 participants will be randomized such that at least 32 evaluable 
participants complete the study. 
Subjects who withdraw or are withdrawn from the study will not be replaced, unless 
fewer complete the study than the estimated number of evaluable subjects (see 
Section 10.1). 
If a subject is replaced, the replacement will be allocated the subject number of 500 plus 
the subject number being replaced (e.g., Subject 
 will be replaced by 
  The 
subject numbers being replaced will be selected such that the replacement subjects 
receive the same treatment sequence as the withdrawn subjects and the sequence balance 
is maintained.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last scheduled procedure shown in the SoA.
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant in the trial.
5.4.
Scientific Rationale for Study Design

This study is a standard single dose fasted BE design.

This study will assess whether the test formulation is bioequivalent to the 
reference treatment.

This is a pivotal study and meets guidelines for all major authorities on 
bioequivalence study design. 
5.5.
Dose Justification
The doses of HCTZ (50 mg) and amiloride hydrochloride (5 mg) in GSK3542503 are 
well established and approved doses, marketed for treatment of hypertension, congestive 
heart failure or hepatic cirrhosis where ascites and oedema are present.
PPD
PPD


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6.
STUDY POPULATION
Specific information regarding warnings, precautions, contra-indications, AEs, and other 
pertinent information on the Test product or other study treatment that may impact 
participant eligibility is provided in the reference 50 mg HCTZ/5 mg amiloride 
hydrochloride product information leaflet [MODURETIC Package Insert, 2015]. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted, as these can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or participant 
safety.
Therefore adherence to inclusion and exclusion criteria as stated in the protocol is 
essential.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participants must be between18 and 65 years of age inclusive, at the time of signing 
the informed consent.
Type of Participant and Disease Characteristics
2.
Healthy, non-smoker, as determined by the investigator or medically qualified 
designee based on a medical evaluation including medical history, physical 
examination, laboratory tests, and cardiac monitoring.
3.
A participant with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the normal reference 
range for the population being studied may be included only if the investigator in 
consultation with the Medical Monitor if required, agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures. 
Weight
4.
Body weight 50 kilogram (kg) and body mass index (BMI) within the range 19-
30kg/m2(inclusive).
Sex
5.
Healthy Male or female participants
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 1 of this 
protocol, for 3 days after each dose of study treatment and refrain from donating 
sperm during that period.


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b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 1), 
not breastfeeding, and at least one of the following conditions applies:
(i)
Not a woman of childbearing potential (WOCBP) as defined in Appendix 1
OR
(ii)
A WOCBP who agrees to follow the contraceptive guidance in Appendix 1
during the treatment period and for at least 30 days after the last dose of study 
treatment.
The investigator is responsible for ensuring that male and female study participants 
understand how to correctly use the methods of contraception described in Appendix 1.
Informed Consent
6.
Capable of giving signed informed consent as described in Appendix 2 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, haematological, or neurological disorders capable of significantly altering 
the absorption, metabolism, or elimination of drugs; constituting a risk when taking 
the study treatment; or interfering with the interpretation of data.
2.
Abnormal renal function measured by creatinine clearance.
3.
Presence of hyperkalaemia where the serum potsassium is >ULN.
4.
History or known  acute angle closure glaucoma or ocular complaints which could 
increase the risk of ophthalmic reactions as deemed by the investigator .
5.
Abnormal BP as determined by the investigator.
6.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) 
7.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
8.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
9.
QT interval corrected for heart rate according to Bazett’s formula (QTcB) >450 
milliseconds (msec) 
NOTES:

For purposes of data analysis, only QTcB, will be used.


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Prior/Concomitant Therapy
10. Past or intended use of over-the-counter or prescription medication including herbal 
medications, within 14 days prior to dosing.  Specific medications listed in 
Section 7.7 may be allowed.
Prior/Concurrent Clinical Study Experience
11. Where participation in the study would result in loss of blood or blood products in 
excess of 500 mL within 90 days.
12. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
13. Current enrolment or past participation within the last 90 days before signing of 
consent in this or any other clinical study involving an investigational study 
treatment.
Diagnostic assessments
14. Presence of Hepatitis B surface antigen (HBsAg) at screening, or a positive Hepatitis 
C antibody test result at screening.
NOTE:  Participants with positive Hepatitis C antibody due to prior resolved disease can 
be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained
15. Positive pre-study drug/alcohol screen
16. Positive HIV antibody test
17. Regular use of known drugs of abuse
Other Exclusions
18. Sensitivity to heparin or heparin-induced thrombocytopenia
19. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy including allergy to penicillin and sulphonamides that, in the opinion of the 
investigator or medical monitor, contraindicates participation in the study. 
20. Regular alcohol consumption within 6 months prior to the study defined as: 

An average weekly intake of >21 units for males or > 14 units for females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 
mL) of wine or 1 (25 mL) measure of spirits. 
21. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 6 months prior to screening.
22. Participants with any risk as described in Table 2 under Section 3.3.1. should be 
excluded from participation in this study. 


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6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit 
juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days 
prior to the first dose of study medication until after the final dose.

Potassium rich foods should be avoided within 7 days of the first dose of study 
medication, and during participation in the study. 

Participants will be administered the treatment in the fasted state.

