Clinical trial NCT04518293
Conditions: Hypertension
Sponsor: George Medicines PTY Limited
Start date: 2021-07-09; Completion date: 2023-09-01
Enrollment: 1385 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Recent hypertension guidelines recommend combination therapy as initial treatment for many or most patients. Several trials suggest triple low-dose combination therapy may be highly effective in terms of achieving blood pressure (BP) control without increasing adverse effects. This trial is designed to investigate the efficacy and safety of GMRx2 in participants with high blood pressure compared to dual combinations.

Detailed description:
TRIAL DRUG:

GMRx2: Single pill combinations of telmisartan/amlodipine/indapamide Dose version 2: telmisartan 20mg/amlodipine 2.5mg/indapamide 1.25mg Dose version 3: telmisartan 40mg/amlodipine 5 mg/indapamide 2.5mg INDICATION: Hypertension TRIAL DESIGN: International, multicenter, randomized, double-blind, active controlled, parallel-group.

OBJECTIVES: To investigate the efficacy and safety of GMRx2 compared to dual combinations

INTERVENTION:

Single-Blind Active Run-In Period. Enrolled participants will be asked to discontinue their current BP-lowering drug(s) and undergo a single-blind active run-in period for 4 weeks with GMRx2 dose version 2. Participants will be advised to take the capsule once daily in the morning at approximately the same time each day. For days on which BP is being measured, the capsule should be taken directly after the morning home BP measurement.

Double-Blind Treatment Period. Participants still eligible after the run-in period will be allocated in a double-blind fashion to one of the following 4 randomized groups: GMRx2 dose version 2, or telmisartan 20mg+amlodipine2.5mg, or telmisartan 20mg+indapamide 1.25mg, or amlodipine 2.5mg+indapamide 1.25mg. At week 6 all doses will be doubled.

Arms: arm 1: Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg. At week 6 visit, forced up-titration to telmisartan 40 mg/amlodipine 5 mg/indapamide 2.5 mg arm 2: Telmisartan 20 mg/amlodipine 2.5 mg . At week 6 visit, forced up-titration to telmisartan 40 mg/amlodipine 5 mg arm 3: Telmisartan 20 mg/indapamide 1.25 mg. At week 6 visit, forced up-titration to telmisartan 40 mg/indapamide 2.5 mg arm 4: Amlodipine 2.5 mg/indapamide 1.25 mg. At week 6 visit, forced up-titration to amlodipine 5 mg/indapamide 2.5 mg
Interventions: intervention 1: Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg intervention 2: telmisartan 40 mg/amlodipine 5 mg/indapamide 2.5 mg intervention 3: Telmisartan 20 mg/amlodipine 2.5 mg intervention 4: telmisartan 40 mg/amlodipine 5 mg intervention 5: Telmisartan 20 mg/indapamide 1.25 mg intervention 6: telmisartan 40 mg/indapamide 2.5 mg intervention 7: Amlodipine 2.5 mg/indapamide 1.25 mg intervention 8: amlodipine 5 mg/indapamide 2.5 mg
Intervention descriptions: intervention 1: Single pill intervention 2: Single pill intervention 3: oral tablet intervention 4: oral tablet intervention 5: oral tablet intervention 6: oral tablet intervention 7: oral tablet intervention 8: oral tablet

Protocol documents:
Prot_000.pdf: 
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CLINICAL TRIAL PROTOCOL 
 
 
 
 
 
Trial Title
Efficacy and safety of GMRx2 (a single pill combination containing 
telmisartan/amlodipine/indapamide) compared to dual combinations for the 
treatment of hypertension: An international, multi-center, randomized, double-
blind, active-controlled, parallel-group trial 
 
Brief Title
Efficacy and safety of GMRx2 compared to dual combinations for the treatment of 
hypertension 
 
Phase of Development
Phase III
 
Trial Drug
GMRx2: Single pill combination of telmisartan/amlodipine/indapamide
Dose version 2: telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg  
Dose version 3: telmisartan 40 mg/amlodipine 5 mg/indapamide 2.5 mg 
 
Trial Number
GMRx2-HTN-2020-ACT1
 
Indication
Hypertension
 
Protocol Version
Version 6.0, 10 October 2023
 
Trial Registration
Clinicaltrials.gov NCT04518293
 
Sponsor
George Medicines Pty Limited
 


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STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with the International Conference on Harmonization Good Clinical 
Practice (ICH-GCP), applicable ethical and regulatory requirements. The Site Investigators will assure that no 
deviation from, or changes to the protocol will take place without prior agreement from the sponsor and 
documented approval from the Institutional Review Board (IRB) or Ethics Committee (EC), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the conduct 
of this trial will have completed ICH-GCP Training. 
 
The protocol, participant information sheet and consent form(s) (PISCF), recruitment materials, and all 
participant materials will be submitted to the IRB/EC for review and approval.  Approval of both the protocol 
and the PISCF must be obtained before any participant is enrolled.  Any amendment to the protocol will require 
review and approval by the IRB/EC before the changes are implemented to the study.  All changes to the PISCF 
will be IRB/EC approved; a determination will be made regarding whether a new consent needs to be obtained 
from participants who provided consent, using a previously approved consent form. 
 
Alterations to the trial conduct in the context of the coronavirus pandemic 
In the context of the COVID-19 pandemic, alterations may be required to trial conduct during the course of 
the trial. These include home delivery of trial medications, conduct of virtual visits and virtual monitoring as 
detailed in the trial’s COVID-19 Risk Management & Mitigation plan. Any such alterations should be 
implemented in keeping with the FDA Guidance on Conduct of Clinical Trials of Medical Products during 
COVID-19 Public Health Emergency Guidance for Industry, Investigators, and Institutional Review Boards, 
March 2020, Updated on May 14, 2020 and any subsequent revisions and any relevant guidance from other 
regulatory bodies. Any such changes should be documented, according to the procedures in this guidance. 
  
 


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Contents 
 
CONTACT LIST ......................................................................................................................................... 7 
1.1. 
Trial Sponsor 
7 
1.2. 
Academic Coordinating Center 7 
 
VERSION HISTORY ................................................................................................................................... 8 
 
ROLES & RESPONSIBILITIES ..................................................................................................................... 8 
3.1. 
Steering Committee 
8 
3.2. 
Data and Safety Monitoring Board 
9 
3.3. 
Trial Sponsor 
9 
3.4. 
Contract Research Organizations 
9 
3.5. 
Academic Coordinating Center 9 
3.6. 
Endpoint Adjudication Committee 
9 
3.7. 
Names, Affiliations & Roles of Protocol Contributors 
9 
 
PROTOCOL SYNOPSIS............................................................................................................................ 10 
 
INTRODUCTION .................................................................................................................................... 12 
5.1. 
Burden of High Blood Pressure and Current Treatment Gaps 
12 
5.2. 
Potential Role of Single Pill Combinations, Including for Initial Treatment 12 
5.3. 
Potential Role of Triple Low-Dose Combination Therapy 13 
5.4. 
The TRIUMPH Trial of Triple Low-Dose Combination Therapy 
13 
5.5. 
The QUARTET trial of quadruple quarter-dose combination 
14 
5.6. 
Need for a New Triple Low-Dose Combination 
15 
5.7. 
Expected Effects of GMRx2 
15 
 
OBJECTIVES ........................................................................................................................................... 16 
6.1. 
Primary Objective 
16 
6.2. 
Secondary Objectives 
17 
 
TRIAL DESIGN ........................................................................................................................................ 17 
7.1. 
Trial Design Rationale 17 
7.2. 
Sub-studies 
17 
 
METHODS: PARTICIPANTS, INTERVENTION & OUTCOMES .................................................................. 18 
8.1. 
Trial Setting & Participant Recruitment 18 
8.2. 
Participant Eligibility 
18 
 
Inclusion Criteria ....................................................................................................................... 18 
 
Exclusion Criteria ....................................................................................................................... 18 
8.3. 
Trial Schema 
21 
8.4. 
Intervention 
21 
 
Single-Blind Active Run-In Period .............................................................................................. 21 
 
Double-Blind Treatment Period ................................................................................................ 21 
8.5. 
Adherence to Trial Medication 22 
8.6. 
Add-on Treatment for Participants with High BP 22 
8.7. 
Down-Titration or Temporary Cessation of Randomized Trial Medication 22 
8.8. 
Early Permanent Discontinuation of Trial Medication 
23 
8.9. 
Post-Trial Medication 
23 
 
OUTCOMES ........................................................................................................................................... 23 
9.1. 
Efficacy Outcomes 
23 
 
Primary ...................................................................................................................................... 23 
 
Secondary .................................................................................................................................. 23 
9.2. 
Safety Outcomes 
24 
 
Primary ...................................................................................................................................... 24 
 
Secondary .................................................................................................................................. 24 
 
Descriptive Safety Outcomes .................................................................................................... 24 


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9.3. 
 
25 
 
PARTICIPANT TIMELINE & ASSESSMENTS ............................................................................................ 26 
10.1. 
Schedule of Evaluations 26 
10.2. 
Visit Procedures 
27 
 
Written Informed Consent ........................................................................................................ 27 
 
Verbal Consent .......................................................................................................................... 27 
 
Assessment of Participant Eligibility ......................................................................................... 28 
 
Medical History ......................................................................................................................... 28 
 
Physical Examination ................................................................................................................. 28 
 
Anthropometric Measurements ............................................................................................... 28 
 
Clinic BP Measurement ............................................................................................................. 28 
 
Home BP Measurement ............................................................................................................ 28 
 
Electrocardiogram ..................................................................................................................... 28 
 Laboratory Investigations ......................................................................................................... 29 
 Allocation of Trial Medication ................................................................................................... 29 
 Dispensation of Trial Medication .............................................................................................. 29 
 Returning of Trial Medication ................................................................................................... 29 
 Concomitant Treatments .......................................................................................................... 29 
10.3. 
Visit Details 
29 
 
Pre-Screening Visit (As Required) ............................................................................................. 29 
 
Screening Visit ........................................................................................................................... 30 
 
Re-Screening ............................................................................................................................. 30 
 
Extended Run-In ........................................................................................................................ 30 
 
Pre-Randomization visit ............................................................................................................ 31 
 
Randomization Visit .................................................................................................................. 31 
 
Week 6 Visit .............................................................................................................................. 31 
 
Week 12 Visit ............................................................................................................................ 31 
 
Week 16 visit (End of Trial Visit) ............................................................................................... 32 
 
METHODS: ASSIGNMENT OF INTERVENTION ....................................................................................... 32 
11.1. 
Allocation Sequence Generation 32 
11.2. 
Allocation Concealment 32 
11.3. 
Blinding (Masking) 
32 
11.4. 
Unblinding 
32 
 
Unblinding of Trial Medication for Expedited Safety Reporting ............................................... 32 
 
Unblinding of Trial Medication in a Clinical Emergency ........................................................... 32 
 
METHODS: DATA COLLECTION, MANAGEMENT & STATISTICAL ANALYSIS ......................................... 32 
12.1. 
Data Collection 32 
12.2. 
Data Management 
33 
12.3. 
Sample Size & Power Calculation 
33 
12.4. 
Statistical Methods 
33 
 
WITHDRAWAL FROM TRIAL PARTICIPATION ........................................................................................ 34 
 
TRIAL MEDICATION MANAGEMENT ..................................................................................................... 34 
14.1. 
Manufacturing 34 
14.2. 
Packaging, Labelling, Distribution & Storage 
34 
14.3. 
Return & Destruction 
34 
 
MANAGING INTERRUPTION OF STUDY MATERIAL SUPPLY TO TRIAL CENTRES ................................... 34 
 
MONITORING........................................................................................................................................ 35 
16.1. 
Data & Safety Monitoring Board 35 
16.2. 
Data Monitoring 
35 
 
SAFETY .................................................................................................................................................. 35 
17.1. 
Safety Definitions 
35 


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Adverse Event ........................................................................................................................... 35 
 
Adverse Event of Special Interest ............................................................................................. 35 
 
Serious Adverse Event ............................................................................................................... 35 
 
Intensity/Severity of an AESI/SAE ............................................................................................. 35 
 
Relationship to the Trial Medication ........................................................................................ 36 
 
Serious Unexpected Suspected Adverse Reaction.................................................................... 36 
17.2. 
Safety Reporting 
36 
 
AESI/SAE Data Collection & Follow-Up Period .......................................................................... 36 
 
Trial Investigator Responsibilities in Reporting AESIs/SAEs ...................................................... 36 
 
Reporting of AESIs & SAEs ......................................................................................................... 36 
 
Reporting of SUSARs ................................................................................................................. 37 
 
Reporting of Pregnancy ............................................................................................................. 37 
 
Reporting of Trial Medication Use Errors or Misuse................................................................. 37 
 
ETHICAL & REGULATORY COMPLIANCE ............................................................................................... 37 
18.1. 
Ethical Approval 
37 
18.2. 
Regulatory Approval 
37 
18.3. 
Confidentiality 37 
18.4. 
Protocol Amendments 37 
18.5. 
Adherence to the Trial Protocol 38 
 
ADMINISTRATIVE SECTION ................................................................................................................... 38 
19.1. 
Insurance 
38 
19.2. 
Quality Assurance 
38 
19.3. 
Trial Documents Retention 
38 
19.4. 
Ownership, Disclosure of Data and Dissemination policy 38 
 
APPENDICES .......................................................................................................................................... 39 
20.1. 
Appendix 1: List of Abbreviations 
39 
20.2. 
Appendix 2: Procedure for the Measurement of Clinic BP 
41 
20.3. 
Appendix 3: Procedure for the Measurement of Home BP 
42 
20.4. 
Appendix 4: Trial Organization 43 
20.5. 
Appendix 5: Prohibited Drugs During the Trial 
44 
20.6. 
Appendix 6: Protocol Signature Page 
45 
 
REFERENCES.......................................................................................................................................... 46 
 
 
 
 


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FIGURES 
Figure 1: Blood pressure over time in the TRIUMPH trial of triple low-dose combination as initial/early treatment vs 
usual care for hypertension ................................................................................................................................ 14 
Figure 2: Trial design summary ......................................................................................................................................... 17 
Figure 3: Trial schema ....................................................................................................................................................... 21 
 
 
TABLES 
 
Table 1: Short-term RCTs of triple or quadruple low-dose combination therapy ............................................................ 13 
Table 2: Adverse events with the lowest approved dose of GMRx2 components vs placebo in previous randomized 
trials .................................................................................................................................................................... 16 
Table 3: Percentage with symptoms attributable to treatment (treated minus placebo) in previous randomized trials 
of lowest-dose monotherapy of GMRx2 component drug classes ..................................................................... 16 
Table 4: Treatment Groups in the Trial ............................................................................................................................. 22 
Table 5: Trial visits schedule and assessments Randomization Period............................................................................. 26 
 


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CONTACT LIST 
1.1. Trial Sponsor 
 
George Medicines  
 
1.2. Academic Coordinating Center 
The George Institute for Global Health 
Level 5, 1 King Street 
Newtown, Sydney, NSW 2042, Australia 
 
 
 
 
 










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INTRODUCTION 
5.1. Burden of High Blood Pressure and Current Treatment Gaps  
High blood pressure (BP) is a leading cause of preventable morbidity and mortality globally.1 The benefits of 
BP lowering in reducing cardiovascular (CV) events are well established2 and there is clear evidence that 
greater BP lowering confers a greater reduction in CV events.3-5 However, globally, control of high BP is poor, 
with only one in three treated patients achieving traditional BP goals.6,7 Most treated patients receive only 
monotherapy, despite guidelines recognizing that the large majority of patients require multiple drugs to 
achieve goal BP.6  There is broad consensus among leading international authorities that key factors driving 
this treatment gap are under treatment of hypertension with monotherapy in most patients.8 In the United 
States of America (USA), about 40% of treated patients receive monotherapy and this has not changed 
between 2005 and 2016.9 Given the recommendations in recent guidelines for target BPs below 130/80 mmHg 
for high-risk patients, the need for effective, tolerable, and affordable therapy is even more imperative.   
5.2. Potential Role of Single Pill Combinations, Including for Initial Treatment 
Historically, hypertension management guidelines have recommended initiating pharmacological treatment 
with monotherapy, with treatment modification (dose up-titration, or adding other drugs) at multiple follow-
up visits. However, in practice, most patients remain uncontrolled on monotherapy for numerous reasons, 
both patient- and physician-related. Lack of adherence to prescribed BP-lowering drugs is a major risk factor 
for poor BP control10 and is worsened by the increased number of pills,11 higher co-payment, adverse drug 
effects, and a poor patient-provider relationship.12-14 ‘Therapeutic inertia’ - the reluctance of physicians to 
initiate or intensify or modify treatment appropriately has also been identified as an important barrier to 
hypertension control.15,16  
 
Combination therapy has the potential to address many of the aforementioned barriers. A recent systematic 
review of 13 trials with 13,095 participants demonstrated initial low-dose dual combination therapy improved 
BP control compared to monotherapy, without an increase in adverse effects.17 Dual combination therapy 
achieves about five times more BP-lowering than doubling the dose of monotherapy18 and adding a third drug 
is several times more effective than increasing the dose of dual combination.17 Two pragmatic randomized 
controlled trials (RCTs) have assessed strategies, rather than mandatory regimens,  comparing initial dual 
combination therapy with monotherapy, with each showing benefits with the former. The STITCH trial 
compared initial therapies of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker 
(ARB) + thiazide diuretic combination with monotherapy and showed improved BP control with combination 
therapy in a primary care setting.19 The STRAtegies of Treatment in Hypertension: Evaluation (STRATHE) trial 
compared initial combination therapy with stepped care and up-titration and showed improved BP control 
without adverse effects with the initial combination therapy.20 Furthermore, in the Prevention And Treatment 
of Hypertension With Algorithm-based Therapy - study 1 (PATHWAY-1) trial,21 combination of losartan and 
hydrochlorothiazide (HCTZ) as initial treatment was superior to monotherapy with either drug alone, with no 
difference in withdrawals due to adverse events (AEs). This trial also demonstrated that the initial combination 
was uniformly more effective than monotherapy, whether monotherapy was personalized by prediction of 
each patient’s best drug (e.g. using renin levels or age) or by systematic crossover between monotherapy 
options. Recent hypertension guidelines, including the 2018 European Society of Cardiology/European Society 
of Hypertension (ESC/ESH) Guideline,22 the 2020 International Society of Hypertension Guideline23  and the 
2021 WHO Hypertension Guideline24 recommend combination therapy as initial treatment for many or most 
patients and the 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline,25 
recommends combination therapy as an initial treatment among patients with BP >140/90 mmHg and average 
BP more than 20/10 mm Hg above their BP target. 




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5.5. The QUARTET trial of quadruple quarter-dose combination 
QUARTET was a multicenter, double-blind, parallel-group, randomized, trial among Australian adults with 
hypertension, who were untreated or receiving single BP-lowering drug.33 Participants were randomly 
assigned to initial quadruple quarter dose (containing irbesartan 37·5 mg, amlodipine 1·25 mg, indapamide 
0·625 mg, and bisoprolol 2·5 mg) or monotherapy control (irbesartan 150 mg). Additional medications could 
be added in both groups among those not at control during follow-up, starting with amlodipine 5 mg. A total 
Figure 2: Blood pressure over time in the QUARTET trial of quadruple quarter-dose combination as initial/early 
treatment vs initial monotherapy for hypertension  
Figure 1: Blood pressure over time in the TRIUMPH trial of triple low-dose combination as initial/early 
treatment vs usual care for hypertension  


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of 591 participants were randomized with baseline mean unattended office BP 141/85 mmHg (standard office 
153/89 mmHg). By 12 weeks, 44 (15%) of 300 participants had additional BP medications in the intervention 
group compared with 115 (40%) of 291 participants in the control group. As seen in Figure , SBP was lower by 
6·9 mm Hg (95% CI 4·9–8·9; p<0·0001) and BP control was higher in the intervention group compared with 
control group (76% vs 58%; relative risk [RR] 1·30, 95% CI 1·15–1·47; p<0·0001). There was no difference in 
adverse event related treatment withdrawals at 12 weeks (intervention 4·0% vs control 2·4%; p=0·27). Among 
the 417 patients who continued in the randomized groups to 12 months, up-titration occurred more 
frequently among control participants than intervention participants (p<0·0001). However, at 12 months 
mean unattended SBP remained lower by 7·7 mm Hg (95% CI 5·2–10·3) and BP control was higher in the 
intervention group compared with control group (81% vs 62%; RR 1·32, 95% CI 1·16–1·50).  
5.6. Need for a New Triple Low-Dose Combination 
Currently available triple single pill combinations (SPCs) of BP-lowering drugs are only indicated for 
substitution among patients already taking all the three-component drugs or as an add-on/switch therapy 
among patients not adequately controlled on two of the component drugs. 34-36 None of the available triple 
SPCs are indicated for initial treatment. Furthermore, there are no existing SPC products with low-doses of an 
ARB, calcium channel blocker (CCB) and a thiazide-like diuretic. To address this unmet need, GM developed a 
new SPC containing telmisartan, amlodipine and indapamide (GMRx2) in three strengths (10/1.25/0.625 mg, 
20/2.5/1.25 mg, and 40/5/2.5 mg, dose versions 1, 2 and 3 respectively).  
 