Following an overnight fast of at least 10 hrs, participants should be 
administered the study drug with 240 mL (8 fluid ounces) of water.  No food 
should be allowed for at least 4 hrs post-dose.  Water is allowed as desired 
except for one hr before and after drug administration.  Participants should 
receive standardized meals scheduled at the same time in each period of the 
study. 
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hrs 
before the start of dosing until after collection of the final PK sample.

During each dosing session, participants will abstain from alcohol for 24 hrs before 
the start of dosing until after collection of the final PK sample. 
6.3.3.
Activity

Participants will abstain from strenuous exercise for 48 hrs before the start of dosing 
until after collection of the final PK sample.  Participants may participate in light 
recreational activities during studies (e.g., watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened. 


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7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Table 4
Study Treatments
Study Treatment
Test Product
Reference Product
Study Treatment Name:
GSK3542503 / HCTZ / 
Amiloride Hydrochloride
(BIDURETTM)
Moduretic
Dosage formulation:
Tablet
Tablet
Unit dose 
strength(s)/Dosage level(s):
50 mg Hydrochloro-thiazide /5 mg Amiloride Hydrochloride
Route of Administration 
Route: oral
Duration: single dose
Dosing instructions:
1 tablet to be taken orally with 240 mL water.
Physical Description
Cream-coloured, circular, flat 
faced uncoated tablet with 
bevelled edges having break 
line on one side and “BD” 
embossed on the other side
Peach-coloured, half scored, 
diamond shaped tablets 
marked “MSD917” 
Manufacturer / Supplier
Manufactured by Panacea 
Biotec, India; supplied by GSK 
India, Mumbai.
Merck Sharpe & Dohme 
Limited, U.K.
7.2.
Dose Modification
Not applicable.


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7.3.
Method of Treatment Assignment
Participants will be assigned to one of two sequences (A-B or B-A) in accordance with 
the randomisation schedule generated by PAREXEL Biostatistics, prior to the start of the 
study, using validated software. Randomization numbers will be assigned sequentially. 
Possible replacements will be handled according to Section 5.2.
A description of each regimen is provided in Table 5.  Treatments administered are as 
follows:

Treatment A – Test GSK3542503 50 mg HCTZ/5 mg Amiloride Hydrochloride 
tablets (BIDURETTM)

Treatment B – Reference 50 mg HCTZ/5 mg Amiloride Hydrochloride tablets 
(Moduretic)
On Day -1, participants will be assigned a unique randomization number.  The 
randomization number encodes the participant’s assignment to one of the 2 sequences. 
On Day 1, each participant will be administered a single dose of open label study 
treatment.  After a washout period of 7-14 days, each participant will be administered a 
single dose of the other treatment not previously received. 
Table 5
Description of each treatment sequence
Sequence
Number of 
Participants Per 
Group
Treatment Period 1
Treatment Period 2
A-B
21
Treatment A
(GSK3542503)
Treatment B
Reference
B-A
21
Treatment B
Reference
Treatment A
(GSK3542503)
7.4.
Blinding
This is an open label study; potential bias will be reduced by assigning treatment by 
randomization. 
7.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.


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
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
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 investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study treatment 
are provided in PAREXEL SOPs. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.6.
Treatment Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation 
of the dose will be confirmed by a second member of the study site staff. 
When participants are dosed, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
Study site personnel will examine each participant’s mouth to ensure that the study 
treatment was ingested.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants must abstain from taking prescription or non- prescription drugs (including 
vitamins and dietary or herbal supplements) for 14 days before the start of the study until 
completion of the follow-up visit, unless, in the opinion of the investigator and sponsor, 
the medication will not interfere with the study. 


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Paracetamol, at doses of  2 grams/day, is permitted for use any time during the study.  
Other concomitant medication may be considered on a case-by-case basis by the 
investigator in consultation with the Medical Monitor if required.  Please refer to the 
summary of interactions with other medicinal products in the Package Insert for 
Moduretic. 
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because only healthy participants are eligible for study participation.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants will be permanently withdrawn from study treatment, at the discretion of the 
investigator in the event of the following medical reasons after receiving the first dose of 
study medication:

anaphylaxis, 

sensitivity reactions (e.g., activation or exacerbation of systemic lupus 
erythematosus)

electrolyte imbalance

hyperkalemia

liver events (see Section 8.1.1).

positive pregnancy test

vomiting within 2 × the median tmax of the reference product
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the Food 
and Drug Administration [FDA] premarketing clinical liver safety guidance).  These 
protocol guidelines are in alignment with FDA premarketing clinical liver safety 
guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the algorithm in 
Figure 2, or if the investigator believes that it is in the best interest of the participant. 
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met:


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Figure 2
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.
8.1.2.
QTc Stopping Criteria
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QT 
corrected (QTc) data being collected for data analysis.  Safety ECGs and other 
non-protocol specified ECGs are an exception.  
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.
See the SoA for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
A participant that meets the bulleted criteria below will be withdrawn from study 
treatment.

QTc, QTcB, >500 msec,

Change from baseline: QTc >60 msec


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8.1.3.
Temporary Discontinuation
Participants withdrawn from study treatment, will continue in the study until completion 
of the follow up visit for the study period.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

Refer to the SoA for data to be collected at the time of study discontinuation and 
follow-up.  Additional assessments may be performed at the discretion of the 
investigator. 
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 


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9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. During screening the following will be 
completed:

Demographic parameters will be captured: Year of birth, sex, race and ethnicity.

Medical /Medication /family history will be assessed as related to the 
inclusion/exclusion criteria in Section 6.

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

Blood samples will be collected as per SoA.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment /study (see Section 8). 


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9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the time a participant consents to participate in 
the study until the follow-up visit at the time points specified in the SoA 
(Section 2).

All AEs will be collected from the start of study treatment until the follow-up 
visit at the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 24 hrs, 
as indicated in Appendix 4. The investigator will submit any updated SAE data 
to the sponsor within 24 hrs of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non serious AEs of special 
interest (as defined in Section 3.3.1), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 


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regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the SMPC and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study treatment and until 3 days 
after the last dose or the follow up visit. 

If a pregnancy is reported, the investigator should inform GSK within 24 hrs of 
learning of the pregnancy and should follow the procedures outlined in Appendix 1.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of study treatment GSK3542503 or comparator greater than 
50mg HCTZ and 5mg Amiloride hydrochloride within a 24-hr time period will be 
considered an overdose.
The sponsor does not recommend any specific antidote as treatment for an overdose. 
Symptomatic and supportive treatment is recommended. Emesis should be induced 
and/or gastric lavage performed if warranted.  The principal investigator will be 
responsible for the appropriate medical management of any participant who has an 
overdose.
In the event of an overdose, the investigator/treating physician should:
1
Contact the Medical Monitor immediately.
2
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
Hydrochlorothiazide and Amiloride can no longer be detected systemically (at 
least 3 days).
3
Obtain a plasma sample for PK analysis within 3 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis).
4
Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF.


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Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2). 
Additional time points for safety tests (such s vital signs, physical exams and laboratory 
safety tests) may be added during the course of the study based on newly available data to 
ensure appropriate safety monitoring.
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.4.2.
Vital Signs

Temperature, pulse rate, respiratory rate, and BP will be assessed.

Blood pressure and pulse measurements will be assessed in a supine position 
with a completely automated device.  Manual techniques will be used only if an 
automated device is not available.

Vital signs will be measured in a supine position after 5 minutes rest and will 
include temperature, systolic and diastolic BP, respiratory rate and pulse.  Three 
readings of BP and pulse will be taken. The first reading should be rejected. The 
second and third readings should be averaged to give the measurement to be 
recorded in the CRF.

Participants will not be dosed if their average pre-dose SBP on Day 1 is <95 mm 
Hg or their average resting ventricular rate is 45 beats per minute.

Pre-dose vital signs will be collected at -2.00 to 0.00 hrs.  Following completion 
of the pre-dose procedures the appropriate dose of study medication will be 
administered.

Vital signs post dose will be obtained within 30 min. 
9.4.3.
Electrocardiograms

Single 12-lead ECG will be obtained at the Screening visit as outlined in the 
SoA (see Section 2) using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals. Refer to Section 8.1.2
for QTc withdrawal criteria and additional QTc readings that may be necessary.


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9.4.4.
Clinical Safety Laboratory Assessments

All clinical laboratory assessments  will be performed by the local laboratory.

Refer to Appendix 5 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 5, must be 
conducted in accordance with the PAREXEL laboratory manual, PAREXEL 
standard operating procedures (SOPs) and the SoA.

If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., 
SAE or AE or dose modification), then the results must be recorded in the CRF.

Refer to the PAREXEL SOPs for appropriate processing and handling of 
samples to avoid duplicate/ and or additional blood draws.
9.5.
Pharmacokinetics
Pharmacokinetic sampling time-points are discussed in the SoA in Section 2. 

Whole blood samples of approximately 8 mL will be collected for measurement 
of plasma concentrations of HCTZ and amiloride as specified in the SoA.  A 
maximum of 2 samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor. 
Instructions for the collection and handling of biological samples will be provided 
in the PAREXEL Bioanalytical Protocol. The actual date and time (24-hr clock 
time) of each sample will be recorded.

Samples will be used to evaluate the PK of HCTZ and amiloride.  Each plasma 
sample will be divided into 4 aliquots of not less than 700 l plasma each 
(2 aliquots for the analysis of HCTZ and 2 aliquots for the analysis of amiloride). 
Samples collected for analyses of HCTZ and amiloride plasma concentration may 


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also be used to evaluate safety or efficacy aspects related to concerns arising 
during or after the study.

Pre-dose PK samples will be collected within 15 minutes prior to dose 

Post dose samples for 0.33-24 hrs will be collected within 2 minutes

Post dose samples for 36 and 48 hrs will be collected within 2 hrs 

Samples collected outside these recommended time windows will be recorded as 
protocol deviations

Participant confidentiality will be maintained. At visits during which whole blood 
samples for the determination of multiple aspects of study treatments will be 
taken, one sample of sufficient volume can be used.

A validated bioanalytical method, as described in the PAREXEL bioanalytical 
protocol will be used for quantitative analysis. 
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study.
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study.