Hypertension guidelines recommend ACEI, ARB, CCB, and thiazide-like diuretics as first-line therapies for the 
treatment of hypertension, with some also recommending HCTZ. ARBs are more tolerable than ACEIs given 
that they do not cause cough and are also about three-times less likely to cause angioedema than ACEIs among 
black patients.37 The most reliable comparisons of ARBs with ACEIs are direct randomized comparisons, and 
these do not show a difference in efficacy in reducing CV events between the two classes but demonstrate 
reduced AEs with ARBs.38-40  Telmisartan has the longest half-life (~24 hours) of the ARBs 41 and provides 
superior or similar BP reduction compared to the commonly used ACEIs.42 Among CCBs, amlodipine has been 
used most commonly in CV outcome trials, has fewest interactions with other products (compared, for 
example, to diltiazem) and has a long half-life (30–50 hours). Thiazide-like diuretics such as indapamide and 
chlorthalidone are superior to thiazide diuretics in reducing BP without increasing metabolic AEs.27,43,44 The 
most consistent and robust evidence of CV events reduction comes from trials involving indapamide or 
chlorthalidone.45,46 Compared to HCTZ, indirect comparisons of the results from RCTs indicate a modest 
additional reduction in CV events and heart failure with thiazide-like diuretics (indapamide and chlorthalidone) 
compared to thiazide diuretics, after correcting for differences in clinic BP reductions.47,48 Indapamide has a 
half-life of 16 to 18 hours,49 and is widely available internationally.   
5.7. Expected Effects of GMRx2 
The placebo-corrected systolic BP (SBP)-lowering efficacy of GMRx2 dose versions 1, 2 and 3 from a baseline 
SBP of 150 mmHg are estimated to be approximately 13 mmHg, 18 mmHg and 25 mmHg, respectively.4 This 
would represent a clinically important BP reduction in comparison to standard-dose monotherapy which 
reduces SBP by 8-9 mmHg, with each doubling of dose conferring only a 1-2 mmHg incremental SBP 
reduction.18,27 Dual combinations typically also have a difference of only 1-2 mmHg between neighboring dose 
versions and a maximum SBP reduction of around 20 mmHg with maximal dose of both drugs.4,18,27 The 
reasoning in developing GMRx2 is, therefore, in line with USA Food & Drug Administration (FDA) observations 
which have stated: “Over the last decade, the Agency has actively discouraged antihypertensive monotherapy 
and combination doses with effects that were very close together, considering them a nuisance to physicians 
seeking to get patients to goal.” 50 
 
RCTs of the lowest-approved dose of monotherapy telmisartan 20 mg, amlodipine 2.5 mg and indapamide 
1.25 mg have demonstrated no statistically significant increase in adverse effects compared to placebo (Table 




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6.2. Secondary Objectives 
To assess the safety of GMRx2 compared to each of the three dual combinations of component drugs of 
GMRx2 at equivalent doses. 
 
 
TRIAL DESIGN 
An international randomized, double-blind, active-controlled, parallel-group trial with a 4-week pre-
randomization single-blind, active run-in, a 12-week randomized treatment period and a 4-week safety follow-
up period. The overall trial design is shown in Figure 2. 
 
Figure 2: Trial design summary 
 
7.1. Trial Design Rationale 
This trial is designed to investigate the efficacy and safety of GMRx2 for reducing BP in adult participants with 
high BP compared to dual combinations. The run-in period will assess participant adherence to trial medication 
and trial procedures, hence maximizing chances of complete follow-up and data collection. The double-blind 
periods will assess the efficacy and safety of GMRx2 Dose 2 and GMRx2 Dose 3, sequentially, compared to the 
corresponding three possible dual combinations of the component drugs. This will enable assessment of the 
contribution of each of the component drugs of GMRx2. The duration of 6 weeks for each double-blind period 
will enable demonstration of the maximum effects of each regimen. Double-blinding will prevent performance 
bias for investigators, study staff and trial participants. The safety follow-up period will assess safety after 4 
weeks of the discontinuation of the randomized trial medication.  
7.2. Sub-studies 
Participants will be invited to provide venous blood specimens at the Week 12 visit for use in planned substudy 
analyses related to measurement of drug metabolite levels. The samples will be immediately processed and 


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stored at −80°C ± 10°C and shipped during or at the end of the study to a central laboratory for storage until 
analyses have been completed.   
 
METHODS: PARTICIPANTS, INTERVENTION & OUTCOMES 
8.1. Trial Setting & Participant Recruitment 
Trial participants will be recruited from clinics or hospital-based out-patient departments or primary care 
centers that provide hypertension care in the participating countries. Based on the recruitment rate and trial 
timelines, other modes of recruitment that could be used include community resources particularly to target 
women and minority/under-served populations (also to ensure adequate representation of these groups), 
referrals from other hospitals/clinics and trial recruitment advertisement in the form of posters, flyers, via 
social media, etc. 
8.2. Participant Eligibility 
The guiding principle of participant eligibility is individuals with hypertension who could be appropriately 
treated with triple or dual combinations, with the component drugs, each at half or standard doses. 
 
Inclusion Criteria 
At screening visit 
1. Provided signed consent to participate in the trial. 
2. Adult of age ≥18 years. 
3. Clinic attended automated seated mean SBP (average of 3 measurements): 
a. 140-179 mmHg on 0 BP-lowering drugs, or 
b. 130-170 mmHg on 1 BP-lowering drug, or 
c. 120-160 mmHg on 2 BP-lowering drugs, or 
d. 110-150 mmHg on 3 BP-lowering drugs. 
 
Note: A single tablet containing 2 or 3 different BP lowering agents (i.e. a combination medication) is 
considered as 2 or 3 BP lowering drugs, respectively. 
 
At randomization visit 
1. Home seated mean SBP 110-154 mmHg in the week prior to the randomization visit. 
2. Adherence of 80-120% to run-in medication. 
3. Tolerated run-in medication. 
4. Adherence to home BP monitoring schedule: in the week before randomization, at least 6 measures 
(e.g. ≥2 sets of triplicate measures, ≥3 sets of duplicate measures) including at least 1 morning and 1 
evening each with ≥2 measures  
5. Morning is defined as any measure in the am and evening as any measure in the pm. Morning and 
evening do not have to be same day. 
 
1.  
 
 
Exclusion Criteria 
At screening visit 
1. Receiving 4 or more BP-lowering drugs.  
2. Receiving any BP lowering drugs for indications other than hypertension e.g. heart failure 
3. Pregnant or had a positive pregnancy test or unwilling to undertake a pregnancy test during the trial 
and up to 30 days after the discontinuation of the trial medication or breastfeeding or of childbearing 
age and not using an acceptable method of contraception (defined in the Manual of Procedures). 
Acceptable methods of birth control include Hormonal prescription oral contraceptives, contraceptive 


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injections, contraceptive patch, intrauterine device, double-barrier method (e.g. condoms, diaphragm, 
or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization. Contraception should 
be used for at least 1 month before the screening visit and until the end of trial participation. 
4. Meets any criteria of local ethical or regulatory requirements related to severe acute respiratory 
syndrome coronavirus-2 (SARS-CoV-2) that would deem participation in a clinical trial unsuitable. 
5. Contraindication, including hypersensitivity (e.g. anaphylaxis or angioedema), to the active run-in 
treatment or to any of the trial medication options in the four randomized groups. 
6. Current/history of transient ischemic attack, stroke, or hypertensive encephalopathy. 
7. Current/history of acute coronary syndrome, unstable angina, myocardial infarction, percutaneous 
transluminal coronary revascularization, or coronary artery bypass graft.  
8. Current atrial fibrillation. Patients with a history of paroxysmal atrial fibrillation are potentially eligible 
as long as there has been no episode in the last 3 months, while patients with a history of persistent or 
permanent atrial fibrillation are not eligible. 
9. Current/history of New York Heart Association class III and IV congestive heart failure.   
10. Current/history of cardiomyopathy or any other cardiovascular condition of sufficient severity to 
contraindicate the trial medications or require a contraindicated medication.   
11. Current/history of a known secondary cause of hypertension, such as primary aldosteronism, renal 
artery stenosis, pheochromocytoma, or Cushing's syndrome. 
12. Current/history of severe uncontrolled diabetes (HbA1c > 11.0% (> 97 mmol/mol)) within last three 
months. 
13. Current/history of end-stage renal disease or anuria; or current estimated glomerular filtration rate 
(eGFR) <60 ml/min/1.73m2 
14. Current electrolyte levels that would be regarded as contraindications for any of the potential treatment 
arms e.g.  serum sodium <132mmol/l or >148 mmol/l or serum potassium <3.1 mmol/l or >5.6mmol/l.  
15. Current/history of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the 
upper limit of normal range within 6 months. 
16. Current concomitant illness or physical impairment or mental condition that in the judgment of the 
investigator could interfere with the effective conduct of the trial or constitute a significant risk to the 
participants’ safety or well-being.  
17. Arm circumference that is too large or too small for available cuffs to allow accurate measurement of 
BP. Upper limit is 55cm in all countries, while lower limit is 15cm or 24cm in different countries, 
depending on available cuff sizes. 
18. Currently taking or might need during the trial, a concomitant treatment which is known to interact with 
one or more of the trial medications: digoxin, lithium, diabetics receiving aliskiren, moderate and strong 
CYP3A4 
inhibitors 
(e.g. 
ritonavir, 
ketoconazole, 
diltiazem], 
simvastatin 
>20 
mg/day, 
immunosuppressants. 
19. Might need treatment with drugs that are prohibited during the trial:  other antihypertensive drugs, 
endothelin receptor antagonists, neprilysin inhibitors, or other drugs that may affect BP  (see Appendix 
5). 
20. Current surgical or medical condition that might significantly alter the absorption, distribution, 
metabolism, or excretion of trial drugs such as prior major gastrointestinal tract surgery (e.g. 
gastrectomy, lap band, or bowel resection) or acute flare of inflammatory bowel disease within one 
year. 
21. Individuals working >2 nightshifts per week. 
22. Participated in any investigational drug or device trial within the previous 30 days.  This does not include 
participants in the extended safety follow-up portion of a trial.  
23. History of alcohol or drug abuse within 12 months. 
 
At randomization visit     
1. Unable to adhere to the trial procedures during the run-in treatment period. 


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2. Any of the following which in the investigator’s judgment may compromise the safety of the participant 
if randomized to the trial medications: 
a. 
High or low clinic BP levels even in the light of the values for home BP that are available for that 
participant. The exact levels of BP are not specified, since there is clinical uncertainty as to the 
relevance of BP levels which are high or low in clinic only; for example, the clinical relevance of 
‘whitecoat hypertension’ is uncertain. 
b. 
High or low home diastolic BP (DBP) levels. The exact levels of DBP is not specified, reflecting 
clinical uncertainty of the implications of isolated diastolic hypertension. However, home DBP 
values of >99 mmHg may typically be considered as requiring treatment intensification, and such 
participants would not be suitable for randomization. 
c. 
Any abnormal laboratory value which in the judgment of the investigator could interfere with the 
effective conduct of the trial or constitutes a significant risk to the participants’ well-being.  
d. 
Fulfilling any of the exclusion criteria mentioned for the screening visit, when verified again at 
randomization visit. 
 


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8.3. Trial Schema 
Figure 3: Trial schema 
  
8.4. Intervention 
 
 Single-Blind Active Run-In Period 
During the screening visit, enrolled participants will be asked to discontinue all current BP-lowering drug(s) if 
applicable and enter a single-blind active run-in period for 4 weeks with GMRx2 dose version 2. Participants 
will be advised to take the run-in capsule once daily in the morning at approximately the same time each day. 
For days on which BP is being measured, the run-in capsule should be taken directly after the morning home 
BP measurement. 
 
 Double-Blind Treatment Period 
The 4-week single-blind active run-in will be followed by a 12-week double-blind period with randomization 
to one of the following four treatment groups: 




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trial medication that the participant was receiving between Weeks 0 and 6. There is no need to unblind trial 
medication in this situation. Consideration should also be given to restarting scheduled medication 
subsequently, if benefits of restarting outweigh the risks as per the medical condition of the participant. If a 
participant discontinues medication at his/her own initiative, the reason should be investigated. If medically 
appropriate, consideration should be given to restarting study medication. 
8.8. Early Permanent Discontinuation of Trial Medication 
Discontinuation of trial medication occurs when a randomized participant permanently ceases taking the trial 
medication regardless of the circumstances, before the Week 12 visit and must be reported immediately to 
the CRO and recorded in the study database. In the case of early discontinuation of a participant from the trial 
medication, the reason for discontinuation will be recorded and immediately reported in the IBM Clinical 
Development trial database.  
 
Early permanent discontinuation of trial medication may happen for the following reasons: 
 
By the participant himself/herself for any reason. 
 
By the investigator at the request of the participant for any reason. 
 
By the investigator if the participant’s safety or wellbeing is or will be compromised by continued trial 
medication, including if the participant becomes pregnant  
 
The trial is terminated (e.g. if in the opinion of the DSMB interim data indicate that it might not be 
justifiable to continue the trial, the SC may terminate the trial).  
 
In general, unblinding is not required in these situations, see Section 11.4.2 Unblinding of Trial Medication in 
a Clinical Emergency. 
 
If necessary, the investigator will arrange for an alternative treatment to be prescribed by the treating 
physician. Participants with early permanent discontinuation of the trial medication are not considered 
withdrawn from the trial and should continue their participation in the trial as normal, completing all trial visits 
and assessments until the final trial visit at Week 16. For withdrawal from trial participation, see Section 13, 
page 34. 
8.9. Post-Trial Medication  
At the Week 12 visit , the investigator or responsible clinician will provide appropriate continued medical 
care to participants in line with local guidelines/practice.  
 
OUTCOMES 
9.1. Efficacy Outcomes 
 
 Primary 
 
Difference in change in home seated mean SBP from randomization to Week 12. 
 
 Secondary 
 
Difference in change in clinic seated mean SBP from randomization to Week 12. 
 
Difference in change in clinic seated mean SBP from randomization to Week 6. 
 
Difference in change in clinic seated mean DBP from randomization to Week 12. 
 
Difference in change in clinic seated mean DBP from randomization to Week 6. 
 
Percentage of participants with clinic seated mean SBP <140 and DBP <90 mmHg at Week 12. 
 
Percentage of participants with clinic seated mean SBP <140 and DBP <90 mmHg at Week 6. 
 
Percentage of participants with clinic seated mean SBP <130 and DBP <80 mmHg at Week 12. 


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 
Percentage of participants with clinic seated mean SBP <130 and DBP <80 mmHg at Week 6. 
 
Difference in change in home seated mean SBP from randomization to Week 6. 
 
Difference in change in home seated mean DBP from randomization to Week 12. 
 
Difference in change in home seated mean DBP from randomization to Week 6. 
 
Difference in change in trough home seated mean SBP from randomization to week 12 
 
Difference in change in trough home seated mean SBP from randomization to Week 6 
 
Percentage of participants with home seated mean SBP <135 and DBP <85 mmHg at Week 12. 
 
Percentage of participants with home seated mean SBP <135 and DBP <85 mmHg at Week 6. 
 
Percentage of participants with home seated mean SBP <130 and DBP <80 mmHg at Week 12. 
 
Percentage of participants with home seated mean SBP <130 and DBP <80 mmHg at Week 6. 
9.2. Safety Outcomes 
 
Primary 
 
Percentage of participants discontinued trial medication due to AE/SAE from randomization to Week 
12. 
 
Secondary 
 
Percentage of participants discontinued trial medication due to AE/SAE from randomization to Week 
6. 
 
Percentage of participants with an SAE from randomization to Week 12. 
 
Percentage of participants with SAE from randomization to Week 6. 
 
Percentage of participants with symptomatic hypotension from randomization to Week 12. 
 
Percentage of participants with symptomatic hypotension from randomization to Week 6. 
 
Percentage of participants with serum sodium concentration below 135 mmol/l at Week 12. 
 
Percentage of participants with serum sodium concentration below 135 mmol/l at Week 6. 
 
Percentage of participants with serum sodium concentration above 145 mmol/l at Week 12. 
 
Percentage of participants with serum sodium concentration above 145 mmol/l at Week 6. 
 
Percentage of participants with serum potassium concentration below 3.5 mmol/l at Week 12. 
 
Percentage of participants with serum potassium concentration below 3.5 mmol/l at Week 6. 
 
Percentage of participants with serum potassium concentration above 5.5 mmol/l at Week 12. 
 
Percentage of participants with serum potassium concentration above 5.5 mmol/l at Week 6. 
 
Percentage of participants with serum sodium <135mmol/l or >145 mmol/l, and/or serum potassium 
<3.5 mmol/l or >5.5mmol/l at week 6.  
 
Percentage of participants with serum sodium <135mmol/l or >145 mmol/l, and/or serum potassium 
<3.5 mmol/l or >5.5mmol/l at week 12.  
 
Percentage of participants with eGFR drop of over 30% from randomization to Week 12. 
 
Percentage of participants with eGFR drop of over 30% from randomization to Week 6. 
 
Percentage of participants with orthostatic hypotension at Week 6, 
 
Percentage of participants with orthostatic hypotension at Week 12 
 
Percentage of participants with orthostatic hypertension at Week 6, 
 
Percentage of participants with orthostatic hypertension at Week 12 
 
 
Descriptive Safety Outcomes 
In addition, descriptive safety data will be reported on: 
 
Percentage of participants discontinued trial medication due to AE/SAE during the active run-in period 


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 
All SAEs, by severity and by System Organ Class (SOC) criteria during the run-in period, by trial 
medication group during the randomized period, and safety follow-up period.  
 
 






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explanation about the requirement to fast for blood sample collection at the screening visit. They will be given 
the opportunity to ask questions about the fasting process and will be receive full answers from the trial site 
staff. Verbal consent can be obtained by telephone and must be clearly documented in participants’ trial 
records. Where feasible and approved by IRB/IEC, the verbal consent process may also be adopted to facilitate 
collection of screening bloods prior to the screening visit. Prior to performing all other trial procedures 
participants must provide written informed consent. 
 
 Assessment of Participant Eligibility 
Each potential participant will be assessed for eligibility to participate in the trial as per the protocol-defined 
eligibility criteria. Responsible site investigator(s) will ensure that only eligible participants are enrolled in the 
run-in treatment period and the randomized treatment period of the trial.  
 
 Medical History 
A detailed medical history will be collected at the screening visit. This will be based on participant medical 
records and/or self/carer-report. Participant’s medical condition will be re-assessed before randomization to 
confirm eligibility for randomization. 
 
 Physical Examination 
The physical examination includes elements of a systems-based examination deemed necessary for the safety 
of participants by the site investigator. Elements of the examination may vary from participant to participant 
depending upon the health status and symptoms reported, the time and type of visit (initial, follow-up). The 
physical examination will not be standardized, and information will be captured in the source documents for 
each participant.  
 
 Anthropometric Measurements 
Height and weight will be measured as per the prevailing practice at the trial sites, and these measurements 
will be used for calculating the body mass index.  
 