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10.
STATISTICAL CONSIDERATIONS
Refer to Analysis Plan (Appendix 6).
Bioequivalence
The primary objective of this study is to demonstrate BE between the test fixed dose 
tablet formulation GSK3542503 and the reference formulation, based on PK endpoints 
Cmax and AUC(0-t) of HCTZ  and amiloride. 
The null hypothesis is that the true ratio of the geometric mean of the test treatment to the 
geometric mean of the reference treatment, (Test)/ (Reference), for the Cmax, and AUC(0-t), is 
either <0.80 or >1.25 for plasma HCTZ and amiloride.
The alternate hypothesis is that the true ratio of the geometric mean of the test treatment 
to the geometric mean of the reference treatment for the Cmax, and AUC(0-t), is either 0.80 
or 1.25 for plasma HCTZ and amiloride.
Symbolically this is expressed as follows:
H0: μ(Test)/μ(Reference) <0.80 or μ(Test)/μ(Reference) >1.25
i.e., treatments are not bioequivalent.
versus
Ha: 0.80≤ μ(Test)/μ(Reference) ≤1.25
i.e., treatments are bioequivalent.
For each PK parameter designated as a primary endpoint, a two one-sided t-test 
(TOST)[Schuirmann, 1987] procedure with =0.05 for each one-sided test will be used 
to test this set of hypotheses. Bioequivalence will be declared if the 90% CI for the true 
ratio of test to reference geometric means falls entirely within the range of 0.80 to 1.25 
for all primary parameters. 
For BE to be declared, the null hypothesis must be rejected, for all primary parameters 
Cmax, and AUC(0-t),for HCTZ and amiloride.
10.1.
Sample Size Determination
Sample Size Rationale:
Bioequivalence is to be determined on the basis of the endpoints Cmax and AUC(0-t) of 
both HCTZ and amiloride . 
Due to unavailability of intra participant coefficient of variation (CVw) estimates in 
recent published data for amiloride , a more conservative intra participant CVw of 23% is 
assumed [MIDAMOR Package Insert, 2010] . The variability of the primary endpoints 
of HCTZ was less than 20%, as per published data[HPRA, 2015] .


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Hence, the sample size for this trial was determined based on maximum possible intra 
participant CV of 23%. Accounting for multiple BE assessments for HCTZ and 
amiloride, i.e. the overall power of the study is the product of the power of the test of 
HCTZ and amiloride.
Based on a BE range of 80.00% to 125.00% for Cmax and AUC(0-t), for HCTZ and 
amiloride assuming intra participant CV to be not more than 23% and a "test/reference" 
mean ratio of 0.95;  thirty two subjects are needed to achieve a power of 90% (in order to 
achieve an overall power greater than 80%) at an alpha level of 0.05 for the single test for 
testing BE.
Up to 42 eligible participants will be entered into the study to complete the study with at 
least 32 evaluable participants. See Section 5.2
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Table 6
Description of Populations for Analysis
Population
Description
Enrolled 
All participants who sign the ICF
Randomized
All participants assigned to study treatment
Safety
All randomized participants who received at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
PK
All subjects who complete the study and for whom primary PK 
parameters can be calculated for all treatment periods will be 
included in the statistical PK analysis of the study.
10.3.
Statistical Analyses
The statistical methodology below describes the statistical analysis as it is foreseen when 
the study is being planned.
If circumstances should arise during the study rendering the analysis inappropriate, or if 
in the meantime improved methods of analysis should come to light, different analyses 
may be made. Any deviations from the statistical methodology, reasons for such 
deviations and all alternative or additional statistical analyses that may be performed, will 
be described in the clinical study report.
See Appendix 6 for a list of Tables, Figures and Listings to be appended in the clinical 
study report.


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10.3.1.
PK Analyses
Pharmacokinetic analysis will be the responsibility of the PAREXEL Quantitative 
Clinical Development (QCD) department.  Plasma hydrochlorothiazide and amiloride  
concentration-time data will be analysed by non-compartmental methods with Phoenix 
WinNonlin 6.3.  The PK parameters will be calculated for each participant and treatment 
using non-compartmental analysis and using the actual sampling time intervals (relative 
to IMP administration) recorded during the study. 
From the plasma concentration-time data, the following PK parameters will be 
determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve [AUC(0-∞) and AUC(0-t)], 
and apparent t1/2 of hydrochlorothiazide and amiloride hydrochloride.
Participants who experience emesis during the course of the study may be deleted from 
the statistical analysis if vomiting occurred at or before 2 times median tmax. For 
participants with pre-dose plasma concentrations, their data may be included without any 
adjustments in all PK measurements and calculations if the pre-dose concentration is 
≤5% of Cmax. If the pre-dose value is > 5% of Cmax, the participant’s data may be 
dropped from all BE evaluations.
The available concentration data of the participants excluded due to vomiting, and of 
those who did not complete the PK sampling will only be listed; it will not be presented 
in descriptive statistics or included in PK evaluations or formal statistical analysis.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. All PK data will be archived by the study sponsor 
GlaxoSmithKline (GSK).
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of 
PAREXEL Biostatistics.
10.3.2.
Protocol Deviations and Changes to Planned Analyses
Permission from the sponsor in writing will be obtained should any changes be required 
to the clinical study protocol.  Should the safety of the subjects necessitate immediate 
action, which represents a deviation from the clinical study protocol, the sponsor will be 
informed as soon as possible.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the PAREXEL Protocol Deviation Specification sheet.
Protocol deviations and changes to planned analyses will be described in the clinical 
study report.
10.3.3.
PK Parameters
Calculation of the PK parameters will be made with Phoenix WinNonlin 6.3 (Certara, 
L.P., 1699 South Hanley Road, St Louis, Missouri 63144, USA). The PK parameters will 


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be calculated for each subject and treatment using non compartmental analysis and using 
the actual sampling time intervals (relative to IMP administration).
10.3.3.1.
Primary Pharmacokinetic Parameters for hydrochlorothiazide and 
amiloride

Maximum observed plasma concentration (Cmax)

Area under the plasma concentration versus time curve, from time zero to t, where t is 
the time of the last quantifiable concentration (AUC(0-t)). 
10.3.3.2.
Secondary Pharmacokinetic Parameters for hydrochlorothiazide and 
amiloride

Time to maximum observed plasma concentration (tmax)

Area under the plasma concentration versus time curve, with extrapolation to infinity 
(AUC(0-))

Apparent terminal elimination half-life (t½)

Percent area under the curve extrapolated (%AUCex). 
10.3.4.
Analysis of Bioequivalence
Table 7
Statistical Analysis Methods to be used for Endpoints
Endpoint
Statistical Analysis Methods
Primary
Following log-transformation of derived pharmacokinetic parameters Cmax and 
AUC(0-t) of hydrochlorothiazide and amiloride will be separately analysed by using 
analysis of variance with sequence, subject (sequence), treatment and period 
effects. Point estimates for the adjusted means on the loge scale, the mean 
difference between treatments and associated 90% CIs for the difference 
Treatment A - Treatment B will be constructed using the residual variance.
These point estimates and confidence intervals will then be exponentially back-
transformed to obtain adjusted (least square) geometric means for each treatment 
and point estimates and associated 90% confidence intervals for the ratio, 
Treatment A/Treatment B.
Distributional assumptions underlying the statistical analyses will be assessed by 
visual inspection of residual plots. Normality will be examined by normal 
probability plots, while homogeneity of variance will be assessed by plotting the 
residuals against the predicted values for the model. If the assumptions are 
seriously violated then alternative statistical methods will be considered.
Secondary
AUC(0-) of HCTZ  and amiloride will be  analysed as per primary analysis; tmax of 
HCTZ and Amiloride will be analysed using a  nonparametric test to compute point 
estimate of the median and associated 90% confidence intervals for the median 
differences, Treatment A –Treatment B
%AUCex will not be statistically analysed. A summary will be created.
For  t½  the n, median, minimum, and maximum values will be presented


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10.3.5.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Safety variables will include vital signs and clinical chemistry results.  Adverse events 
(AEs) and concomitant medication will also be listed and summarized by treatment.
10.3.6.
Other Analyses
No other analyses are planned.
10.3.7.
Interim Analyses
No interim analysis is planned.


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11.
REFERENCES
APO-AMILIZIDE (hydrochlorothiazide and amiloride hydrochloride 50:5mg Tablets 
USP, Product Monograph) Product Information. February, 2013. 
Beermann B. Aspects on Pharmacokinetics of some Diuretics. Acta Pharmacol Toxicol 
(Copenh). 1984;54 (Suppl):17-29. 
DG Vidt DG. Mechanism of Action, pharmacokinetics, adverse effects, and therapeutic 
uses of amilorde hydrochloride, a new potassium-sparing diuretic. Pharmacotherapy. 
1981;Nov-Dec; 1(3):179-187. 
Gerber JG Gerber, Nies AS. Goodman and Gilman's The Pharmacological Basis of 
Therapeutics, Chapter 33 Antihypertensive Agents and the Drug Therapy of 
Hypertension. 8th ed. New York, USA:Pergamon Press; 1990. 
Health Products Regulatory Agency (HPRA). Public Assessment Report, Scientific 
Discussion Olmesartan/ Hydrochlorothiazide Clonmel 20mg/12.5mg, 20mg/25mg, 
40mg/12.5mg and 40mg/25mg Film-coated 
MIDAMOR (Amiloride Hydrochloride Tablets, USP 5mg) Product Information. August, 
2010. (https://www.aapharma.ca/downloads/en/PIL/midamor_pm.pdf).
MODURETIC (Amiloride hydrochloride and hydrochlorothiazide, Summary of Product 
Characteristics) Product Information. Sep, 2015.  
https://www.medicines.org.uk/emc/medicine/9646
MODURETIC (Hydrochlorothiazide and Amiloride Hydrochloride) Product 
Information. April, 2015.  https://www.medicines.org.uk/emc/PIL.18951.latest.pdf
Schuirmann DJ. A comparison of the two one sided tests procedure and the power 
approach for assessing the equivalence of average bioavialbility. J Pharmacokinet and 
Biopharm. 1987;15:657-680. 
Tablets Olmesartan Medoxomil IE/H/437/001-004/DC. HPRA, Ireland; 2015. 
CRN2140342.  (http://www.hpra.ie/img/uploaded/swedocuments/LicenseSPC_PA0126-
260-001_20052016174320.pdf)
Weiner IM WIM. Chapter 28 Diuretics and Other Agents employed in the Mobilisation 
of Edema Fluid. In: Goodman Gilman A, editor. Goodman and Gilman's The 
Pharmacological Basus of Therapeutics. New York, USA:Pergamon Press, 1990:713-
731. 
Welling PG. Pharmacokinetics of the Thiazide Diuretics. Biopharmaceutics and Drug 
Disposition. 1986;7:501-535. 
Willem H. Birkenhager WH. Diuretics and Blood Pressure Reduction: Physiologic 
aspects. Journal of Hypertension. 1990;8 (suppl2):s3-s7. 