 Clinic BP Measurement 
Clinic BP will be measured in the seated position during all scheduled trial visits using a standard procedure 
(See Appendix 2). To allow flexibility in site visit scheduling and maintenance of participants typical time of 
taking trial medication, and since all morning home BP measures are to be taken before the next dose of the 
trial medication, clinic measures are not required to be conducted at trough. 
 
 Home BP Measurement 
For the days on which home BP is measured, BP measurements should be at the same time in the morning and 
evening on each measurement day during the following time ranges:  
1. morning (ideally between 06:00-10:00 hours) – prior to taking trial medication;  
2. evening (ideally between 18:00-22:00 hours).  
Participants should aim to have at least 6 hours interval between the morning and evening measurements.  
In the week before the Randomization, Week 6 and Week 12 trial visits, BP measurements should be taken on 
the 4 days immediately prior to the day of the day of the on-site trial visit. In other weeks, measurements 
should ideally be performed on a single set day. Each home BP measurement should be done as a triplicate i.e., 
three individual measurements,, following the protocol outlined in Appendix 3, page 42. Telemonitored BP 
values will be monitored for adherence with measurement schedules and high values (as noted in Section 8.6, 
page 22), with reporting to the clinic and for medical management as needed. 
 
Participants eligible for run-in medication will be issued with a home BP monitor at the screening visit and will 
be asked to bring it with them to the randomization visit. If they continue to randomization, they will continue 
to use the same home BP monitor. 
 
 Electrocardiogram 
A 12-lead electrocardiogram (ECG) will be obtained at the screening visit to determine the occurrence of silent 
myocardial infarction, atrial fibrillation, and left ventricular hypertrophy. Site investigators will review ECG 
reports and comment as either normal or abnormal, and if latter whether clinically significant.     


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  Laboratory Investigations 
The 2017 ACC/AHA-recommended laboratory investigations will be performed at the screening visit. These 
investigations will help in ascertaining participant safety and eligibility for trial participation. For investigations 
that are to be done in the fasting state, participants will be informed beforehand to fast for blood sample 
collection. Protocol-required laboratory investigations will be performed at a local laboratory in each 
participating country following the usual standard procedures of sample collection, analysis, and reporting.  
Optional substudy blood samples will be immediately processed and stored at −80°C ± 10°C and shipped during 
or at the end of the study for storage and future analyses.  
 Allocation of Trial Medication  
During the single-blind run-in period (Week -4 to Week -1 inclusive) all participants will be allocated GMRx2 
dose version 2. During the double-blind period (Week 1 to Week 12 inclusive) all participants will be allocated 
GMRx2 or one of the three dual combinations as per the randomization scheme. Neither the site staff nor the 
participants will have foreknowledge of the treatment allocation at randomization. After the completion of the 
double-blind treatment period at Week 12, participants will be switched to non-trial medication as per local 
guidelines/practice. 
 Dispensation of Trial Medication 
Starting at the screening visit (Week -4), participants will receive sufficient quantities of the trial medication 
until the next scheduled trial visit. In the case of lost/damaged dispensed treatment, participants will be asked 
to notify the site immediately and replacement treatment will be dispensed by the site. In circumstances where 
a participant is unable to return to the site to collect replacement trial medication between two scheduled trial 
visits, trial medication delivery will be arranged to the participant’s location. Delivery of trial medication to 
participant’s location may also occur in other circumstances and where feasible e.g. if blood test results are not 
available during the screening and randomization visits and randomization and/ or dispensing is delayed or due 
to pandemic restrictions. Sites will maintain accurate and up-to-date records of all trial medication dispensation 
to participants. Such records must be available for inspection at all times. 
 Returning of Trial Medication  
Trial participants will return all unused trial medication to the sites during scheduled trial visits (or in between 
in some circumstances – e.g. discontinuation of treatment). Sites will collect all the returned trial medication 
and keep an accurate record, to be available for inspection at all times.  
 Concomitant Treatments 
Starting at the screening visit, during all scheduled and unscheduled visits until the end of participation, the 
investigator/site will review participant concomitant treatments and update the relevant section in source 
documents and electronic case report form (eCRF) keeping in view the trial allowed and prohibited concomitant 
treatments. Non-trial BP lowering medication must be ceased prior to starting trial medication and 
documented in the eCRF. Prescription of non-trial BP-lowering drugs will only be allowed as noted in Section 
8.6, page 22. Treatment with other drugs that do not affect BP significantly will be unrestricted and will be at 
the discretion of the treating physician. For the prescription of concomitant treatments, contraindications and 
drug-drug interactions should be taken into consideration as per the regulatory-approved prescribing 
information of drug prescribed. All other medical care should be delivered according to local 
guidelines/standards by the treating physician.  
10.3. Visit Details 
 
Pre-Screening Visit (As Required) 
 
Can be conducted by telephone. 
 
Assess potential participant’s interest for participation and eligibility for the trial. 
 
Discuss the trial with the participant, including using the PISCF, and obtain signed informed consent. 
Participants may be provided time to consider their participation, with a follow-up visit arranged as 
needed. 


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 
Consider modifying current treatments to facilitate trial eligibility, if clinically appropriate and 
considered safe. Informed consent must be obtained before the modification of medication(s). If 
medications are altered, a period of at least 14 days is required between alteration of BP treatment(s) 
and trial enrolment. 
 
If locally preferred and/or feasible, Screening Visit blood tests can be pre-arranged following informed 
consent. 
 
Screening Visit 
 
Assess the potential participant’s interest and eligibility for the trial. 
 
Discuss the trial with the participant, including using the PISCF, and obtain signed informed consent. 
This can also be done before the screening visit. The participant can be given the opportunity to 
consider information and return within the time window for randomization. 
 
Collect demographic information. 
 
Collect information on medical history, perform a physical examination.  
 
Measure height and weight. 
 
Measure BP and pulse. 
 
Perform 12-lead ECG. 
 
Collect blood samples for pre-run-in assessment, including pregnancy, if applicable . If pre run-in blood 
tests (sodium, potassium, chloride, creatinine, liver function) have been conducted within the past 3 
months, these results can be utilized to assess suitability for run-in. Results must be reviewed and 
eligibility confirmed prior to enrolment into the study and run-in medication start. If laboratory results 
are not available on the day of the screening visit, the participant may be required to return to the 
clinic for collection of run-in medication and the home BP monitor as soon as results become available 
and eligibility has been confirmed. Alternately, if feasible according to local practice and if the 
participant consents, the home BP monitor and run-in medication may be delivered by courier to the 
participant’s home. A flexible approach in accordance with local logistics and practice is permitted, so 
long as within local IRC/EC approval. 
 
In case of a delayed start to run-in medication, a run-in that is ideally 28 days and at least 21 days is 
still required and therefore the randomization visit may need to be delayed accordingly.  
 
Arrange laboratory investigations required to be reviewed before randomization, which includes 
fasting blood sample. This must be done during run-in while receiving run-in treatment. 
 
Assess eligibility as per the trial inclusion and exclusion criteria. 
 
Demonstrate home BP measurement and dispense home BP monitor (record serial number) to 
participant. 
 
Discontinue non-trial BP lowering medications. 
 
Dispense run-in medication.  
 
Re-Screening 
Participants can be re-screened up to three times in total during the recruitment period. Participants not 
meeting the eligibility criteria at Pre-Screening or Screening Visit can be re-screened if the reason for non-
eligibility was transient (e.g. a short-term illness, abnormal laboratory finding, etc.), or if eligibility is expected 
to change (e.g. due to an alteration in BP regimen), or a remediable non-medical issue prevented completion 
of run-in (eg. BP machine malfunction).  However, participants cannot be re-screened if they were intolerant 
of the run-in medication, if they required add-on medication during run-in or if valid home BP measurements 
did not meet criteria for entering run-in. Before re-screening, a new consent must be signed if more than 2 
months have elapsed since signing the consent the first time. All eligibility criteria must be re-assessed on re-
screening. Trial-specific laboratory investigations results available from within 30 days of the date of re-
screening may be used to assess eligibility for trial participation. 
 
Extended Run-In 
The run-in period can be extended by up to 1 week if needed for reasons such as technical issues with the BP 


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machine or measurement protocol or administrative issues, such as a delay in receiving test results. However, 
the run-in period cannot be extended if the treatment was not tolerated or if valid home BP measurements did 
not meet criteria for randomization.  If the run-in is extended, participants should measure home BP in the 4 
days prior to the new Randomization Visit date. 
 
Pre-Randomization visit 
 
Collect blood and urine samples for which the results should be available prior to Randomization (see 
Table 5. 
 
 
Randomization Visit 
 
Measure BP and pulse. 
 
Record any AESIs or SAEs that have occurred since the screening visit. 
 
Collect unused run-in medication. 
 
Assess adherence to run-in medication. 
 
Assess adherence to home BP monitoring schedule. 
 
Record all medication currently being taken by the participant. 
 
Review home BP measurement technique. 
 
Assess eligibility as per the trial inclusion and exclusion criteria. 
 
Review pre-randomization laboratory results.* 
 
Confirm that participant is suitable to be randomized.* 
 
If relevant, discuss with female participants of child-bearing potential the need to conduct home 
pregnancy tests every 4 weeks during the treatment period and provide pregnancy test kits. (Applies 
in some jurisdictions including Czech Republic, Poland and South Korea). 
 
Randomize participant. 
 
Dispense treatment according to the allocated kit number selected by IBM database. 
 
For participants not suitable to continue, collect home BP monitor. 
*If laboratory results are not available for review prior to or on the same day end of run-in /randomization visit, 
randomization must be delayed until the results are available and eligibility has been confirmed. If eligible, the 
participant will either be required to return to the clinic for the collection of randomized treatment,  or 
alternatively, if feasible according to local practice and if the participant consents, the randomized medication 
may be delivered to by courier to the participant’s home. Run-in treatment should be continued until 
randomization, If randomization is delayed. 
 
Week 6 Visit 
 
Measure BP and pulse. 
 
Record AESIs or SAEs since the previous visit. 
 
Collect blood for measurement of electrolytes, creatinine, and eGFR 
 
Review all medications being taken by the participant.  
 
Collect unused trial medication. 
 
Dispense treatment according to the allocated kit number selected by IBM database. 
 
Week 12 Visit  
All participants 
 
Measure BP and pulse. 
 
Record AESIs or SAEs since the previous visit. 
 
Review all medications being taken by the participant and update medications.  
 
Collect unused trial medication and review medication adherence. 
 
Collect the Week 12 fasting blood and urine samples for laboratory investigations. 


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 
Collect blood sample for storage for substudy (if applicable) 
 
Week 16 visit (End of Trial Visit) 
 
Contact participant by telephone. 
 
Record AESIs or SAEs since the previous visit. 
 
Review all medications being taken by the participant and update medications 
 
Explain that the trial follow-up is now completed and thank participant 
 
METHODS: ASSIGNMENT OF INTERVENTION 
11.1. Allocation Sequence Generation 
A central, computer-based randomization sequence will be generated, stratified by trial site.  
11.2. Allocation Concealment 
Randomization sequence will be incorporated into an online electronic data capture (EDC) application by a 
statistician. Neither the Investigators nor site staff will have access to the randomization sequence.  
Participants meeting eligibility for randomization, can be randomized in the online EDC. The EDC application 
will generate the randomization record with the participant identification number and date and time. 
11.3. Blinding (Masking) 
Neither the site staff, including those measuring the outcomes nor the participants will be aware of the 
treatment allocated since all trial medication will be provided in identical capsules. Access to information on 
allocated treatment will be restricted. Breaking of treatment code (unblinding) will be restricted to situations 
that necessitate ascertainment of type of medication for a given participant to provide appropriate care. To 
protect blinding, all medications will have an identical appearance.  None of the trial committees will have 
access to the code list of allocated treatments.   
11.4. Unblinding 
 
Unblinding of Trial Medication for Expedited Safety Reporting  
Where country regulatory safety reporting requirements mandate the reporting of unblinded data, treatment 
assignment will be unblinded before they are reported to the Competent Authorities and IRB/IEC in accordance 
with the local safety reporting requirements. The trial medication assignment will only be made available to 
the relevant Competent Authorities and IRB/IEC and not be communicated to participants, investigators, or the 
CRO staff.  
 
Unblinding of Trial Medication in a Clinical Emergency 
In general, unblinding will only be required in certain specific circumstances which are expected to be very rare. 
If a contraindication to trial medication develops after randomization, the trial medication should simply be 
stopped and usual standard care given. Unblinding should be done only in those rare cases when the clinician 
believes that clinical management depends importantly upon knowledge of which treatment the participant 
received. In these cases when urgent unblinding is considered necessary, a 24-hour access service will be 
available. An unblinding report form should then be completed by the investigator.  
 
METHODS: DATA COLLECTION, MANAGEMENT & STATISTICAL ANALYSIS 
12.1. Data Collection 
The investigator will be responsible for ensuring the accuracy, completeness, and timeliness of the data 
collected for the trial. All source data should be legible and complete to ensure accurate interpretation.  
 


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The trial will use an eCRF for data collection. Trial site staff will be trained on eCRF. Delegated site staff provided 
with the access (with username, password) will enter data in the eCRF regularly according to instructions for 
completion and any data queries will be resolved promptly. Data entered in eCRF should be consistent with the 
source data. For home BP values, the home BP machine is the data originator and the eCRF is regarded as the 
source record.60  For BP values measured in clinic in which a paper transcription step is used, then the paper 
documentation should be retained and made available for inspection.60 The investigator will sign each 
participant’s eCRF confirming and certifying that the data entered is accurate and complete. All data collected 
in the eCRF will be securely stored with access restricted to representatives authorized for data management, 
and data analysis at the end of the trial.  
12.2. Data Management 
All data entry will be completed via the secure web-based data management system, IBM Clinical Development. 
Data entry will be performed at the participating sites by authorized site staff who have completed training and 
been given appropriate role-based access to the system. Data logic and consistency checks will be programmed 
into the data entry forms so that data entry errors can be caught real time and queries auto-generated.  Manual 
queries may also be generated and listings will be run to perform manual data checks which cannot be 
programmed. Authorized electronic signatures will be used to lock completed data entry forms once all data 
queries have been resolved within the system. Data entry and all subsequent changes or deletions will be 
captured in an accessible audit trail. Coding will be centrally performed either automatically via the IBM coding 
module or manually. Data will be stored and backed up on the IBM’s cloud servers in the USA. 
12.3. Sample Size & Power Calculation 
A sample size of 1500 participants (600 in GMRx2 and 300 in each of the dual combination groups) provides 
97% power to detect a minimum difference of 3 mmHg in home seated mean SBP for each of the three 
comparisons of GMRx2 vs dual therapy, assuming a common standard deviation of 11 mmHg within each group. 
The overall power for all three comparisons will therefore be over 90%. Randomizing 1500 may necessitate at 
least 2000 participants entering the run-in treatment. A systematic review of previous trials of triple vs dual 
combination therapy demonstrated, on average, a 5.4/3.2 mmHg greater reduction in clinic BP with triple 
therapy,61 and it is anticipated that the current trial will have similar rates of drop-in and drop-out as observed 
in those trials. A systematic review comparing BP reductions from different BP measurement methods 
indicated that on average reductions in home BP were about 20% less than those seen for clinic BP.62 In three 
recent trials that utilized home BP measurement protocols very similar to those planned for this trial, the 
average SD of change in home SBP was 11 mmHg.21,63,64 
12.4. Statistical Methods 
All analyses will be performed on an intention-to-treat basis. Baseline characteristics by the group will be 
compared using descriptive analyses. The primary outcome of difference in change in home SBP from baseline 
to Week 12 will be analyzed using a mixed model for repeated measures with baseline BP, visit, treatment 
group, and visit by treatment group interaction as a fixed effect and accounting for correlation within 
participant and clustering at the site level. Other continuous outcomes of difference in change in BP will also 
be analyzed as the primary outcome. All continuous outcomes will be reported along with 95% CI and the 
corresponding p-value. The percentage of participants achieving target BP at Week 6 and Week 12 will be 
summarized descriptively and analyzed using generalized estimating equations with the visit, treatment group, 
and visit by treatment group interaction as a fixed effect and accounting for correlation within participant and 
clustering at the site level. Percentages by treatment groups with 95% CI will be presented along with the 
associated estimated odds ratio and its corresponding p-value. Other binary outcomes of efficacy and safety 
will be analyzed as the percentage of participants achieving target BP. The primary analysis dataset will be 
locked after the last participant has reached the 16 week follow-up visit. 


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WITHDRAWAL FROM TRIAL PARTICIPATION 
Participants will be informed at the time of consenting and enrolment that; they are free to withdraw from the 
trial at any time and for any reason without influencing any aspect of their usual medical care. If a participant 
wishes to withdraw from the study prior to completion and explicitly revokes consent or if the trial investigator 
decides it is in the best interest of the participant to withdraw from the trial, every effort should be made for 
the participant to complete a final follow-up assessment to record BP, AESI and SAEs and collect all unused trial 
medication. Data collected up to the point of withdrawal will be included in trial analyses unless the participant 
expressly requests their data to be excluded. 
 
TRIAL MEDICATION MANAGEMENT 
14.1. Manufacturing 
The formulation development and manufacturing of GMRx2 will be conducted as per Good Manufacturing 
Practice and in accordance with the applicable regulatory requirements. 
14.2. Packaging, Labelling, Distribution & Storage 
Packaging, labeling, quality release, storage, and distribution of the trial medication to the local country depot 
or directly to participating sites will be conducted as per the local regulatory and set-up requirements. All 
shipments will be temperature-monitored, and where required, temperature-controlled shipments will be 
conducted. The CRO will keep accurate records of trial medication supplies to trial sites. At each trial site, the 
Investigator will be responsible to store and maintain accurate records of trial medication and report to the 
CRO. Trial sites will store trial medication as per the labeled instructions and will instruct the trial participants 
accordingly.  
14.3. Return & Destruction 
At the end of the trial, following the accountability of the returned/unused trial medication, and on the 
authorization of the ACC, trial medication will be destroyed on-site or returned to the depot for destruction. 
Once destroyed, a destruction certificate or record will be provided to the site. 
 
MANAGING INTERRUPTION OF STUDY MATERIAL SUPPLY TO TRIAL CENTRES 
Supply chain-related interruptions of study materials to trial centres may occur, especially in the context of a 
pandemic, in which case the following strategies should be adopted. If study BP machines are not available at 
the centre, participants should not be entered into run-in, but asked to return when BP machines are available, 
which may necessitate re-screening. If study treatment for any trial phase (Run-in/Period 1, Period 2 or Period 
3 as in  Figure 2) is not available at the centre or not certain to arrive in adequate time, the participant should 
delay the start of Run-in, which may necessitate rescreening. If a participant is on Run-in/Period 1 and Period 
2 and/or 3 study treatment is not available or not certain to arrive in adequate time, then randomization should 
be delayed, which may necessitate extending or repeating run-in. If a participant is randomised and receiving 
Period 2 study treatment (see Figure 2, ie. could be receiving GMRx2-dose2, telmisartan 20mg/amlodipine 
2.5mg, telmisartan 20mg/indapamide 1.25mg, or amlodipine 2.5mg/indapamide 1.25mg) but Period 3 study 
treatment is not available, then at the week 6 study visit participants should switch to open-label telmisartan 
40mg and amlodipine 5mg. This open-label treatment should be continued until Period 3 study treatment is 
available at the centre, at which time a repeat clinic visit should be arranged and Period 3 treatment instituted. 
Home BP monitoring should be continued throughout and any additional tests instituted as required to ensure 
patient safety. There is no need to unblind.  The final clinic visit of the randomised phase should be rescheduled 
for 6 weeks after the new start date of the Period 3 study treatment. 