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12.
APPENDICES
12.1.
Appendix 1: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
23. Premenarchal
24. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
25. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined time 
frame in Section 6.1: 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 


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
Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 8 when having penile-vaginal 
intercourse with a woman of childbearing potential 

Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration for 3 days after each dose of study treatment. 

Refrain from donating sperm for 3 days after each dose of study treatment. 
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in  
Table 8. 
Table 8
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen-containing ) hormonal contraception associated 
with inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition 
of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the study and the preferred and usual lifestyle of the participant.)


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NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants in clinical 
studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the 
efficacy of the contraceptive method. In this case two highly effective methods of contraception should 
be utilized during the treatment period and for at least  30 days after the last dose of study treatment 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test 

Additional pregnancy testing should be performed on Day -1 during the treatment 
period.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing, with a sensitivity of 10 mIU/mL (dipstick) and serum 0.100 to 
10 000 mIU/mL (automated) will be performed and assayed in a certified laboratory.
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy, by facsimile transmission to the 
medical monitor / LOC Pharmacovigilance team . 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 


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be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of foetal status (presence 
or absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating  

will discontinue study treatment or be withdrawn from the study


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12.2.
Appendix 2: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Financial disclosure will not be collected for this study, as data will not be used to 
support any marketing applications with any regulatory authorities.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines,  where applicable, and the IRB/IEC or study center. 


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
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
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 site or other mutually 
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GSK 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 participants, 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 Policy.
Study information and tabular study results, from this protocol will be posted on the US 
National Institutes of Health’s website www.ClinTrials.gov, other publically-accessible 
sites, and the GSK Clinical Trials Register. In addition, results may also be published in 
peer-reviewed publications, to ensure the scientific integrity and credibility of publication 
activities performed by or on behalf of the company. Access to analyzable datasets from 
clinical studies will be granted through a secure system, following an independent 
assessment of the scientific merit of a rigorously defined research question from a third 
party.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 


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Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the PAREXEL SOPs .

SOP-EP.CL-WW-009-01: Data Collection, Transcription, Quality Control 
and Clarification

MAN-EP.CL-WW-044-01: Data Collection, First Time Quality and 
Correction of Data Entries
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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12.3.
Appendix 3: Liver Safety: Required Actions and Follow-up 
Assessments.
Phase I Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology  (in alignment with the FDA premarketing clinical 
liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 3 days of  
last dose

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 


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Liver Chemistry Stopping Criteria 
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009].

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et.al.. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

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 treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
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).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings 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 participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 


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leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant 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 AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 


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not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant 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.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
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.


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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

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.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

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 in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

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.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology. 

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to  GSK within 24 hours of 
receipt of the information.


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Reporting of SAE to GSK
SAE Reporting to GSK via Paper CRF

The primary mechanism for the Investigator to report SAEs and updated data on 
previously reported SAEs to GSK, will be the SAE paper data collection tool.

Facsimile transmission of the GSK SAE reporting form (paper) is the preferred 
method to transmit this information from the Investigator site to the medical 
monitor / LOC Pharmacovigilance team .

The LOC Pharmacovigilance team will enter the SAE into the Local Affiliate 
Module (LAM) with the SAE copy attached. The SAE will then be visible to Central 
Pharmacovigilance.

The Pharmocovigilance assistant will report the SAE to the Regulatory Authority 
(MCC)

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

The Investigator must ensure that SAEs are reported to the local ethics committee, 
within the required timelines.

Contact for SAE reporting:
GSK, South Africa - Pharmacovigilence
Facsimile: PPD


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12.5.
Appendix 5: Clinical Laboratory Tests

The tests detailed in Table 1 will be performed by the local laboratory. 

If the local laboratory results are used to make either a study treatment decision 
or response evaluation, the results must be entered into the CRF.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 9
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
MCHC
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose [fasting]
Calcium
Alkaline 
phosphatase
Chloride
Magnesium
Coagulation 
Profile

PT and aPTT
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick

Microscopic examination (if blood or protein is abnormal)


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Laboratory 
Assessments
Parameters
Other 
Screening 
Tests

Breath alcohol and urine drug screen (to include at minimum: 
amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
phencyclidine (phenylcyclohexalpiperidine), tetrahydrocannabinol, 
methadone, methamphetamine, tricyclic antidepressants, oxycodone and 
propoxyphene)

Cotinine

Serum or urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)2

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody)] Hepatitis C RNA test for Hepatitis C antibody positive 
Participants 
The results of each test must be entered into the CRF.
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 3 All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.