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 MONITORING 
16.1. Data & Safety Monitoring Board 
An independent DSMB will monitor the trial data and advise the SC on the continuing safety of trial participants 
and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial.  
16.2. Data Monitoring 
In addition to pre-programmed edit checks in the eCRF, regular remote data monitoring will be conducted by 
the responsible CRO and designated monitors for confirmation of participant eligibility, identification of missing 
data, data consistency, and general data quality checks.  Automated queries may be generated via 
programming in the eCRF and can also be manually generated by monitoring staff. On-site monitoring visits will 
also be conducted to review source documents and to resolve any issues at the site. Full details of monitoring 
activities will be described in the Trial Monitoring Plan. The investigator should allow the monitors, the 
persons responsible for the audit, the representatives of the sponsor, the IRB/IEC, and of the Regulatory 
Authorities to have direct access to source data/documents. The CRO will also undertake regular remote 
monitoring of data. 
 
SAFETY 
17.1. Safety Definitions  
 
Adverse Event 
An AE is any untoward medical occurrence in a participant administered a pharmaceutical investigational 
medicinal product and which does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. Only AEs that are defined as AESIs will be collected. 
 
Adverse Event of Special Interest 
The following AEs are considered AESIs and will be collected: 
 
Symptomatic hypotension: Dizziness or any other symptom or event possibly related to hypotension 
 
Abnormal laboratory findings of sodium, potassium, uric acid, glucose, lipids, creatinine or eGFR 
 
Headache 
 
Peripheral edema 
 
Any other symptom or laboratory abnormality that led to permanent discontinuation of trial 
medication. 
 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose; results in death, is life-threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, or is a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Hospitalization means the participant has been formally 
admitted to a hospital for medical reasons. It does not include a presentation at a casualty or emergency room. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen during the study is not 
considered an SAE or AE. Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or otherwise meets seriousness criteria, the event is an SAE. 
 
Intensity/Severity of an AESI/SAE 
All AESI/SAEs will be graded as mild, moderate, or severe by the investigator based on her/his medical judgment 
and the following guidance: 


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 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
 
Moderate: limiting age-appropriate instrumental activities of daily living (e.g. preparing meals, 
shopping for groceries or clothes, using the telephone). Minimal, local or non-invasive intervention 
indicated. 
 
Severe: Medically-significant but not immediately life-threatening; disabling; limiting self-care 
activities of daily living (e.g. bathing, dressing and undressing, feeding self); hospitalization or 
prolongation of hospitalization indicated. 
 
Relationship to the Trial Medication 
All AESIs/SAEs will be assessed for causal relationship to the study medication by the investigator and reported 
as either definitely, probably, possibly, unlikely related, or not related. 
 
Serious Unexpected Suspected Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a suspected adverse reaction related to an 
investigational medicinal product that is both unexpected and serious. An SAE will be considered unexpected 
if the nature, severity, or frequency of the event is not consistent with the information previously described for 
the trial medication in the Investigator Brochure (IB). 
17.2. Safety Reporting 
 
AESI/SAE Data Collection & Follow-Up Period 
AESI/SAE data will be collected and followed-up from the time signed informed consent is obtained and up to 
the Week 16 EOT visit for the double-blind period.    Follow-up information on ongoing AESIs/SAEs obtained 
after the participant’s respective EOT visit (as applies) will not be collected in the eCRF but all attempts will 
made to follow-up SAEs/AESIs until they have resolved or stablised. 
 
Trial Investigator Responsibilities in Reporting AESIs/SAEs 
Regardless of the suspected causality, every AESI/SAE must be reported by the site investigators as per the 
local regulatory and ethical requirements. All SAEs should be reported by completing the paper (Council for 
International Organizations of Medical Sciences [CIOMS] or relevant form) and eCRF SAE Form. The reports 
should identify participants by unique identification numbers assigned to the trial participants. SAEs should 
be promptly reported to the concerned parties and followed-up until resolution as per the local ethical and 
regulatory requirements. The Investigator should supply additional information (e.g. laboratory results, 
specialist/hospital letters, and autopsy results, etc.) if required by the CRO. Investigators are responsible for 
assessing if an AE meets the criteria for reporting as serious, the intensity of the event, and the relationship of 
the event with the trial medication. 
 
Reporting of AESIs & SAEs 
At each trial scheduled visit and unscheduled visits during the trial, site staff will ask participants about the 
incidence of any AESIs or SAEs since the previous visit. Other AEs will not be recorded since these drugs are 
well-known and established with widespread use. Site staff may also become aware of the incidence of AEs 
during a phone call with participants. All SAEs that site staff becomes aware of from the time informed consent 
is obtained until 30 days after discontinuation of the trial medication must be recorded. The following 
information will be collected for each AESI and SAE: event name, date of onset, severity, a possible cause of 
the event, relationship to trial medication, action taken regarding the trial medication, treatment given to 
manage the event (if applicable), the outcome of event, and date of resolution (if applicable). 
 
An increase in the severity of a previously reported AESI or SAE during the trial will be reported as a new AESI 
or SAE with higher severity. A decrease in the severity of a previously reported AESI or SAE during the trial, will 
not require changes to the reported severity. Worsening of a condition, recurrent episodes, and further 
complications if any are to be reported as a follow-up of the original event. 
 
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of the event. Additional information will be collected including, seriousness criteria, hospitalization date and 
discharge (if applicable), and procedures performed (if applicable).   
 
Reporting of SUSARs 
The Medical Monitor assigned by George Clinical Safety will assess all suspected serious adverse reactions in 
order to determine expectedness in accordance with the known adverse effects of each investigational drug as 
listed in the IB.  If a suspected serious adverse reaction is determined to be unexpected i.e. a SUSAR, the CRO 
will report to the applicable regulatory authorities within the required timelines. Follow-up reports will be 
generated in accordance with applicable regulatory requirements. Reports will also be provided to the 
overseeing IRB/IEC and Investigators as per country requirements. 
 
Reporting of Pregnancy 
Any occurrence of pregnancy in a trial participant during the trial from the time to signing the informed consent 
until 30 days after discontinuation of the trial medication will be reported by the site staff, using a pregnancy 
form, to the trial sponsor within 24 hours of the site staff first becoming aware of it. Pregnancy will be followed 
until final resolution (i.e., delivery or early termination). Congenital abnormalities/birth defects and 
spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without complications 
should not be handled as AEs. 
 
Reporting of Trial Medication Use Errors or Misuse  
Reports of trial medication overdose, abuse, off-label use, misuse, or any other medication error should only 
be reported as an SAE if they are associated with suspected adverse drug reactions.  Medication error refers to 
any unintentional error in the prescribing, dispensing, or administration of a medicinal product while in the 
control of the healthcare professional or participant. All trial medication overdose, misuse and other 
medication errors associated with suspected adverse drug reactions should be routinely followed-up to ensure 
that the information is as complete as possible with regards to the symptoms, treatments, outcomes, context 
of occurrence (e.g., error in prescription, administration, dispensing, dosage, etc.). 
 
ETHICAL & REGULATORY COMPLIANCE 
This trial will be designed, conducted, analyzed, and reported in compliance with ICH-GCP and local regulatory 
& ethical requirements.  
18.1. Ethical Approval 
All participating sites will submit to relevant IRB/IEC the trial protocol, PISCF and other trial-related essential 
documents, as required by the IRB/IEC, for review and approval. No sites will start the trial before the written 
approval of the IRB/IEC.  
18.2. Regulatory Approval 
Where applicable, the trial protocol, PISCF, and other trial-related essential documents will be submitted to the 
local regulatory agency as per the applicable requirement in the country. 
18.3. Confidentiality 
All documents and data relating to this trial are strictly confidential. Documents given to the investigators 
and trial sites by the CRO should not be disclosed to other parties without the written approval of the 
sponsor. The investigators/sites should maintain the confidentiality of the identification of all trial participants 
and assure the security and confidentiality of trial data and documents. 
18.4. Protocol Amendments 
Any change to the protocol will be made through a protocol amendment by the SC. The participating sites will 
submit the amendment to the relevant IRB/IEC, and the sponsor will submit to the regulatory agencies as per 
the local requirements. 


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18.5. Adherence to the Trial Protocol 
Investigators/sites will adhere to the trial protocol, comply with the ethical and regulatory requirements for 
the conduct of the trial. Any deviations from the protocol must not be implemented unless such a deviation is 
required to prevent/eliminate immediate harm to the trial participant(s). The investigator/site will document 
protocol deviations along with reasons and notify them to the sponsor/CRO as per the local requirements. 
 
ADMINISTRATIVE SECTION 
19.1. Insurance 
The sponsor provides insurance to cover medical expenses and/or pay compensation in the event of a trial-
related injury or death to a trial participant and indemnify (with both legal and financial coverage) the 
investigator/site against claims arising from the trial, except in the case of claims that arise from malpractice 
and/or negligence, in compliance with local regulatory and ethical requirements. 
19.2. Quality Assurance 
Quality assurance will be achieved via compliance with relevant standard operating procedures, regulatory and 
ethical requirements; database design and data monitoring; training of all study staff on protocol and 
procedures; documentation of all procedures and processes; communication with stakeholders by the trial 
coordinating team; and direction and leadership of the trial by the SC. 
19.3. Trial Documents Retention 
All essential trial documents (as defined by ICH-GCP) will be archived and retained at the trial sites as long as 
to comply with the requirements of the sponsor (as specified in the agreement between the sponsor and the 
sites) and the national and international regulations (whichever is the longest period). At the end of such period, 
the investigator shall notify in writing to the sponsor of the intent to destroy all such documents. If the site 
investigator is unable to archive or cannot guarantee the archival requirements for some or all the documents, 
arrangements must be made between the investigator and the sponsor to store documents outside the site, in 
such a way that they can be accessed in the event of a regulatory inspection. These documents should not be 
destroyed without prior written approval from the sponsor. In the case of investigator wanting to assign the 
trial records to another party, or move them to another location, the sponsor must be notified in advance. 
 
For sites using an electronic system to store trial participants medical records and it cannot be confirmed that 
the electronic system is validated (as per 21 Code of Federal Regulations Part 11 or equivalent standard) or the 
sponsor representatives or the regulatory inspectors cannot be provided access to the electronic system the 
site will be requested to print the source documents needed for verification. Such printed copies should be 
numbered, stapled, and should be certified by the site investigator that they are exact copies with the same 
information as in the original source record.  
19.4. Ownership, Disclosure of Data and Dissemination policy 
The Sponsor will have full ownership of the trial data. The sponsor will register the trial and post results on 
public platforms such as ClinicalTrials.gov within the timelines stipulated by the applicable IRBs/IECs and/or 
regulatory agencies. The sponsor will develop a clinical trial report documenting results that will be submitted 
to the regulatory agencies. The SC will be primarily responsible for publications arising from the trial, which will 
be submitted for presentations at conferences and publications in journals. Authorship on publications will be 
as per the International Committee of Journal Editors criteria. Draft publications should be shared with the 
Sponsor, who will provide any comments within 30 days of receipt.  
 




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SOC 
System Organ Class 
SPC 
Single Pill Combination 
STRATHE 
STRAtegies of Treatment in Hypertension Evaluation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TRIUMPH 
Triple Pill versus Usual Care Management for Patients with Mild-to-Moderate Hypertension 
USA 
United States of America 
 
 
 


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20.2. Appendix 2: Procedure for the Measurement of Clinic BP 
Procedures for clinic BP measurement are taken from AHA recommendations65 and will be performed using a 
supplied FORA D40g BP machine (also known as Medisanté BP800 machine),66,67 which is a validated, electronic, 
automatic, digital upper-arm cuff monitor,68 and the same model as that used for home BP. 
 
1. 
Ensure the paper clinic BP data collection form is ready with participant’s identifying information added 
and a pen is available so that BP measures can be written down directly on the form, for subsequent 
transcription to the eCRF. The paper clinic BP data collection form should be retained for monitoring. 
2. 
Participants should be asked to avoid caffeine, smoking and exercise for at least 30 minutes before their 
BP measurement procedure begins. This preparation is ideal not essential – if not possible, the 
measurement should still proceed 
3. 
Ensure the participant has emptied his/her bladder. 
4. 
Remove all clothing covering the location of cuff placement. Make sure to avoid rolling up sleeves, this 
may cause a (partial) tourniquet effect. 
5. 
Support the participant’s arm (e.g., resting on a desk). 
6. 
Sit with back straight and supported (e.g. on a straight-backed dining chair). 
7. 
Sit with feet flat on the floor and legs uncrossed. 
8. 
Use the correct cuff size according to arm circumference, from the Small (15 - 24cm, different cuff sizes 
available in different  countries), Medium/Large (M-L = 24 - 43cm) and Extra Large (XL = 38 - 55cm) sizes 
available, such that the bladder encircles 80-100% of the arm circumference.  
9. 
Position the center of the BP cuff over the upper arm brachial artery at least 1 inch above the crease of 
the elbow. 
10. 
Position the middle of the cuff on the participant’s upper arm at the level of the right atrium (the 
midpoint of the sternum).  
11. 
Once the participant is prepared, have him/her relax, sitting in a chair with feet flat on the floor and back 
supported. The participant should be seated for 5 min without talking or moving around before recording 
the first BP reading. 
12. 
Site staff will initiate BP measurement and will be present until all the measurements are made. 
13. 
Immediately after three seated BP measurements are taken, ask the participant to stand up and take an 
additional single BP measure after 1 minute of standing. 
14. 
Neither the participant nor the person measuring the BP should talk during the rest period or the 
measurement. 
15. 
A single press of the on/off button on the bottom right of the FORA D40g device will take a single measure 
(for initial left arm, right arm BP measures, at screening and re-screening visits only and for standing BP 
measures) and a single press of the AVG button on the bottom left of the device should be used for all 
seated measures. This will provide the average of three measurements, each spaced by 1 minute.  
16. 
At the first visit, record a single BP from each the arm. If one arm gives a reading that is more than 
10mmHg SBP higher than the other arm, then the arm with the higher measure should be used for all 
readings throughout the trial. If the SBP difference between arms is 10mmHg or less, a choice of arm 
should be made and all measures should be taken from the same arm throughout the trial for that 
participant. 
17. 
Ensure that the BP readings are transcribed from the paper clinic BP data collection form to the eCRF. 
 


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20.3. Appendix 3: Procedure for the Measurement of Home BP 
Procedures for home BP measurement are taken from AHA recommendations65 with reference to recent trials 
and clinical use.64,69  BP measurements will be performed using a supplied FORA D40g BP  machine (also known 
as Medisanté BP800 machine), which is a validated, electronic, automatic, digital upper-arm cuff monitor, and 
the same model as that used for clinic BP.  
 
Home BP will be measured according to the following schedule: 
 
on four consecutive days immediately prior to the trial visit (i.e. Weeks -1, 5, and 11), and ideally on a 
single set day of participant’s preference in other weeks.  
 
in triplicate in the morning and in the evening, ideally at approximately the same time each morning 
and evening and between 06:00-10:00 hours and 18:00-22:00 hours. If these time ranges are not 
possible, measures in the am and pm are sufficient as morning and evening measures, as long as there 
is at least a 6-hour interval between the morning and evening measurements 
 
the morning measurements should be immediately before the next trial medication dose 
 
Each participant will be provided a BP monitor for her/his sole use for the duration of the trial. BP readings 
will be encrypted and transferred automatically to the trial database via SIM connection. Physical recording of 
BP measurement values by participants will not be required, unless there is a technical failure in data transfer, 
in which case BP readings should be captured in the BP diaries provided and the BP monitor brought to the 
trial site for inspection. 
 
Device setting and handover to participant (site staff) 
1. 
Switch on the device. 
2. 
Ensure the supplied cuff is appropriately sized based on the arm circumference such that the bladder 
encircles 80-100% of the arm circumference. Small (15 - 24cm, available only in some countries), 
Medium/Large (M-L = 24 - 43cm) and Extra Large (XL = 38 - 55cm) sizes are available.  
3. 
Perform a demonstration measurement following the instructions below and ask participants if they 
have any queries.  
4. 
Ask participants to contact site staff if they have any questions related to home BP measurement or 
their device is not functioning properly. 
 
Information and instructions to participants 
1. 
Avoid smoking, caffeinated beverages or exercise within 30 minutes before the BP measurements. 
This preparation is ideal not essential – if not possible, the measurement should still proceed 
2. 
Urinate to empty the bladder before BP measurements. 
3. 
Start BP measurements after 5 minutes of seated rest.  
4. 
Sit with back straight and supported (e.g. on a straight-backed dining chair). 
5. 
Sit with feet flat on the floor and legs uncrossed. 
6. 
Remove all clothing covering the location of BP measurement cuff placement. 
7. 
Keep arm supported on a flat surface (such as a table), with the upper arm at heart level. 
8. 
Place the bottom of the cuff directly above the antecubital fossa (bend of the elbow). 
9. 
Take BP measurements from the arm advised by the trial site staff. 
10. Take 3 BP measurements with a 1-minute interval between each measurement. 
 
 


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20.4. Appendix 4: Trial Organization 
Steering Committee  
Chair  
 
 
Members  
 
ACC members – non-voting 
  
 
Coordination 
 
 
Data and Safety Monitoring Board 
 
Members  
 
Statisticians 
Executive Secretary  
 
 
Coordination 
 
 
 
 
 


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20.5. Appendix 5: Prohibited Drugs During the Trial 
Participants receiving the following drugs are not eligible for participation in the trial, and these drugs should 
not be initiated during the trial unless clinically essential and treatment cannot be provided with add-on 
medication as mentioned in Section 8.6, page 22. Past use does not contraindicate eligibility, but any 
prohibited drug should be ceased at or before the Screening visit and a period of at least 2 weeks or 5 half-
lives (whichever is longer) must elapse between permanent drug cessation and randomization. 
 
1. Antihypertensive drugs 
1.1. 
Non-trial angiotensin receptor blockers 
1.2. 
Non-trial calcium channel blocker 
1.3. 
Non-trial diuretics of all types, including thiazide, thiazide-like, loop and potassium sparing 
diuretics 
1.4. 
Alpha-adrenergic blockers 
1.5. 
Angiotensin-converting enzyme inhibitors 
1.6. 
Beta-adrenergic blockers 
1.7. 
Central alpha-agonists 
1.8. 
Renin-inhibitors 
1.9. 
Reserpine 
1.10. 
Vasodilators 
 
2. Endothelin receptor antagonists 
 
3. Neprilysin inhibitors 
 
4. Other drugs that may affect BP 
4.1. 
Corticosteroids (e.g. cortisone, hydrocortisone) excluding topical inhaled and intranasal use  
4.2. 
Liquorice 
4.3. 
Erythropoiesis stimulating agents (e.g. epoetin alfa) 
4.4. 
Calcineurin inhibitors (e.g. cyclosporine, tacrolimus) 
4.5. 
Sodium-glucose co-transporter-2 (SGLT2) inhibitors (eg. dapagliflozin, empagliflozin, 
canagliflozin) 
4.6. 
Psychiatric drugs that affect blood pressure:70 venlafaxine, bupropion, tricyclics, monoamine 
oxidase inhibitors (MAOis)  
4.7. 
Cocaine, amphetamines or other stimulants, including the appetite suppressant phentermine 
4.8. 
Pseudoephedrine, phenylephrine or other nasal decongestants, excluding topical and 
intermittent use 
4.9. 
Yohimbine 
4.10. 
Vascular endothelial growth factor pathway inhibitors (e.g. bevacizumab, SORAfenib) 
 
5. Intermittent use of  phosphodiesterase (PDE) inhibitors (eg  sildafenil)  do not constitute a contraindication 


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20.6. Appendix 6: Protocol Signature Page 
The signatures below constitute approval of this protocol by the signatories and provide the assurances that 
this trial will be conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality, applicable ethical and regulatory requirement, laws and ICH-GCP. 
 