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12.6.
Appendix 6:  Analysis Plan
Rules for handling decimals
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of safety data:
All data will be listed according to the number of decimal places presented in the source 
data.
Mean and median will be tabulated to one more decimal place than the source data. 
Minimum and maximum values will be tabulated to the same number of decimal places 
as the source data.
Standard deviation (SD) will be tabulated to two more decimal places than the source 
data.
A maximum of three decimal places will apply to all summary statistics.
Missing data
AEs with missing start dates/times will be handled as follows for the tabulations:

Missing start date:
If the start date is completely missing but the end date is known and shows 
that the AE ended on or after the dosing date in a specific treatment period, 
then the start date will be imputed as the day of dosing in that period 
(therefore first dosing in the run-in period).
If the end date is known and shows that the AE ended before the first dosing 
date in the run-in period, then the screening date will be used for the start 
date.
If the end date is known and shows that the AE ended before the dosing date 
in the treatment period (but after dosing in the run-in period), then the first 
dosing date of the run-in period will be used for the start date.
If the end date is non-informative (i.e., is missing or does not contain enough 
information), the start date will be imputed as the date of first dosing in the 
run-in period will be used.

Missing start day:
If only the start day is missing the day will be imputed as the first day on 
which a dose was given in that month unless the end date is known and shows 
that the AE ended before a dose was given in that month; in which case the 
date will be imputed as 01.


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If the end date is non-informative (i.e., is missing or does not contain enough 
information), the start date will be imputed as the first date of dosing in the 
known month. If the month is not a dosing month the date will be imputed as 
01.

Missing start day and month:
If the start day and month are missing the date will be imputed as the first day 
of dosing in the known year unless the end date is known and shows that the 
AE ended before a dose was given in that year; in which case the start day 
and month will be imputed as 01Jan or with the date of screening if this is 
later. If the end date is non-informative (i.e., is missing or does not contain 
enough information), the start date will be imputed as the first date of dosing 
in the known year. If the year is not a year of dosing then the date will be 
imputed as 01Jan or with the date of screening if this is later.

Missing times
Missing times will be imputed as 00:00 h or with the time of dosing for 
events starting on a dosing day.
Presentation of PK Data, Descriptive Statistics and PK Assessment
This section describes outputs to be presented.
The actual blood sampling times and time deviations will be listed for each participant 
dosed, treatment and scheduled sampling time.  A listing of plasma concentrations of 
hydrochlorothiazide and amiloride per treatment will be provided.
Summary table reflecting summary statistics (n, arithmetic mean, geometric mean, 
median, coefficient of variation, standard deviation, minimum and maximum) per 
treatment will be provided for plasma concentrations of hydrochlorothiazide and 
amiloride.
Concentrations below the lower limit of quantification (LLOQ) will be indicated as 
below the limit of quantification (BLQ).  These BLQ concentrations will be handled as 
follows:

For descriptive statistics, pre-dose BLQ concentrations will be substituted by 
zeros.  All other BLQ values will be substituted by ½LLOQ value before the 
calculation of the summary statistics.  Values reported as ‘NS’ (no sample) will be 
set to “missing”.

For PK assessment, all BLQ values at pre-dose and in the absorption phase, 
before the first reported concentration, will be substituted by zeros.  The BLQ 
values between evaluable concentrations will be substituted by ½LLOQ, before 
the calculation of the PK parameters.  The terminal BLQ values will be set to 
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These measures are taken to prevent an over-estimation of AUC.
For PK calculations, missing concentrations will be deleted, resulting in an interpolation 
between the nearest two concentration values.
A listing for PK parameters of hydrochlorothiazide and amiloride per treatment will be 
provided.  A summary table reflecting summary statistics (n, arithmetic mean, geometric 
mean, median, coefficient of variation, standard deviation, minimum and maximum) per 
treatment will be provided for PK parameters of hydrochlorothiazide and amiloride.
The individual plasma hydrochlorothiazide and amiloride concentration versus actual 
time profiles for each participant and treatment, as well as the mean (arithmetic and 
geometric) plasma hydrochlorothiazide and amiloride concentration versus scheduled 
time profiles for each treatment, will be presented graphically on a linear-linear and log-
linear scale. Individual plasma concentrations will be presented using actual, rather than 
planned, sampling times.  Combined individual concentration versus time graphs per 
treatment will also be presented on a linear-linear scale, together with the geometric mean 
values.  The individual log-linear graphs reflecting the WinNonlin modeling results, will 
be presented using SAS.
The data listings, descriptive statistics, statistical analysis and graphs of this study will be 
generated using SAS/STAT and SAS/GRAPH software1.
Data Precision
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings concentration data.
The individual plasma concentration will be reported to the same precision as the source 
data (e.g., if the source data is presented to five significant digits, the individual values 
will be presented to five significant digits).
The mean, SD, geometric mean and median will be tabulated to one more significant 
digit compared to the source data, but with a maximum of four significant digits.
Minimum and maximum values will be tabulated to the same precision as the source 
data, but with a maximum of four significant digits.
Geometric coefficient of variation (CV) % will be presented to once decimal place.
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of PK parameters.
Individual PK parameters will be presented to four significant digits, with the exception 
of tmax, which will be presented to two decimal places.  In addition, PK parameters 
                                                
1 SAS Version 9.2 or higher of the SAS System.  Copyright2002-2003.  SAS Institute Inc.  SAS and all 
other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS 
Institute Inc., Cary, North Carolina, USA.


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directly derived from source data (e.g., Cmax) will be reported with the same precision as 
the source data (if this is not four significant digits).
The mean, geometric mean, median and SD values will be reported to four significant 
digits, all other descriptive statistics will be reported to three significant digits except for 
CV% which will be presented to one decimal place.  For tmax the minimum and maximum 
will be presented to two decimal places and the rest of the descriptive statistics to three 
decimal places.
Estimates and confidence intervals in the form of percentages will be presented two 
decimal places.
Source data will be used in all derived PK parameter calculations without prior rounding.
Analysis of Bioequivalence
Refer to Table 7.
The following SAS code will be used, with the treatments sorted in the order reference 
first and then test:
ODS OUTPUT LSMeans=lsmean estimates=est nobs=nobs OverallANOVA=anova;
PROC GLM DATA=pk ALPHA=0.1;
BY Analyte Parameter;
CLASS treatment period participant sequence1
MODEL var= treatment period sequence participant (sequence)/ clparm;
(where var = log [Cmax], log[AUC(0-t)])
OUTPUT OUT= routput R=res P=pred;
LSMEANS treatment / pdiff=control('A') CL;
ESTIMATE 'Test versus Reference' treatment -1 1;
RUN;
                                                
1SAS Version 9.2 or higher of the SAS System.  Copyright2002-2003.  SAS Institute Inc.  SAS and all 
other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS 
Institute Inc., Cary, North Carolina, USA.


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Bioequivalence of the test and reference products will be assessed on the basis of the 
90% confidence intervals for estimates of the geometric mean ratios between the primary 
PK parameters of the test and reference products in relation to the conventional 
bioequivalence range of 80.00% to 125.00%.
Presentation of Baseline Characteristics and Safety Data
Baseline characteristics and safety data will be presented as mentioned below.  Data 
captured but not presented as listed or summarized data will be available in the CRFs or 
the source data capture system.
Demographic and anthropometric data will be listed for all participants in the safety 
population.  Demographic characteristics will be tabulated by treatment (n, mean, 
median, standard deviation, minimum and maximum for age and BMI; and frequency 
counts and percentages for race, age groups and sex).
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), and listed and summarized by treatment for all participants in the 
safety population. 
Vital signs data will be listed and summarized for all participants in the safety population.
List of Tables, Figures and Listings
The following tables, figures and listings will be provided for inclusion into the 
mentioned sections of the clinical study report.
Tables
Demographic characteristics
Statistical analyses of HCTZ PK parameters (ANOVA)
Statistical analyses of Amiloride PK parameters (ANOVA)
Plasma HCTZ concentration (unit)
Plasma Amiloride concentration (unit)
Adverse events summary by treatment
Concomitant Medication summary by treatment
Summary Statistics of Vital Signs Values
Summary Statistics of Chemistry Values.
Figures
Plasma HCTZ arithmetic and geometric mean concentrations (unit)


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Plasma Amiloride arithmetic and geometric mean concentrations (uni
Median concentration vs. Time for HCTZ and Amiloride 
Median concentration vs. Time for Amiloride 
Combined individual plasma HCTZ concentrations (unit)
Combined individual plasma Amiloride concentrations (unit)
Individual plasma HCTZ concentrations (unit) (linear-linear scale and log-linear scale)
Individual plasma Amiloride  concentrations (unit) (linear-linear scale and log-linear 
scale)
Adjusted geometric mean treatment ratio (with 90% CI) for HCTZ and Amiloride 
Listings
Statistical output
Participant disposition
Randomization
Demography and anthropometry
Adverse events
Concomitant Medication
Vitals Signs
Chemistry
Actual blood sampling times
Plasma HCTZ concentrations (unit)
Plasma Amiloride  concentrations (unit)
Plasma HCTZ PK parameters (unit)
Plasma Amiloride PK parameters (unit)
The bulleted lists above indicate requirements and are not necessarily the exact names of 
each table, figure or listing.  The naming conventions as provided will be adhered to as 
far as feasible, but if deemed necessary the name of the output might be changed to fit the 
data.


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12.7.
Appendix 7: Abbreviations and Trademarks
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
APTT
Activated Partial Thromboplastin Time 
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero 
(pre-dose) extrapolated to infinite time
%AUCex
Percentage of AUC(0-) obtained by extrapolation
AUC(0-t)
Area under the concentration-time curve from time zero 
(pre-dose) to last time of quantifiable concentration within a 
participant across all treatments
BE
Bioequivalence
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
CV
Coefficient of variation
Cmax
Maximum observed concentration 
CPK
Creatine phosphokinase
CRF
Case Report Form
ECG
Electrocardiogram
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HRT 
Hormone replacement therapy
hCG
Human chorionic gonadotropin
HCTZ
Hydrochlorothiazide
HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
INR
International Normalized Ratio
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IP
Investigational Product
IRB
Institutional Review Board
kg
Kilogram
LAM
Local Affiliate Module
LDH
Lactate Dehydrogenase


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MCV
Mean corpuscular volume
MCH
Mean corpuscular hemoglobin 
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
Msec
Milliseconds
PK
Pharmacokinetic
PT
Prothrombin Time
QTc
QT corrected
QTcB
QT interval corrected for heart rate according to Bazett’s 
formula
RBC
Red blood cells
SAE
Serious adverse event(s)
SBP
Systolic Blood Pressure
SD
Standard deviation
SoA
Schedule of Activities
SOP
Standard Operating Procedure
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
t½
Terminal phase half-life
Tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
WBC
White blood cells
WCBP
Women of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
BIDURET
Apo-amilizide
Midamor
Moduretic
Phoenix
SAS
WinNonlin