Trial Number: GMRx2-HTN-2020-ACT1 
Indication: Hypertension 
 
 
 
 
 
 
GEORGE MEDICINES CHIEF INVESTIGATOR 
 
 
 
Signature  
___
________________________________________________ 
 
 
Date  
 
_______________________________________________________________________ 
 
 
Name  
____________________________________________ 
 
 
Title  
 
_______________________________________________________________________ 
 
 
 
 
 
 
TRIAL SITE INVESTIGATOR 
 
 
Trial Site Name   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature  
_______________________________________________________________________ 
 
 
Date  
 
_______________________________________________________________________ 
 
 
Name  
_______________________________________________________________________ 
 
 
Title  
 
_______________________________________________________________________ 
8 March 2024


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Murray CJL, Aravkin AY, Zheng P, . . .Lim SS. Global burden of 87 risk factors in 204 countries and 
territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet. 
2020;396(10258):1223-49. 
2. 
Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: 
results of prospectively-designed overviews of randomised trials. The Lancet. 2003;362:1527-35. 
3. 
Ettehad D, Emdin CA, Kiran A, . . .Rahimi K. Blood pressure lowering for prevention of cardiovascular 
disease and death: a systematic review and meta-analysis. The Lancet. 2016;387(10022):957-67. 
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Contents 
1 
ADMINISTRATIVE INFORMATION ............................................................................................................. 5 
1.1 
Trial Identifiers .................................................................................................................... 5 
1.2 
Revision History .................................................................................................................. 5 
1.3 
Contributors to The Statistical Analysis Plan ...................................................................... 6 
1.3.1 
Approvals..................................................................................................................... 7 
2 
INTRODUCTION ........................................................................................................................................ 8 
2.1 
Trial Objective ..................................................................................................................... 8 
2.2 
Trial Population .................................................................................................................. 8 
2.2.1 
Inclusion Criteria ......................................................................................................... 8 
2.2.2 
Exclusion Criteria ......................................................................................................... 8 
2.2.3 
Trial design ................................................................................................................ 10 
2.3 
Intervention ...................................................................................................................... 11 
2.3.1 
Treatment Groups ..................................................................................................... 11 
2.3.2 
Randomization .......................................................................................................... 11 
2.3.3 
Changes & Additions on Trial Medication ................................................................. 11 
2.4 
Outcomes ......................................................................................................................... 12 
2.4.1 
Efficacy Outcomes ..................................................................................................... 12 
2.4.2 
Safety Outcomes ....................................................................................................... 12 
2.5 
Sample Size ....................................................................................................................... 13 
2.6 
Changes in the Conduct of the Study or Planned Analyses .............................................. 14 
2.6.1 
Changes in the Conduct of the Study ........................................................................ 14 
2.6.2 
Changes in Planned Analysis ..................................................................................... 14 
3 
STATISTICAL ANALYSIS ............................................................................................................................ 14 
3.1 
Interim Analyses ............................................................................................................... 14 
3.2 
Multi-Center Trials ............................................................................................................ 14 
3.3 
Multiplicity Adjustment .................................................................................................... 14 
3.4 
Populations for Analysis ................................................................................................... 15 
3.4.1 
Screened Set .............................................................................................................. 15 
3.4.2 
Safety Set ................................................................................................................... 15 
3.4.3 
Efficacy Populations .................................................................................................. 15 
3.5 
General Methods .............................................................................................................. 15 
3.5.1 
Computing Environment ........................................................................................... 16 
3.5.2 
Baseline Definitions ................................................................................................... 16 
3.5.3 
Study Period for Analysis........................................................................................... 17 
3.6 
Subject Disposition ........................................................................................................... 17 
3.7 
Baseline Characteristics .................................................................................................... 17 
3.8 
Prior/Concomitant Medications ....................................................................................... 18 
3.9 
Adherence ........................................................................................................................ 18 
3.9.1 
Adherence to Trial Medication ................................................................................. 18 
3.9.2 
Adherence to Home BP Measurement ..................................................................... 19 
3.9.3 
Protocol Deviations ................................................................................................... 19 
3.10 
Analysis of the Efficacy Outcomes .................................................................................... 20 
3.10.1 
Estimand .................................................................................................................... 20 
3.10.2 
Primary Efficacy Analysis ........................................................................................... 25 
3.10.3 
Analysis of Secondary Efficacy Outcomes ................................................................. 32 
3.11 
Analysis of Safety Outcomes ............................................................................................ 34 
3.11.1 
Adverse Events of Special Interest ............................................................................ 34 
3.11.2 
Laboratory Parameters: Hematology, Biochemistry & Urine ................................... 35 


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3.11.3 
Other Safety Analysis ................................................................................................ 36 
4 
REFERENCES............................................................................................................................................ 37 
 
 
 


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Appendices 
 
Appendix 1: List of Abbreviations ....................................................................................................................................... 38 
Appendix 2: Additional Power Calculations ........................................................................................................................ 39 
Appendix 3: Schedule of Assessment ................................................................................................................................. 40 
Appendix 4: Predictive Margins and Average Marginal Effects Macro and Implementation ............................................. 42 
 
Tables 
 
Table 3-1 Planned Treatment Assignments Period 2 and Period 3 .................................................................................... 16 
Table 3-2 Estimands ............................................................................................................................................................ 22 
Table 3-3 Definitions of Home Blood Pressure Derivations ................................................................................................ 25 
 
 
 
 






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1.3.1 
Approvals 
The undersigned have reviewed this statistical analysis plan (SAP) and approve it as final.  
 
Signature 
Date 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2 INTRODUCTION 
2.1 
Trial Objective 
This trial is an international, multi-center, parallel-group, double-blind, randomized, controlled trial to 
investigate the efficacy and safety of GMRx2, a fixed-dose combination of telmisartan, amlodipine and 
indapamide compared to three dual combinations of the component drugs for the treatment of hypertension. 
 
Section 5 of the Protocol introduces the history and development of combination therapies for treatment of 
hypertension and describes the potential role of triple low-dose combination and expected effects. 
 
This statistical analysis plan (SAP) defines derivations, algorithms, key components, and statistical analysis 
methods to be applied in the analysis and summary of data collected in the study GMRx2-HTN-2020-ACT1. 
Sample SAS programming code is provided for a select group of statistical models. This code is provided as 
example and may require modifications to accommodate the data collected. 
2.2 
Trial Population 
The guiding principle of participant eligibility is individuals with hypertension who could be appropriately 
treated with triple or dual combinations, with the component drugs each at half or standard doses. 
2.2.1 
Inclusion Criteria 
At screening visit: 
• 
Provided signed consent to participate in the trial. 
• 
Adult of age ≥18 years. 
• 
Clinic attended automated seated mean SBP (average of 3 measurements): 
o 140-179 mmHg on 0 BP-lowering drugs, or 
o 130-170 mmHg on 1 BP-lowering drug, or 
o 120-160 mmHg on 2 BP-lowering drugs, or 
o 110-150 mmHg on 3 BP-lowering drugs. 
 
Note: A single tablet containing 2 or 3 different BP lowering agents (i.e. a combination medication) is 
considered as 2 or 3 BP lowering drugs, respectively. 
 
At randomization visit: 
• 
Home seated mean SBP 110-154 mmHg in the week prior to the randomization visit. 
• 
Adherence of 80-120% to run-in medication. 
• 
Tolerated run-in medication. 
• 
Adherence to home BP monitoring schedule: in the week before randomization, at least 6 measures 
(e.g. ≥2 sets of triplicate measures) including at least 1 morning and 1 evening each with ≥2 measures.  
• 
Morning is defined as any measure in the am and evening as any measure in the pm. Morning and 
evening do not have to be same day. 
 
2.2.2 
Exclusion Criteria 
Section 8.2.2 of the protocol delineates exclusion criteria at screening visit and at randomization visit. Key 
exclusion criteria as follows. 
 


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At screening visit:  
1. Receiving 4 or more BP-lowering drugs.  
2. Receiving any BP lowering drugs for indications other than hypertension e.g. heart failure. 
3. Pregnant or had a positive pregnancy test or unwilling to undertake a pregnancy test during the trial 
and up to 30 days after the discontinuation of the trial medication or breastfeeding or of childbearing 
age and not using an acceptable method of contraception. Acceptable methods of birth control 
include Hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, 
intrauterine device, double-barrier method (e.g. condoms, diaphragm, or cervical cap with spermicidal 
foam, cream, or gel), or male partner sterilization. Contraception should be used for at least 1 month 
before the screening visit and until the end of trial participation. 
4. Meets any criteria of local ethical or regulatory requirements related to severe acute respiratory 
syndrome coronavirus-2 (SARS-CoV-2) that would deem participation in a clinical trial unsuitable. 
5. Contraindication, including hypersensitivity (e.g. anaphylaxis or angioedema), to the active run-in 
treatment or to any of the trial medication options in the four randomized groups. 
6. Current/history of transient ischemic attack, stroke, or hypertensive encephalopathy. 
7. Current/history of acute coronary syndrome, unstable angina, myocardial infarction, percutaneous 
transluminal coronary revascularization, or coronary artery bypass graft.  
8. Current atrial fibrillation. Patients with a history of paroxysmal atrial fibrillation are potentially eligible 
as long as there has been no episode in the last 3 months, while patients with a history of persistent 
or permanent atrial fibrillation are not eligible. 
9. Current/history of New York Heart Association class III and IV congestive heart failure.   
10. Current/history of cardiomyopathy or any other cardiovascular condition of sufficient severity to 
contraindicate the trial medications or require a contraindicated medication.   
11. Current/history of a known secondary cause of hypertension, such as primary aldosteronism, renal 
artery stenosis, pheochromocytoma, or Cushing's syndrome. 
12. Current/history of severe uncontrolled diabetes (HbA1c > 11.0% (> 97 mmol/mol)) within last three 
months. 
13. Current/history of end-stage renal disease or anuria; or current estimated glomerular filtration rate 
(eGFR) <60 ml/min/1.73m². 
14. Current electrolyte levels that would be regarded as contraindications for any of the potential 
treatment arms e.g.  serum sodium <132mmol/l or >148 mmol/l or serum potassium <3.1 mmol/l or 
>5.6mmol/l.  
15. Current/history of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the 
upper limit of normal range within 6 months. 
16. Current concomitant illness or physical impairment or mental condition that in the judgment of the 
investigator could interfere with the effective conduct of the trial or constitutes a significant risk to 
the participants’ safety or well-being.  
17. Arm circumference that is too large or too small for available cuffs to allow accurate measurement of 
BP. Upper limit is 55cm in all countries, while lower limit is 15cm or 24cm in different countries, 
depending on available cuff sizes. 
18. Currently taking or might need during the trial, a concomitant treatment which is known to interact 
with one or more of the trial medications: digoxin, lithium, diabetics receiving aliskiren, moderate and 
strong CYP3A4 inhibitors (e.g. ritonavir, ketoconazole, diltiazem], simvastatin >20 mg/day, 
immunosuppressants. 
19. Might need treatment with drugs that are prohibited during the trial:  other antihypertensive drugs, 
endothelin receptor antagonists, neprilysin inhibitors, or other drugs that may affect BP. 
20. Current surgical or medical condition that might significantly alter the absorption, distribution, 
metabolism, or excretion of trial drugs such as prior major gastrointestinal tract surgery (e.g. 
gastrectomy, lap band, or bowel resection) or acute flare of inflammatory bowel disease within one 


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year. 
21. Individuals working >2 nightshifts per week. 
22. Participated in any investigational drug or device trial within the previous 30 days. This does not 
include participants in the extended safety follow-up portion of a trial.  
23. History of alcohol or drug abuse within 12 months. 
 
At randomization visit:  
1. Unable to adhere to the trial procedures during the run-in treatment period. 
2. Any of the following which in the investigator’s judgment may compromise the safety of the 
participant if randomized to the trial medications: 
a. High or low clinic BP levels even in the light of the values for home BP that are available for 
that participant. The exact levels of BP are not specified, since there is clinical uncertainty as 
to the relevance of BP levels which are high or low in clinic only; for example, the clinical 
relevance of ‘whitecoat hypertension’ is uncertain. 
b. High or low home diastolic BP (DBP) levels. The exact levels of DBP is not specified, reflecting 
clinical uncertainty of the implications of isolated diastolic hypertension. However, home DBP 
values of >99 mmHg may typically be considered as requiring treatment intensification, and 
such participants would not be suitable for randomization. 
c. Any abnormal laboratory value which in the judgment of the investigator could interfere with 
the effective conduct of the trial or constitutes a significant risk to the participants’ well-being.  
d. Fulfilling any of the exclusion criteria mentioned for the screening visit, when verified again at 
randomization visit. 
 
2.2.3 
Trial design 
The trial design is described in detail in Section 7 of the protocol, with the following figure summarising the 
overall design: 
 
GMRx2 Dose2 = T 20 / A 2.5 / I 1.25; GMRx2 Dose3 = T 40 / A5 / I 2.5; T = telmisartan; A = amlodipine; I = indapamide; RI = run-in; R = 
randomization; FU = follow-up; EOT = end of trial; V = visit; Forced up-titration at FU1; EOT will be telephonic.  
 


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Of particular note are the two study visits Week 6/Follow-up 1 (FU1) and Week 12/Follow-up 2 (FU2). 
Preceding both visits, participants will be requested to perform extra home BP measurements in the week 
running up to the clinic visit. At FU1, all participants are expected to be up-titrated to the higher level of study 
drug, unless there is a specific contraindication, such as symptomatic hypotension. At FU2, the participant will 
complete the double-blinded part of the trial and continue on non-trial treatment in a safety follow-up period. 
Although time periods have been nominated (6 weeks for FU1 and 12 weeks for FU2) these are indicative only 
and actual time periods may vary within an expected window, as specified within the study protocol.  
2.3 
Intervention 
2.3.1 
Treatment Groups  
The trial will comprise an approximately 4-week single-blind active run-in on GMRx2 dose version 2 
(telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg), followed by a double-blind period (targeted at 
12 weeks) with randomization to one of the following four treatment groups: 
 
1. Triple – TAI:  telmisartan (T) 20 mg/amlodipine (A) 2.5 mg/indapamide (I) 1.25 mg.  
(GMRx2) 
At Follow-up visit 1, forced up-titration to 
telmisartan 40 mg/amlodipine 5 mg/indapamide 2.5 mg 
2. Dual – TA:  
telmisartan 20 mg/amlodipine 2.5 mg.  
At Follow-up visit 1, forced up-titration to telmisartan 40 mg/amlodipine 5 mg 
3. Dual – TI:  
telmisartan 20 mg/indapamide 1.25 mg.   
At Follow-up visit 1, forced up-titration to telmisartan 40 mg/indapamide 2.5 mg 
4. Dual – AI: 
amlodipine 2.5 mg/indapamide 1.25 mg.  
At Follow-up visit 1, forced up-titration to amlodipine 5 mg/indapamide 2.5 mg 
2.3.2 
Randomization 
Randomization (permuted with variable block sizes and stratified by trial site) will be conducted via a 
password-protected, secure website/interactive voice response service. Following successful randomization, 
each participant will be assigned a unique ‘participant study number’ and be assigned to receive either GMRx2 
or one of the three dual combination of Blood Pressure (BP) lowering drugs. The ratio of randomization will 
be 2:1:1:1, i.e. GMRx2 assigned to twice more participants than each of the dual combinations: 
 
1. Triple – TAI (GMRx2):  N=600 
2. Dual – TA:  
 
N=300 
3. Dual – TI:  
 
N=300 
4. Dual – AI: 
 
N=300 
 
Study participants, treating clinicians, study investigators and data collectors will be blinded to treatment 
group allocation. 
2.3.3 
Changes & Additions on Trial Medication 
Sections 8.6, 8.7 and 8.8 of the protocol describe the different possible changes and additions on trial 
medication: 
1. Add-on non-study treatments for participants with high BP, 
2. Down-titration or temporary cessation of trial medication, 
3. Temporary change from investigational medicinal product (IMP) to open label therapy arising from 


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pandemic-related IMP supply shortages, 
4. Early discontinuation of the trial medication. 
 
Add-on non-study treatments, down-titration and temporary cessation as described in the protocol will aim 
to retain participants on trial medication while addressing symptoms and/or out of range blood pressure 
levels. For early discontinuation of trial medication, the participant will be followed-up until the end of the 
trial unless the participant withdraws consent. In all these scenarios, there is no need to unblind the 
participants – the specific scenarios for unblinding are referred to in the protocol Section 11.4. 
2.4 
Outcomes 
2.4.1 
Efficacy Outcomes 
2.4.1.1 
Primary  
Difference in change in home seated mean SBP from randomization to follow-up Week 12. 
2.4.1.2 
Secondary  
• 
Difference in change in clinic seated mean SBP from randomization to follow-up Week 12. 
• 
Difference in change in clinic seated mean SBP from randomization to follow-up Week 6. 
• 
Difference in change in clinic seated mean DBP from randomization to follow-up Week 12. 
• 
Difference in change in clinic seated mean DBP from randomization to follow-up Week 6. 
• 
Percentage of participants with clinic seated mean SBP <140 and DBP <90 mmHg at follow-up Week 12. 
• 
Percentage of participants with clinic seated mean SBP <140 and DBP <90 mmHg at follow-up Week 6. 
• 
Percentage of participants with clinic seated mean SBP <130 and DBP <80 mmHg at follow-up Week 12. 
• 
Percentage of participants with clinic seated mean SBP <130 and DBP <80 mmHg at follow-up Week 6. 
• 
Difference in change in home seated mean SBP from randomization to follow-up Week 6. 
• 
Difference in change in home seated mean DBP from randomization to follow-up Week 12. 
• 
Difference in change in home seated mean DBP from randomization to follow-up Week 6. 
• 
Difference in change in trough home seated mean SBP from randomization to follow-up Week 12. 
• 
Difference in change in trough home seated mean SBP from randomization to follow-up Week 6. 
• 
Percentage of participants with home seated mean SBP <135 and DBP <85 mmHg at follow-up Week 12. 
• 
Percentage of participants with home seated mean SBP <135 and DBP <85 mmHg at follow-up Week 6. 
• 
Percentage of participants with home seated mean SBP <130 and DBP <80 mmHg at follow-up Week 12. 
• 
Percentage of participants with home seated mean SBP <130 and DBP <80 mmHg at follow-up Week 6. 
2.4.2 
Safety Outcomes 
2.4.2.1 
Primary  
Percentage of participants discontinued trial medication due to an Adverse Event (AE) or a Serious Adverse 
Event (SAE) from randomization to follow-up Week 12. 
2.4.2.2 
Secondary  
• 
Percentage of participants discontinued trial medication due to AE/SAE from randomization to follow-up 
Week 6. 
• 
Percentage of participants with an SAE from randomization to follow-up Week 12. 
• 
Percentage of participants with an SAE from randomization to follow-up Week 6. 


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• 
Percentage of participants with symptomatic hypotension from randomization to follow-up Week 12. 
• 
Percentage of participants with symptomatic hypotension from randomization to follow-up Week 6. 
• 
Percentage of participants with serum sodium concentration below 135 mmol/l at follow-up Week 12. 
• 
Percentage of participants with serum sodium concentration below 135 mmol/l at follow-up Week 6. 
• 
Percentage of participants with serum sodium concentration above 145 mmol/l at follow-up Week 12. 
• 
Percentage of participants with serum sodium concentration above 145 mmol/l at follow-up Week 6. 
• 
Percentage of participants with serum potassium concentration below 3.5 mmol/l at follow-up Week 12. 
• 
Percentage of participants with serum potassium concentration below 3.5 mmol/l at follow-up Week 6. 
• 
Percentage of participants with serum potassium concentration above 5.5 mmol/l at follow-up Week 12. 
• 
Percentage of participants with serum potassium concentration above 5.5 mmol/l at follow-up Week 6. 
• 
Percentage of participants with serum sodium <135mmol/l or >145 mmol/l, and/or serum potassium <3.5 
mmol/l or >5.5mmol/l at follow-up Week 12. 
• 
Percentage of participants with serum sodium <135mmol/l or >145 mmol/l, and/or serum potassium <3.5 
mmol/l or >5.5mmol/l at follow-up Week 6. 
• 
Percentage of participants with eGFR drop of over 30% from randomization to follow-up Week 12. 
• 
Percentage of participants with eGFR drop of over 30% from randomization to follow-up Week 6. 
• 
Percentage of participants with orthostatic hypotension at Week 6, 
• 
Percentage of participants with orthostatic hypotension at Week 12 
• 
Percentage of participants with orthostatic hypertension at Week 6, 
• 
Percentage of participants with orthostatic hypertension at Week 12 
 
In addition, descriptive safety data will be reported on: 
• 
Percentage of participants discontinued trial medication due to AE/SAE during the active run-in period. 
• 
All SAEs, by severity and by System Organ Class (SOC) criteria in the run-in period and by trial medication 
group in the randomized period and safety follow-up period. 
2.5 
Sample Size 
As noted in Section 12.3 of the protocol, a sample size of 1500 participants randomized (600 in GMRx2 and 
300 in each of the dual combination groups) provides 97% power with a two-sided type I error rate of 5% to 
detect a minimum difference of 3 mmHg in home seated mean SBP for each of the three pairwise comparisons 
of GMRx2 vs dual therapy, assuming a common standard deviation of 11 mmHg within each group. Efficacy 
can be claimed only if all three comparisons are statistically significant at the two-sided 5% level. The overall, 
family-wise power for all three comparisons will therefore be over 90%.  
 
The study was planned using a simple, conservative sample size calculation by intention. The actual 
experimental design and subsequent statistical modelling approach is expected to provide greater power than 
this. Additional calculations are specified in Appendix 2.  
 
An updated power analysis was performed mid-trial using the observed overall standard deviation and 
hypothesized treatment effect for the DSMB and Steering Committee. Calculations of the standard deviation 
were based on the pooled sample, not requiring unblinding or any efficacy calculations. 


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2.6 
Changes in the Conduct of the Study or Planned Analyses 
2.6.1 
Changes in the Conduct of the Study 
Recruitment to the study was terminated before randomizing 1500 participants. Details are provided in 
Appendix 2.  
2.6.2 
Changes in Planned Analysis 
Multiple analysis sections have been expanded within this document from the protocol-specified analyses. 
Clarifications and expansions include: 
• 
The addition of an estimands section 
• 
Detailed descriptions of mixed models for repeated measures and multiple imputations 
• 
Clarified calculation methods for derivation of primary endpoint 
• 
Use of multiple populations for analysis, including the use of supportive and sensitivity analysis 
• 
Expansion of analysis methods to be used for secondary efficacy and secondary safety endpoint 
analysis 
3 STATISTICAL ANALYSIS 
3.1 
Interim Analyses 
The DSMB met periodically throughout the duration of the trial for data review. No analyses on unblinded 
efficacy results were performed. Observed standard deviation of the home BP measurements on the overall 
sample informed updated power calculations periodically through the study: see Appendix 2. 
3.2 
Multi-Center Trials 
Analysis of demographic and baseline characteristics, efficacy and safety data will be pooled across all sites.  
 
For the primary analysis, mixed models with repeated measures (MMRM) will be applied accounting for 
correlation between observations within site.  
3.3 
Multiplicity Adjustment 
All tests are to be two-sided with a nominal level of α set at 5%. Since the purpose of the trial is to demonstrate 
effects on all three of the designated primary efficacy endpoint comparisons simultaneously (i.e. GMRx2 has 
to be statistically significantly superior at two-sided p<0.05 to each of the possible dual combinations for the 
trial to be regarded as positive), there is no need for adjustment of the Type I error for the primary endpoint, 
according to ICH E9 Guidance and FDA Guidance ‘Multiple Endpoints in Clinical Trials. Guidance for Industry, 
2017’. The impact on Type II error and sample size has been carefully considered, in that the estimated power 
for each separate comparison is >97% and so the power for all three comparisons is >91% (i.e., 0.973 = 0.91).  
 
The secondary efficacy parameters measure different aspects of the same underlying treatment effect 
evaluated in the primary efficacy endpoint, that is the effect of GMRx2 compared to dual combinations on 
blood pressure, and do not demonstrate additional new treatment effects of the drug, but rather clarify the 
effect already demonstrated by the primary analysis. No type I error adjustment is proposed to account for 
multiplicity for secondary efficacy endpoint analyses. 


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3.4 
Populations for Analysis 
3.4.1 
Screened Set 
The Screened Set includes all participants who have provided consent and have a screening number, 
regardless of whether they have been randomized or treated with study treatment.  
3.4.2 
Safety Set 
The Safety Set is defined as all participants who took at least one dose of study treatment, including during 
Period 1 single-blind run-in. For the analysis of the safety endpoints, participants will be analyzed in the 
treatment group they actually received.  
3.4.3 
Efficacy Populations 
For all efficacy analyses, participants will be analyzed in the treatment group to which they have been 
randomized. 
 
The Randomized Set will be the set of reference for reporting primary and secondary endpoints to preserve 
the intention-to-treat (ITT) principle. The Full Analysis Set (FAS) and other strategies proposed will be used to 
evaluate the robustness of the results.  
3.4.3.1 
Randomized Set  
The Randomized Set includes all participants who have been randomized. Participants will be analyzed in the 
treatment group to which they have been randomized. 
3.4.3.2 
Full Analysis Set  
The FAS is defined as all participants in the randomized set who have taken at least one dose of randomly 
assigned treatment. If the Randomized Set and the FAS are very similar (≤5% difference) in size, the efficacy 
analysis will not be rerun on the FAS set as a sensitivity analysis. 
3.4.3.3 
Per Protocol Set 
The Per Protocol Set is defined as all randomized participants who did not experience an intercurrent event 
or major protocol deviation. Intercurrent events are defined within the Estimand Statements (Section 3.10.1). 
Protocol deviations are defined within Section 3.9.3. As receipt of an incorrect study treatment (wrong study 
treatment kid dispensed) is a major protocol deviation, participants will be grouped according to the 
treatment received.  
3.5 
General Methods 
All data listings that contain an evaluation date will contain a relative study day. Two relative study days will 
be defined: Period 1 Relative Day (P1 Rel Day) and Post-Randomization Relative Day (PR Rel Day). For Period 
1 Relative Day, pre-treatment and on-treatment study days are numbered relative to the day of the first dose 
of single-blind study treatment which is designated as P1 Day 1. The preceding day is P1 Day -1, the day before 
that is P1 Day -2, etc. Post-Randomization Relative Day will be numbered relative to the day of the first dose 
of the randomized medication which is designated as PR Day 1. 
 
The planned treatment group for all participants in Period 1 is GMRx2.  In Period 2, the planned treatment 
group is randomly assigned to be: 


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1. Triple – TAI (GMRx2) : telmisartan (T) 20 mg/amlodipine (A) 2.5 mg/indapamide (I) 1.25 mg.  
2. Dual – TA:  
telmisartan 20 mg/amlodipine 2.5 mg.  
3. Dual – TI:  
telmisartan 20 mg/indapamide 1.25 mg.   
4. Dual – AI: 
amlodipine 2.5 mg/indapamide 1.25 mg.  
Up-titration is planned to occur prior to Period 3, resulting in planned treatment at increased dose levels; 
however, the up-titration may not occur for reasons as specified in the protocol (Section 8.4.2). Therefore, 
treatments in period 3 include: 
Table 3-1 Planned Treatment Assignments Period 2 and Period 3 
Treatment Group 
Period 2: Treatment 
(Planned) 
Period 3: With Up-
titration (Planned) 
Period 3: No Up-Titration 
Triple – TAI 
telmisartan (T) 20 mg/ 
amlodipine (A) 2.5 mg/ 
indapamide (I) 1.25 mg. 
(GMRx2 Dose2) 
telmisartan 40 mg/ 
amlodipine 5 mg/ 
indapamide 2.5 mg 
(GMRx2 Dose3) 
same as in Period 2 
Dual – TA 
telmisartan 20 mg/ 
amlodipine 2.5 mg 
telmisartan 40 mg/ 
amlodipine 5 mg 
same as in Period 2 
Dual – TI 
telmisartan 20 mg/ 
indapamide 1.25 mg 
telmisartan 40 mg/ 
indapamide 2.5 mg 
same as in Period 2 
Dual – AI 
amlodipine 2.5 mg/ 
indapamide 1.25 mg 
amlodipine 5 mg/ 
indapamide 2.5 mg 
same as in Period 2 
 
All output will be incorporated into Microsoft Word or Adobe Acrobat PDF files, sorted and labelled according 
to the ICH recommendations, and formatted to the appropriate page size(s). 
 
Tables will be produced for appropriate demographic, baseline, efficacy, and safety parameters. For 
categorical variables, summary tables of the number and percentage of participants within each category (with 
a category for missing data) of the parameter will be presented. For continuous variables, the number of 
participants, mean, median, standard deviation (SD), minimum, and maximum values will be presented. 
Summarizations will be presented by treatment group and overall. For efficacy and safety summaries, Period 
1 (active run-in period) will be summarized separately from the randomized treatment period and follow-up. 
3.5.1 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software using version 9.4 or higher, 
unless otherwise noted. Medical history and adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 24.0 (or higher, as up-versioning may occur). Concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary March 2021 version 
(or later, as up-versioning may occur). 
3.5.2 
Baseline Definitions 
For Period 1, Baseline for safety and in-clinic assessments is defined as the most recent measurement prior to 
the first administration of study treatment.  
 
For in-clinic efficacy parameters including change from baseline measurements at post-Randomization 
timepoints, Baseline is the last Clinic BP measurement occurring prior to the first dose with randomized study 
treatment. 
 
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with derivation defined in Table 3-3.  
3.5.3 
Study Period for Analysis 
The study is planned with 4 periods (Section 2.2.3) with varying treatment assigned in both trial medication 
and dose level during the specified periods. For a minority of participants, Follow-Up visits 1 and 2 may not 
occur at 6 and 12 weeks, respectively and screening visit is not always 4 weeks before baseline visit, due to 
protocol-specified visit windows and IMP supply interruptions. Therefore, the analysis periods will be defined: 
• 
Period 1: From Week -4 to Randomization, defined as from screening to Randomization and Baseline 
Visit, 
• 
Period 2: From Randomization to Week 6, defined as from Randomization and Baseline Visit to Follow-
up Visit 1, 
• 
Period 3: From Week 6 to Week 12, defined as from Follow-up Visit 1 to Follow-up Visit 2, 
• 
Randomized Period: From Randomization to Week 12, defined as from Randomization and Baseline 
Visit to Follow-up Visit 2 (Period 2 and Period 3), 
• 
Period 4: From Week 12 to Week 16, defined as from Follow-up Visit 2 to end of study (Week 16). 
3.6 
Subject Disposition 
All participants screened who met study inclusion criteria for Period 1 (active run-in) will be accounted for. 
The number of participants who were randomized; and reasons for exclusion for non-randomized participants 
will be summarized.  
 
Subject disposition will be tabulated for the following categories and will include all participants in the 
Screened Set: 
• 
Number (%) of participants screened 
• 
Number (%) of participants entered run-in period 
• 
Number (%) of participants randomized 
• 
Number (%) of participants randomized, ineligible for randomization  
• 
Number (%) of participants randomized but did not receive study treatment 
• 
Number (%) of participants completing Period 2 (defined as attending Week 6, Visit FU1) 
• 
Number (%) of participants completing Period 3 (defined as attending Week 12, Visit FU2) 
• 
Number (%) of participants completing the trial, including safety follow-up (defined as attending Week 
12, Visit FU2 and Week 16, Visit EOT) 
• 
Number (%) of participants prematurely and permanently discontinuing the trial medications and 
reasons 
• 
Number (%) of participants prematurely and permanently discontinuing from the trial and reasons 
• 
Number (%) of participants in each analysis population (Section 3.4). 
3.7 
Baseline Characteristics 
Description of the participant baseline characteristics will be presented by treatment group and overall. 
Baseline characteristics will be summarized on the Safety Set by treatment group, Safety Set by Randomization 
Eligibility and Randomized Set by treatment group, including the below parameters:  
• 
Demographic characteristics: age (years), sex, race, ethnicity, height (cm), weight (kg), BMI (kg/m²), 
country/region, education 
• 
Lifestyle: Smoking status and alcohol consumption 
• 
12-lead ECG: Interpretations will be tabulated  


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• 
Screening visit number of prior BP medications 
 
The following parameters will be summarized: 
• 
Demographic characteristics, lifestyle, and 12-lead ECG 
• 
Screening visit clinic BP (SBP and DBP) 
• 
Average home BP at Randomization (last week of Period 1 SBP) (see Section 3.10.2 for derivations) 
• 
Change in clinic BP from Screening Visit to Randomization visit  
• 
Change in home BP from 1st to last week of Period 1 will be summarized by Randomization Eligibility 
 
Medical history will be provided in by-participant data listings. Summaries may also be presented. 
3.8 
Prior/Concomitant Medications 
Prior and concomitant medications will be summarized by treatment group. Prior medications are medications 
that were being taken at the time of screening. Concomitant medications are medications that started or were 
ongoing from run-in period to the end of trial. Concomitant medications will be summarized separately for 
medications taken during Period 1 (pre-Randomization) and post-Randomization. 
 
Prior/Concomitant medication will be summarized using descriptive statistics: 
• 
Number (%) of participants with at least one prior medication, by ATC code level 1 and preferred term 
• 
Number (%) of participants with at least one concomitant medication during Period 1, by ATC code 
level 1 and preferred term 
• 
Number (%) of participants with at least one concomitant BP lowering medication during Period 1, by 
ATC code level 1 and preferred term 
• 
Number (%) of participants with at least one concomitant medication post-Randomization, by ATC 
code level 1 and preferred term 
• 
Number (%) of participants with at least one concomitant BP lowering medications post-
randomization, by ATC code level 1 and preferred term 
 
Concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) term according to 
the WHO Drug Dictionary (WHO DD) (March 2021 version or later if up-versioning occurs) used for drug coding 
(https://www.whocc.no/atc_ddd_index/).  
3.9 
Adherence 
3.9.1 
Adherence to Trial Medication  
The planned daily dose is 1 pill per day. Low and standard doses are dispensed in separate bottles. Adherence 
to trial medication will be computed overall (across both low and standard doses). 
 
Trial medication adherence over the run-in period will be presented as below: 
• 
Adherence to active run-in treatment specified as the number of pills taken compared to the planned 
number of pills for the period, expressed in percentage. The planned number of pills for the period 
will be determined as the expected number of days of treatment between the Period 1 first dose date 
and Period 1 last dose date. The number of pills taken is determined as the difference between 
number of pills dispensed and the number of pills returned. For participants with missing pill-return 
data, 100% adherence will be assumed for the associated period.  
 
Trial medication adherence over the randomized period (from randomization to Week 12) will be assessed 


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using the following parameters: 
• 
Denominator: Planned number of pills for the period is defined as the number of days between the 
scheduled first and last treatment intake. The medication log CRF will be used to determine the 
number of expected days by computing the number of days between the start and stop dates for each 
record and summing across all records reported for each participant. Note, if there is a gap between 
the stop and start records for sequential medication logs, gap days will be assigned an expected count 
of 0. 
• 
Numerator: The number of pills taken is determined as the difference between number of pills 
dispensed and the number of pills returned. For participants with missing pill-return data, it will be 
assumed that the number of pills taken equals the minimum of the number of pills dispensed for that 
period and the number of days between the logged start and stop date for the corresponding trial 
medication log.  
 
Adherence to trial medication will be calculated as numerator ÷ denominator and expressed in percentage. 
Adherence is confirmed if ≥80% and ≤120%.  
 
Additional details surrounding the calculations of numbers of pills dispensed and adherence will be described 
within a specifications document. 
3.9.2 
Adherence to Home BP Measurement 
As per Section 8.2.1 in the protocol, adherence to home BP monitoring schedule will be assessed at the 
randomization visit. In the week before randomization (week -1), at least 6 measures (e.g., ≥2 sets of triplicate 
measures, ≥3 sets of duplicate measures) are required including at least 1 morning and 1 evening, each with 
≥2 measures. Morning is defined as any measure in the AM and evening as any measure in the PM. Morning 
and evening do not have to be same day.  
 
Following randomization, a minimally valid half-day of BP measurements is defined as one that has either: 
• 
 ≥1 BP values in the morning (earlier than 12:00 hours), or 
• 
≥1 BP values in the evening (12:00 hours or later). 
 
Study protocol Section 10.2.8 instructs that in the week before the Randomization, Week 6, and Week 12 trial 
visits, BP measurements should be taken on the 4 days immediately prior to the day of the on-site trial visit. 
In other weeks, measurements should be performed on a single day.  
 
Adherence to home BP measurement will be evaluated by looking at the number of minimally valid half-days 
and will be summarized by counting the number of minimally valid AM and PM periods of BP measurements 
per week of follow-up, by treatment group and overall.   
3.9.3 
Protocol Deviations  
Over a blind review meeting, before database lock, the different protocol deviations will be classified as minor 
or major and categorized by type (e.g. non-compliance to treatment, prohibited medication etc.) by the clinical 
team. The number of major protocol deviations will be summarized by type of deviations.  
 
Major protocol deviation categories include, but are not limited to: 
• 
Randomized even though ineligible. 
• 
Received the wrong treatment. 
• 
Non-adherence to study treatment (adherence < 80% or > 120%), for reasons known to be unrelated 


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to tolerability or efficacy e.g. participant moved overseas.  
• 
Interruption to study treatment as a result of supply chain issues in which protocol-specified 
procedures were not followed. 
• 
Insufficient valid home BP measurements for home blood pressure calculation at one or more of: 
baseline, Week 6 Follow-up Visit 1, Week 12 Follow-up Visit 2.  
• 
Up-titration at Week 6 Follow-up Visit 1 was not performed for reasons other than those specified in 
the protocol. 
• 
Other 
 
A summary table will present the tabulations by major protocol deviation on the Safety Set. All protocol 
deviations (recorded or programmed) will be listed.  
3.10 Analysis of the Efficacy Outcomes 
3.10.1 
Estimand 
3.10.1.1 Primary Estimand 
The population for the primary estimand includes adults (aged ≥18 years) with hypertension. The variable of 
interest is the difference between the home measured SBP during Week 12 of treatment post-randomization 
and the home measured SBP immediately prior to randomization. The primary analysis will be performed on 
the Randomized set including all participants who were randomized to treatment.  
 
Intercurrent events for the primary analysis are listed below: 
• 
Received the wrong treatment (i.e., a treatment other than the randomly assigned treatment) 
• 
IMP interruption for supply-related reasons 
• 
Up-titration at Week 6 was not performed for reasons not allowed by study protocol 
• 
Discontinuation from the study treatment for reasons related to the study protocol or study treatment 
(e.g., due to safety findings, adverse event, disease worsening, or lack of efficacy) 
 
For the primary analysis, the Treatment Policy Strategy will be applied where intercurrent events that do not 
result in missing BP measurements are considered irrelevant and data will be analyzed regardless of the 
occurrence of the event. The use of a Treatment Policy Strategy most closely aligns to an ITT analysis, where 
all available and imputed data contribute toward the estimated treatment effects. Participants with 
intercurrent events and missing data will have imputations performed from those participants with 
intercurrent events and non-missing data. (Section 3.10.2.7) Participants without intercurrent events and 
missing data will have imputations performed from those participants without intercurrent events and non-
missing data. 
 
The primary analysis will be performed using a mixed model with repeated measures (MMRM), including 
Week 6 and Week 12 assessments. A sensitivity analysis will be performed using the same methods applied 
to Week 12 home BP results only (Section 3.10.2.3). Additional sensitivity analyses adjusted for covariates are 
planned for the primary endpoint (Section 3.10.2.3). Subgroup analyses will also be performed among the 
primary analysis set (Section 3.10.2.6). 
 
Supplemental analyses will be performed among the following analysis sets: 
1) Full Analysis Set, including participants who have taken at least 1 dose of study treatment post-
randomization and applying imputation methods in the same manner as the primary analysis method 
(analysis to be performed if samples differ by >5%) 


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2) Randomized Set excluding participants with IMP interruptions for supply-related reasons 
3) Complete cases with Clinic BP Substitution: Participants with missing Baseline, Week 6, or Week 12 
Home BP assessments with Clinic BP recorded will have their clinic measured value substituted for the 
missing Home BP assessment at the respective visit. Any participants with missing Baseline or Week 
12 assessments without an in-clinic assessment at the designated visit will be excluded. 
4) Per Protocol Analysis Set: Excluding any participants with an intercurrent event or major protocol 
deviation. 
3.10.1.1 Secondary Estimands 
The population for the secondary estimands includes adults (aged ≥18 years) with hypertension. Participants 
in the trial will complete a 4-week single-blind active run-in on the experimental product GMRx2-Dose2 and 
then be randomized to treatment. The variables of interest are listed in Section 2.4.1.2.  
 
Hypothesis testing is not planned for secondary endpoints and, therefore, the results of the planned analyses 
are considered exploratory. Statistical analyses for continuous secondary endpoints will be performed on 
Complete Cases only. Statistical analyses for binary secondary endpoints will be performed on the Randomized 
Set, where participants with missing endpoints values will be assumed to have not achieved the endpoint (i.e., 
missing data will be singly imputed as “failure”). 
 


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Table 3-2 Estimands 
Estimand Label 
Treatment 
Comparison 
Population 
Population-level summary 
Analysis 
Population  
Handling of Intercurrent 
events 
Primary Analysis 
GMRx2 vs dual 
combinations 
at week 12 
Adults with 
hypertension 
 
 
Difference in change in home SBP, for 
GMRx2 vs each dual combination separately 
 
Analysis will be performed using Mixed 
Model with Repeated Measures (MMRM) 
with Multiple Imputation 
Randomized Set 
Treatment policy strategy 
with intercurrent events only 
used as part of missing data 
imputation strategy  
Primary Estimand, 
Sensitivity 
Analysis – Week 
12 only 
GMRx2 vs dual 
combinations 
at week 12 
Adults with 
hypertension 
 
 
Difference in change in home SBP, for 
GMRx2 vs each dual combination separately 
 
Analysis will be performed using Mixed 
Model with Repeated Measures (MMRM) 
with Multiple Imputation, Week 12 results 
only 
Randomized Set 
Treatment policy strategy 
with intercurrent events only 
used as part of missing data 
imputation strategy  
Primary Estimand, 
Sensitivity 
Analysis – 
Adjusted Analysis 
GMRx2 vs dual 
combinations 
at week 12 
Adults with 
hypertension 
 
 
Difference in change in home SBP, for 
GMRx2 vs each dual combination separately 
 
Analysis will be performed using Mixed 
Model with Repeated Measures (MMRM) 
with Multiple Imputation, adjusted for 
covariates 
Randomized Set 
Treatment policy strategy 
with intercurrent events only 
used as part of missing data 
imputation strategy  


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Estimand Label 
Treatment 
Comparison 
Population 
Population-level summary 
Analysis 
Population  
Handling of Intercurrent 
events 
Primary Estimand, 
Sensitivity 
Analysis – 
Subgroup Analysis 
GMRx2 vs dual 
combinations 
at week 12 
Adults with 
hypertension 
 
 
Difference in change in home SBP, for 
GMRx2 vs each dual combination separately 
 
Analysis will be performed using Mixed 
Model with Repeated Measures (MMRM) 
with Multiple Imputation, with interaction 
terms for specified subgroups 
Randomized Set 
Treatment policy strategy 
with intercurrent events only 
used as part of missing data 
imputation strategy  
Primary Estimand, 
Supplemental 
Analysis 
GMRx2 vs dual 
combinations 
at week 12 
Adults with 
hypertension 
Difference in change in home SBP, for 
GMRx2 vs each dual combination separately 
 
Analysis will be performed using MMRM 
with Multiple Imputation 
Full Analysis Set 
Treatment policy strategy 
with intercurrent events only 
used as part of missing data 
imputation strategy 
Primary Estimand, 
Supplemental 
Analysis 
GMRx2 vs dual 
combinations 
at week 12 
Adults with 
hypertension 
Difference in change in home SBP, for 
GMRx2 vs each dual combination separately 
 
Analysis will be performed using MMRM 
with Multiple Imputation 
Randomized Set 
excluding 
participants with 
IMP 
interruptions for 
supply-related 
reasons 
Treatment policy strategy 
with intercurrent events only 
used as part of missing data 
imputation strategy, 
excluding participants with 
IMP interruptions due to 
supply-related reasons 
Primary Estimand, 
Supplemental 
Analysis 
GMRx2 vs dual 
combinations 
at week 12 
Adults with 
hypertension 
 
 
Difference in change in home SBP, for 
GMRx2 vs each dual combination separately 
 
Analysis will be performed using MMRM 
with Clinic BP Substitution 
Randomized Set, 
Complete Cases 
with Clinic BP 
Substitution 
Treatment policy strategy 
with substitution of missing 
home BP assessments with 
clinic BP assessment values 
(participants missing both 
home and clinic BP values will 
be excluded from analysis) 


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Estimand Label 
Treatment 
Comparison 
Population 
Population-level summary 
Analysis 
Population  
Handling of Intercurrent 
events 
Primary Estimand, 
Supplemental 
Analysis 
GMRx2 vs dual 
combinations 
at week 12 
Adults with 
hypertension 
Difference in change in home SBP, for 
GMRx2 vs each dual combination separately 
 
Analysis will be performed using MMRM 
Per Protocol Set 
All participants with 
intercurrent events and 
major protocol deviations 
excluded from analysis 
Secondary 
Estimands, 
Continuous 
Endpoints 
GMRx2 vs dual 
combinations 
at specified 
timepoints 
Adults with 
hypertension 
Continuous Endpoints: Analysis will be 
performed using MMRM, Summary variable 
will be LS Means and LS Mean Difference 
 
 
Randomized Set 
Treatment Policy Strategy for 
intercurrent events with 
results reported. Complete 
cases only with no 
imputation for missing data. 
Secondary 
Estimands, 
Binary Endpoints 
GMRx2 vs dual 
combinations 
at specified 
timepoints 
Adults with 
hypertension 
Dichotomous Endpoints: Analysis will be 
performed using GEE, Summary variable will 
be Odds Ratios, Risk Difference, and 
corresponding confidence intervals (CIs) 
Randomized Set 
Treatment Policy Strategy for 
intercurrent events with 
results reported. Missing 
data will be imputed as 
“failure”. 
 


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3.10.2 
Primary Efficacy Analysis 
3.10.2.1 Definition – Home BP 
Home seated systolic and diastolic BP measurements will be averaged as described in Table 3-3 and the 
following endpoints will be derived: 
• 
Average home SBP during the 7 days prior to Randomization visit, Week 6 FU1 visit and Week 12 FU2 
visit 
• 
Average home DBP during the 7 days prior to Randomization visit, Week 6 FU1 visit and Week 12 FU2 
visit 
• 
Average trough (i.e. measurement taken before morning dose) home SBP during the 7 days prior to 
Randomization visit, Week 6 FU1 visit and Week 12 FU2 visit 
Note that trough will be assumed to be any BP measure taken in the morning, as participants are instructed 
to perform the BP measurement prior to taking their daily medication and to take that medication in the 
morning.  
Table 3-3 Definitions of Home Blood Pressure Derivations 
Measure 
Rules 
Randomization, week 6 and 
week 12 home BP 
• 
Defined as the home BP in the week before randomization, FU visit 
1 (scheduled at Week 6) and FU visit 2 (scheduled at Week 12), 
respectively. FU visits 1 and 2 may not occur exactly at 6 and 12 
weeks, respectively.  
Individual BP measurement 
• 
Each BP measurement must consist of valid SBP and DBP values. 
(i.e., SBP>60 mmHg and <250 mmHg and DBP>40mmHg and 
<150mmHg). If valid SBP and DBP are not recorded, the entire 
measure will be discarded.  
• 
Recommended home BP measurements were for 4 consecutive days 
immediately prior to the trial visits (i.e. Week -1, Week 5, Week 11) 
and on a single set day of the participant’s preference in other 
weeks. 
Grouping of measurements 
into sessions 
• 
Individual BP measurements must be grouped into 5-minute 
“sessions”. 
• 
To group individual BP measurements into sessions, the start of a 5-
minute period is at the time of the first measurement with all BP 
measurements in those 5 minutes being assigned to the single 
session.  
• 
A new session starts at the first BP measure encountered after the 
completion of an existing session.  
• 
If more than two measures are captured in a session then, as with 
three measures, the second and third measures with be flagged for 
use. The first and any measures after the third are ignored.  
• 
In the case of fewer than three BP measures in a session, all 
measures will be flagged for use.  
Selection of a single session 
per half-day period 
 
 
• 
Each day is divided into two half-days – AM and PM.  
• 
If more than one session occurs in one period e.g., two sessions in 
the AM period of a given day, one session only will be selected for 
use using two prioritisation steps: 


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- Sessions containing three or more BP measures will be 
prioritised over those with two. Those with only one BP measure 
will be used as a last resort.  
- If the first step does not uniquely select one session for the 
period, the earliest session of those selected in the first step will 
be used.  
Calculation of averages 
• 
To calculate an average, perform a simple, unweighted mean of the 
flagged BP measurements in the selected sessions for the period of 
interest.  
- At Randomization: A minimum of 6 measures (e.g. ≥2 sets of 
triplicate measures or ≥3 sets of duplicate measures) are 
expected, including at least 1 morning and 1 evening, each with 
≥2 measures per protocol-specified eligibility criteria. 
- Post-Randomization: At least 4 consecutive calendar days (8 
measurement sessions, 24 BP readings) were recommended. 
- Calculations: For all timepoints, calculations of averages will be 
performed if there is at least 1 valid BP measurement. 
• 
The home BP values for the purpose of Baseline, FU visit 1 Week 6 
and FU visit 2 Week 12 are averages (as defined above) across up to 
7 calendar days immediately preceding each in-clinic visit.  
- Each of the up to 2 selected sessions per day (1 morning and 1 
evening) may be included in the calculation.  
- Days with no valid measures reported will be excluded from the 
calculation (i.e., only days with SBP measurements recorded will 
be included in average). 
 
In addition, for descriptive plots of SBP and DBP measurements post-randomization, weekly average BP will 
be computed where Week is defined in relation to the randomization date with Week 1 initiating on Day 1, 
the first treatment with randomized trial medication:  
𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊 = (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝐵𝐵𝐵𝐵 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 –  𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡)/7 
Week is rounded up to the nearest integer. Averages will otherwise be calculated in the same manner as 
described in Table 3-3. 
3.10.2.2 Main Analysis 
Blood pressure values will be summarized using descriptive statistics, including actual values and changes from 
baseline to Week 6 and Week 12, by timepoint and treatment groups. Graphical presentations of group means 
over time will be presented. Summaries will be presented on the Safety Set by Randomization Status and 
Randomization Set. Additional summaries may be presented. 
 
The difference in change of home SBP from Baseline to Week 12 will be analyzed using a MMRM. The outcome 
will be the post-Baseline home SBP values with fixed effects for treatment group, time (visit as categorical 
variable), treatment by time (visit) interaction, and Baseline home SBP. The variance will be estimated using a 
Huber-White sandwich estimator and the model will account for correlation within participant and within site. 
An unstructured covariance matrix for within participant observations will be used with fall-backs to first a 
compound symmetry (exchangeable) matrix and finally an independent matrix if the model does not converge. 
A compound symmetry covariance matrix will account for correlation within site with a fall back of an 
independent matrix if the model does not converge. Least Square Means and corresponding standard errors 
will be estimated for each post-Baseline visit and treatment group. Pairwise comparisons between GMRx2 and 
dual treatments will be performed at Week 6 and Week 12. The comparisons at Week 12 will serve as the 


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primary endpoints analysis.  
 
Sample SAS Code: 
PROC MIXED DATA = ADEFF EMPIRICAL METHOD = REML; 
      CLASS SITEID SUBJID VISIT TRTP; 
      MODEL AVAL = BASE VISIT TRTP VISIT*TRTP / CL; 
      REPEATED VISIT SUBJID / SUBJECT = SITEID TYPE = UN@CS; 
      WHERE VISIT IN ('WEEK6','WEEK12'); 
      LSMEANS VISIT*TRTP / DIFF CL ALPHA=0.05; 
      RUN; 
 
Where ADEFF is the ADaM dataset for efficacy, AVAL represents the Week 6 or Week 12 home SBP 
measurement, BASE is the Baseline value, VISIT is the visit (Week 6 or Week 12), TRTP is the planned 
treatment, and VISIT*TRTP is the interaction between visit and planned treatment. 
 
Superiority of the triple combination over the dual combinations will be shown if the 3 comparisons listed 
above are statistically significant (when the null hypothesis of equal adjusted means is rejected).  
 
The main analysis of the primary endpoint will be performed using multiple imputation to account for missing 
data (Section 3.10.1.1; Section 3.10.2.7).   
 
Supportive analyses will be performed on: 
1) The Full Analysis Set (if the analysis set differs from the Randomized set by at least 5%) using the same 
multiple imputation rules as the primary analysis 
2) The Randomized set excluding participants with IMP interruptions for supply-related reasons using 
the same multiple imputation rules as the primary analysis 
3) Complete Cases with Clinic BP Substitution 
4) Per Protocol Set using no imputations 
3.10.2.3 Sensitivity Analysis at Week 12 Only 
The primary analysis methods (Section 3.10.2.2) will be repeated including Week 12 only (excluding Week 6 
from the MMRM). The variance will be estimated using a Huber-White sandwich estimator and the model will 
account for correlation within site. The handling of intercurrent events and imputation methods will be the 
same as the primary analysis. 
 
Sample SAS Code: 
PROC MIXED DATA = ADEFF EMPIRICAL METHOD = REML; 
      CLASS SITEID SUBJID TRTP; 
      MODEL AVAL = BASE TRTP / CL; 
      REPEATED SUBJID / SUBJECT = SITEID TYPE = CS; 
      WHERE VISIT IN ('WEEK12'); 
      LSMEANS TRTP / DIFF CL ALPHA=0.05; 
      RUN; 
3.10.2.4 Sensitivity Analysis Pooled Control 
The primary analysis methods (Section 3.10.2.2) will be repeated comparing GMRx2 to a pooled control group, 
inclusive of all three dual control treatment groups. The imputation from the primary analysis and primary 
analysis methods will otherwise remain unchanged. 
3.10.2.5 Adjusted Analyses 
Adjusted analyses will be performed as a sensitivity analysis by adding (as a group of variables) the following 


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covariates: age (continuous), sex, race, BMI category, diabetes, and number of treatments at screening. The 
adjusted treatment effect will be reported as the adjusted mean difference and 95% CI.  
3.10.2.6 Subgroup and Additional Analyses 
Pre-specified subgroup analyses will be carried out irrespective of whether there is a statistically significant 
treatment effect on the primary endpoint. Subgroups are defined as follows: 
• 
Sex (Male; Female) 
• 
Age (<55; 55-65; > 65 years)  
• 
Race (black; non-black) 
• 
BMI (<30,>=30 kg/m2) 
• 
Diabetic; non-diabetic 
• 
Region (US; Other) 
• 
Baseline (at Randomization) home SBP category (<130, 130-139, >=140 mmHg) 
• 
Number of BP medications at Screening (0, 1, 2, 3) 
• 
Hypertension status at Screening – office BP <140/90 mmHg, ≥140/90 mmHg; office BP <130/80 
mmHg, ≥130/80 mmHg 
• 
Orthostatic hypotension at Randomization (measured at clinic BP): see Section 3.10.3.2 for definitions.  
 
Subgroup analyses will be performed by inclusion of the subgroup main effect as well as two- and three-way 
interaction terms as fixed effects with visit and treatment within the MMRM.  Heterogeneity of treatment 
effect between subgroups will be evaluated using contrast statements, to test whether the LS Mean difference 
between GMRx2 and each dual control treatment group differs between levels of the subgroup. Comparisons 
will be performed separately for each dual control treatment group. A comparison of GMRx2 against a 
combined dual control treatment group will also be performed. Assessments of heterogeneity will be 
performed at Week 6 and Week 12 timepoints. LS Means, LS Mean Differences between GMRx2 and dual 
control treatment groups and 95% CIs will be reported for each category of subgroup. If any subgroup does 
not have sufficient participants for statistical modelling (i.e., model convergence), descriptive statistics will be 
provided. A forest plot will also be provided to visualize the subgroup analysis.   
 
Sample SAS Code accounting for Sex as Subgroup: 
PROC MIXED DATA = ADEFF EMPIRICAL METHOD = REML; 
      CLASS SITEID SUBJID VISIT TRTP SEX; 
      MODEL AVAL = BASE VISIT|TRTP|SEX / CL; 
      REPEATED VISIT SUBJID / SUBJECT = SITEID TYPE = UN@CS; 
      WHERE VISIT IN ('WEEK6','WEEK12'); 
      LSMEANS VISIT*TRTP*SEX / DIFF CL ALPHA=0.05; 
      lsmestimate VISIT*trtP*sex "(VTS211-VTS221)-(VTS212-VTS222)"  
        [1, 2 1 1] [-1, 2 2 1] [-1, 2 1 2] [1, 2 2 2]; *TRTP=1 vs TRTP=2; 
      lsmestimate VISIT*trtP*sex "(VTS211-VTS231)-(VTS212-VTS232)"  
        [1, 2 1 1] [-1, 2 3 1] [-1, 2 1 2] [1, 2 3 2]; *TRTP=1 vs TRTP=3; 
      lsmestimate VISIT*trtP*sex "(VTS211-VTS241)-(VTS212-VTS242)"  
        [1, 2 1 1] [-1, 2 4 1] [-1, 2 1 2] [1, 2 4 2]; *TRTP=1 vs TRTP=4; 
      RUN; 
 
There is clinical interest in the effects of BP lowering by time of day, particularly trough BP in the morning. The 
telemonitored home BP devices provide a timestamp of each BP measurement taken. Additional analyses will 
be completed analysing difference between study arms of home SBP by AM and PM time periods. 
 
The clinical use of GMRx2 is expected to involve use in participants who were previously on 0-3 medications. 


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As such, a graphical descriptive analysis of blood pressure changes during run-in on GMRx2 will be presented 
separately for different blood pressure regimens participants were receiving at screening, noting participants 
could be on 0-3 antihypertensives at the time, before being switched to GMRx2-dose 2. Additional descriptive 
analyses will be conducted according to hypertension control status and number of antihypertensives at 
screening. 
3.10.2.7 Treatment of Missing Data 
For the primary endpoint requiring a valid weekly average home BP value preceding the Randomization and 
Week 12 visits, if a participant does not have a valid endpoint measure, that value will be flagged as missing 
and requiring imputation. Imputation will also be performed for missing Week 6 results. In all cases it is the 
BP weekly average that will be imputed for each time interval, not each component measure used to calculate 
the average. Imputations will be performed separately by analysis set, as required (i.e., Randomized Set, Per 
Protocol). 
 
For missing Baseline (prior to Randomization) SBP results, missing data are considered missing at random and 
a multiple imputation will be applied.  
 
For post-Randomization missing data, a Retrieved Data Multiple Imputation will be applied to account for the 
occurrence of intercurrent events which aligns to the Treatment Policy Strategy for handling of Intercurrent 
Events:  
1) Participants with missing Baseline measurements will be assumed to have data missing at random and 
will have results imputed from the full baseline sample of participants (pre-randomization). 
2) Participants with missing Week 6 or Week 12 home BP assessments and experiencing intercurrent 
events will have their result imputed for the primary analysis using multiple imputation. Participants 
with intercurrent events will have their missing result based on other participants with intercurrent 
events within the same treatment group.  
a. Receive Wrong Treatment: 
i. Participants who received the wrong treatment and have missing Week 12 results will 
have results imputed from the sample of participants who received the same 
treatment they received during Period 3. The participants will be grouped as 
randomized for the primary analysis. 
ii. Participants who received the wrong treatment and have missing Week 6 results will 
have results imputed from the sample of participants who received the same 
treatment they received during Period 2. The participants will be grouped as 
randomized for the primary analysis. 
b. Participants with IMP interruption for supply-related reasons will have missing Week 6 or 
Week 12 results imputed from the sample of participants with intercurrent events and 
assigned the same randomized treatment. 
c. Participants with missing Week 12 who do not have up-titration at Week 6 will have results 
imputed from the sample of participants randomly assigned to the same treatment and have 
an intercurrent event. Week 6 results will be used to impute the Week 12 timepoint.  
d. Participants who discontinue treatment for reasons related to study treatment or study 
procedures will be imputed using a control-based imputation from the sample of participants 
with intercurrent events and randomly assigned to one of the control groups (AI, TA, TI). 
2) Participants non-adherent to study treatment: 
a. Participants who were non-adherent to study treatment during Period 2 with missing Week 6 
home BP measurement will be imputed from the sample of participants with intercurrent 
events and randomly assigned to one of the control groups (AI, TA, TI).  
b. Participants who were non-adherent to study treatment during Period 3 with missing Week 


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12 home BP measurements will be imputed from the sample of participants with intercurrent 
events and randomly assigned to one of the control groups (AI, TA, TI). 
3) Participants with missing Week 6 or Week 12 home BP assessments who were adherent to study 
treatment and did not experience intercurrent events will have their results imputed for the primary 
analysis using multiple imputation. Participants without intercurrent events will have their missing 
result based on other participants also without intercurrent events and within the same treatment 
group. 
If there is not a sufficient sample size to perform multiple imputations as described, participants with and 
without intercurrent events will be included in the source sample for imputation. 
 
Multiple imputation (MI) will be applied, replacing each missing average SBP home assessment with a set of 
plausible values from the identified subsample, listed above. This will represent the uncertainty of the correct 
value based on the observed results. The multiply imputed datasets will be analyzed using standard 
procedures for complete data with their results combined with a variance-adjustment. The multiple 
imputation will be computed as follows: 
1) Imputation: 
a. For missing baseline, a regression method will impute missing data from the overall 
randomized sample. 
b. For missing Week 12 SBP results, a regression method will impute missing data from the 
respective subsample with or without intercurrent events, as specified above, and within the 
respective treatment group. Imputation will be performed using a Fully Conditional 
Specification (FCS) model using the regression method and will include the following factors: 
• 
Age, sex, race, BMI, and ethnicity 
• 
Patient smoking and alcohol consumption 
• 
Baseline (at Randomization) average home SBP, Week 6 average home SBP 
2) Analyzing: The final multiple imputed datasets will be analyzed using Ruben’s Rule. 
Proc MI and Proc MIANALYZE in SAS will be used to generate the datasets and run the analyses. 
Sample SAS Code: 
PROC MI DATA = SBP OUT = SBP2 SEED = 20231010 NIMPUTE = 100 
     MINIMUM = . . . . . . . 80 80 80  
ROUND = . . . . . . . . . . 1 1 1 
     MAXIMUM = . . . . . . . 200 200 200  MINMAXITER = 5000 SIMPLE NOPRINT; 
     FCS REG (BASE = TRTPN AGE SEX RACE BMI ETHNIC SMK ALC/ DETAILS); 
     FCS REG (SBP6 = TRTPN AGE SEX RACE BMI ETHNIC SMK ALC BASE/ DETAILS) 
     FCS REG (SBP12 = TRTPN AGE SEX RACE BMI ETHNIC SMK ALC BASE SBP6/  
              DETAILS) 
     CLASS TRTPN SEX RACE ETHNIC SMK ALC; 
     VAR TRTPN AGE SEX RACE BMI ETHNIC SMK ALC BASE SBP6 SBP12; 
     RUN; 
*SBP2 will be reformatted into an analysis dataset, here titled ADEFF with 
each observation is on a separate line; 
*Note that in actual implementation, the imputations will be done separately 
for those with intercurrent events and those without intercurrent events. 
Note also that baseline values will be imputed from all observations; 
 
PROC MIXED DATA = ADEFF EMPIRICAL METHOD = REML; 
      BY IMPUTNUM; 
      CLASS SITEID SUBJID VISIT TRTP; 
      MODEL AVAL = BASE VISIT TRTP VISIT*TRTP / CL; 
      REPEATED VISIT SUBJID / SUBJECT = SITEID TYPE = UN@CS; 


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      WHERE VISIT IN ('WEEK6','WEEK12'); 
      LSMEANS VISIT*TRTP / DIFF CL ALPHA=0.05; 
      ODS OUTPUT COVPARMS = CP LSMEANS = LSM DIFF = DIFFS; 
      RUN; 
PROC SORT DATA = DIFF;  
     BY TRTP _TRTP VISIT _VISIT; 
     RUN; 
PROC MIANALYZE DATA = DIFF ALPHA = 0.05; 
     BY TRTP _TRTP VISIT _VISIT; 
     WHERE TRTP = 1 AND _TRTP NE 1 AND VISIT = _VISIT; 
     *TRTP = 1 corresponds to GMRx2 in this example; 
     MODELEFFECTS ESTIMATE; 
     STDERR STDERR; 
     ODS OUTPUT PARAMETERESTIMATES=SBP_PROP; 
     RUN; 
 
TRTPN is the planned treatment group, SEX is the sex of the participant, RACE is participant race, ETHNIC is 
participant ethnicity, SMK is participant smoking status, ALC is alcohol use. BASE is the baseline (at 
Randomization) average SBP value, SBP6 is the average SBP value at Week 6 (Visit 1), and SBP12 is the average 
SBP value at Week 12 (Visit 2). The minimum and maximum values for SBP imputation may be modified 
according to the observed minimum and maximum within the sample. If the multiple imputation models 
cannot converge, model reduction (excluding covariates) may be performed. 
 
For binary endpoints with missing results, a single value imputation of “failure” will be performed for analysis 
(Section 3.10.1.1). 
3.10.2.8 Tipping point analysis 
If the primary analysis is statistically significant in favor of GMRx2, a MI tipping point analysis may be 
performed in the Randomized Population to assess the impact of missing data under the assumption that data 
are not missing at random. A two-dimensional tipping point analysis will be performed where the trajectories 
of participants in the GMRx2 treatment group with missing Week 12 data will be imputed separately from the 
trajectories from the active control treatment groups with missing Week 12 data. A shift parameter, delta, will 
be added to each imputed value. The three active control treatment groups will be imputed with a shift of 0. 
The shift parameter applied to the GMRx2 treatment group will be applied across a range of values. 
Successively larger deltas will be imposed on the imputed values of GMRx2 treatment group until statistical 
significance is lost, i.e. two-sided p-value is >0.05 and no longer in favor of GMRx2 for at least one of the 
pairwise comparisons.  
3.10.2.9 Descriptive figures 
The following graphical displays are planned: 
• 
Plot of the LS Mean home SBP with 95% CI derived from the MMRM for the primary analysis will be 
presented.  
• 
Results from the tipping point analysis will be presented graphically. 
• 
Forest plots of the LS Means, 95%CI and p-values for determining heterogeneity by subgroup will be 
presented. 
• 
Descriptive scatter plots to display the average weekly SBP post-randomization, where Week 1 begins 
at first treatment post-randomization, Week 2 begins at Day 8 of treatment post-randomization, etc.  
• 
Descriptive scatter plots to display the change in average weekly SBP from randomization through the 
Randomization Period. Randomization will be defined as the 7 calendar days prior to the 
Randomization clinic visit (Table 3-3). The Randomization Period will begin on the first day of 
randomized treatment and will extend until the earliest of: Week 12 visit, End of Study visit, or 14 


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weeks of post-randomized BP home measurements. 
• 
Descriptive scatter plots to display the change in average weekly SBP from end of Phase 2/FU1 visit 
through Period 3. End of Phase 2/FU1 visit will be defined as the 7 calendar days prior to the FU1 Week 
6 clinic visit (Table 3-3). Period 3 will begin on the first day of treatment following FU1 Week 6 clinic 
visit and will extend until the earliest of: Week 12 visit, End of Study visit, or 7 weeks of Period 3 BP 
home measurements. 
Scatter plots may be presented for the treatment groups overall as well as by subgroups, as appropriate. 
Similar plots may be presented for home DBP, as appropriate. 
3.10.3 
Analysis of Secondary Efficacy Outcomes 
3.10.3.1 Home Blood Pressure  
Analysis of home SBP and DBP secondary continuous endpoint analysis on change from baseline 
(randomization) will be performed on Complete Cases only, including all data available. Summary statistics, 
including number with missing observations, at each timepoint will be presented. Mixed models with repeated 
measures (MMRM) will be applied for continuous variables using the same approach as the primary endpoint 
(with no imputations applied).  
• 
Difference in change in mean home SBP from randomization to Week 6, 
• 
Difference in change in mean home DBP from randomization to Week 12, 
• 
Difference in change in mean home DBP from randomization to Week 6, 
• 
Difference in change in trough (i.e. before morning dose) home mean SBP from randomization to 
Week 12, 
• 
Difference in change in trough (i.e. before morning dose) home mean SBP from randomization to 
follow-up Week 6 
Additional exploratory analyses, including longitudinal models for all home SBP measurements collected 
during Week 6 and Week 12 may be performed. 
 
Descriptive summaries of binary endpoints will include the number and percentage of participants with 
controlled BP, i.e.: 
• 
weekly averaged SBP <135 and DBP <85 mmHg at Week 12, 
• 
weekly averaged SBP <135 and DBP <85 mmHg at Week 6, 
• 
weekly averaged SBP <130 and DBP <80 mmHg at Week 12, 
• 
weekly averaged SBP <130 and DBP <80 mmHg at Week 6 
Frequency of missing data will be reported. 
 
Data will be summarized as reported, including only complete cases. Estimated proportions by treatment 
groups with exact Clopper-Pearson 95% CI will be presented along with the associated estimated risk 
difference, risk ratio, and corresponding p-values. The number and percentage with 95% CI of participants 
with controlled BP at Week 12 will be summarized by treatment group by: 
• 
Number of prior therapies at enrolment  
• 
Controlled or uncontrolled BP status at Randomization 
 
Binary secondary endpoints will be analyzed using Generalized Estimating Equations (GEE) to account for 
repeated measures. For the regression analysis, participants with missing endpoint data (Week 6 or Week 12) 
will be imputed as “failure” at the respective timepoint(s). The GEE regression analyses will be performed on 
the Randomized Set. The outcome will be the post-Baseline occurrence of the event at Week 6 and Week 12 
with fixed effects for treatment group, time (visit as categorical variable), treatment by time (visit) interaction, 


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and Baseline home SBP. The variance will be estimated using a sandwich estimator and the model to account 
for correlation within participant and within site. A compound symmetry covariance matrix will account for 
correlation within participant and site, with a fall back of an independent matrix if the model does not 
converge. The odds ratios and 95% CIs for the occurrence of the events will be estimated for each post-
Baseline visit and treatment group. In addition, risk differences and 95% CI will be computed for each post-
Baseline visit to evaluate pairwise differences between GMRx2 and dual treatments at Week 6 and Week 12.  
 
Sample SAS Code: 
PROC GENMOD DATA = ADEFF; 
     CLASS SITEID SUBJID VISIT TRTP; 
     MODEL AVAL = BASE VISIT TRTP VISIT*TRTP / DIST = BIN CL; 
     REPEATED SUBJECT = SUBJID(SITEID) / TYPE = EXCH; 
     WHERE VISIT IN ('WEEK6','WEEK12'); 
     LSMEANS VISIT*TRTP / DIFF CL ALPHA=0.05; 
     RUN; 
Risk differences and 95%CI for comparisons between the occurrence of events in GMRx2 group versus each 
dual control will be computed using the Predictive Margins and Average Marginal Effects SAS Macro 
(https://support.sas.com/kb/63/038.html). Sample SAS code with implementation to simulated data is 
provided in Appendix 4.  
3.10.3.2 In Clinic Blood Pressure  
At each scheduled trial visit, triplicate BP measurements will be performed “in clinic” after 5 minutes of seated 
rest and with a 1-minute interval between measurements. The last two measurements will be averaged. If 
only two measures were taken, both will be averaged, and if only 1 measure is taken that value will be used. 
The Baseline value for clinic BP measurement is the value recorded at Randomization.  
 
As per the home BP measurements, any zero SBP or DBP values will be treated as missing. 
 
In clinic BP endpoints are listed below: 
• 
Difference in change in clinic seated SBP from randomization to Week 12, 
• 
Difference in change in clinic seated SBP from randomization to Week 6, 
• 
Difference in change in clinic seated DBP from randomization to Week 12, 
• 
Difference in change in clinic seated DBP from randomization to Week 6, 
• 
Percentage of participants with clinic seated SBP <140 and DBP <90 mmHg at Week 12, 
• 
Percentage of participants with clinic seated SBP <140 and DBP <90 mmHg at Week 6, 
• 
Percentage of participants with clinic seated SBP <130 and DBP <80 mmHg at Week 12, 
• 
Percentage of participants with clinic seated SBP <130 and DBP <80 mmHg at Week 6,  
• 
Percentage of participants with orthostatic hypotension at Week 6, 
• 
Percentage of participants with orthostatic hypotension at Week 12 
• 
Percentage of participants with orthostatic hypertension at Week 6, 
• 
Percentage of participants with orthostatic hypertension at Week 12 
 
Orthostatic hypotension is defined as a decrease from measured in clinic sitting to standing blood pressure of 
≥20 mmHg SBP or ≥10 mmHg DBP. Orthostatic hypertension is defined as an increase from measured in clinic 
sitting to standing blood pressure of ≥20 mmHg SBP or ≥10 mmHg DBP.  
 
Descriptive statistics will be used to summarize secondary endpoints by visit on complete cases only. 


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Continuous endpoints will be summarized using descriptive statistics. Binary endpoints will be summarized 
with frequency and proportions by treatment group with exact Clopper-Pearson 95% CIs along with associated 
estimated risk difference, risk ratio, and corresponding p-values. Frequency of missing data will be presented. 
 
Mixed models with repeated measures (MMRM) will be applied for continuous endpoints using the same 
approach as the primary endpoint (with no imputations applied). Results will be presented in a similar fashion 
as home BP. Standing clinic BP measurements will be summarised descriptively by visit. Complete case analysis 
will be performed with no imputations for continuous endpoints. 
 
Binary secondary endpoints will be analyzed using GEE regression methods in the same manner as home BP 
endpoints. Risk differences and 95% confidence intervals will be computed for comparisons between GMRx2 
and dual control treatments. Missing values at Week 6 and Week 12 will be imputed as “failures” for the 
analysis. 
3.11 Analysis of Safety Outcomes 
3.11.1 
Adverse Events of Special Interest 
3.11.1.1 Definitions & Derivations 
An Adverse Event (AE) is any undesirable medical event occurring to a subject in a clinical trial, whether or not 
related to the trial medications.  
 
Drug-related AEs are AEs with a causality to drug being possibly, probably, definitely related or with a missing 
causality. 
 
The only non-serious Adverse Events to be recorded are Adverse Events of Special Interest (AESIs). An AESI is 
the subset of AEs that are due to: 
• 
Dizziness or any other symptom or event possibly related to hypotension, 
• 
Abnormality detected in laboratory assessments of sodium, potassium, uric acid, glucose, lipids, 
creatinine or eGFR, 
• 
Symptom of pedal edema reported by the participant, 
• 
Any other symptom or laboratory abnormality that led to treatment withdrawal. 
AESI include events occurring during Run-in, Randomization Period, and Follow-up.  
 
A Serious Adverse Event (SAE) is any AE that meets one or more of the following criteria: 
• 
Results in death; 
• 
Is life-threatening; 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
 
AESIs and SAEs will be recorded from time of informed consent up to 30 days after trial medication 
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3.11.1.2 Adverse Event Summaries 
For the summary of safety parameters, AEs will be classified according to the treatment period and treatment 
received as of the start date of the AE (Section 3.5.3). If an AE is ongoing at the time of randomization, it will 
be allocated to the Period 1 treatment. If a treatment ongoing at randomization worsens following 
randomization, the AE worsening will be allocated to the Period 2 treatment.  
 
AESIs and SAEs will be classified according to the MedDRA (Medical Dictionary for Regulatory Activities) system 
(version 24.0, March 2021) and summarized by system organ class and preferred term.  
 
Treatment periods for AE summary include: Period 1, Period 2, Period 3, Randomization Period, and Period 4. 
The total number of events and incidence of participants experiencing AESIs will be tabulated by treatment 
group and overall for the specified study periods. 
 
For each period, any AESI or SAEs that emerges or worsens during the period of interest will be summarized: 
• 
Adverse Events of Special Interest, 
• 
Serious AE, 
• 
Related AESIs – defined as those judged by the investigator to be ‘possibly’, ‘probably’ or ‘definitely’ 
related 
• 
Related SAEs – defined as those judged by the investigator to be ‘possibly’, ‘probably’ or ‘definitely’ 
related, 
• 
AE leading to trial medication discontinuation 
• 
AE leading to trial discontinuation – defined as a request by the participant to withdraw from future 
follow-up visits 
 
AESIs of abnormality detected in laboratory assessments for Period 1 will only include those whose lab value 
for that parameter was in the normal range at baseline. Summaries of AESI and SAEs occurring during the 
Randomized Period will include risk differences with 95% CI, computed using the Newcombe hybrid score 
method (with continuity correction; https://pubmed.ncbi.nlm.nih.gov/21996567/), to evaluate GMRx2 
against each dual control treatment group and overall. System organ classes and preferred terms with events 
occurring in at least 1% of the sample will be included. 
 
In addition, the frequency and percentage of participants discontinuing treatment due to an AE will be 
reported with risk differences between treatment groups computed using the Newcombe hybrid score 
method (with continuity correction) to evaluate the primary safety endpoint among GMRx2 treatment 
participants compared to each dual control treatment group, and overall. 
3.11.2 
Laboratory Parameters: Hematology, Biochemistry & Urine 
Blood hematology, biochemistry and urine parameters will be collected according to the schedule of events. 
Only scheduled visit results will be presented in summary tabulations. Unscheduled visits will be included in 
data listings only. The baseline value for each parameter will be the latest non-missing value recorded before 
randomization (i.e., prior to Period 2). 
 
Estimated Glomerular Filtration Rate (eGFR) results provided by the various pathology laboratories across 
study may be calculated by different equations; however any differences are expected to be balanced across 
randomized treatment groups and no adjustments will be made.  
 
Actual values and changes from baseline for all laboratory parameters will be descriptively summarized by 


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treatment group. A subset by-participant listing of out-of-range values will be presented. 
 
In addition, tabular descriptive summaries will present the number and percentage of participants at Week 6 
and 12 with: 
• 
serum sodium concentration below 135 mmol/l  
• 
serum sodium concentration above 145 mmol/l  
• 
serum potassium concentration below 3.5 mmol/l  
• 
serum potassium concentration above 5.5 mmol/l  
• 
serum sodium <135mmol/l or >145 mmol/l, and/or serum potassium <3.5 mmol/l or >5.5mmol/l at 
week 6 
• 
serum sodium <135mmol/l or >145 mmol/l, and/or serum potassium <3.5 mmol/l or >5.5mmol/l at 
week 12 
• 
eGFR (estimated GFR) drop of over 30% from baseline  
 
Frequencies and proportions, including frequency of missing data will be presented. Risk differences with 95% 
CI, computed using the Newcombe hybrid score method (with continuity correction), to evaluate GMRx2 
against each dual control treatment group will be performed. The analysis of binary secondary safety 
endpoints will be performed on the Safety Analysis Set, limited to those participants who were randomized. 
Participants will be grouped as treated. 
3.11.3 
Other Safety Analysis 
Weight and BMI will be summarized descriptively using at actual values and changes from baseline by 
treatment groups. 
 
 
 


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4 REFERENCES 
1. Holm S. A Simple Sequentially Rejective Multiple Test Procedure. Scandinavian Journal of Statistics 
1979; 6: 65-70. 
2. Moher D, Schulz KF, Altman D. The CONSORT statement: revised recommendations for improving the 
quality of reports of parallel-group randomized trials. JAMA 2001; 285: 1987-91. 
3. van Buuren, S. Multiple imputation of discrete and continuous data by fully conditional specification, 
Stat Meth Med Res 2007; 16: 219-242. 
4. Nevalainen J, Kenward MG, Virtanen SM. Missing values in longitudinal dietary data: a multiple 
imputation approach based on a fully conditional specification. Statistics in Medicine. 2009; 28(29): 
3657-3669.  
5. Huque, MH, Carlin, JB, Simpson, JA et al. A comparison of multiple imputation methods for missing 
data in longitudinal studies. BMC Med Res Methodol. 2018; 18(168). 
6. Jakobsen, JC, Gluud, C., Wetterslev, J. et al. When and how should multiple imputation be used for 
handling missing data in randomised clinical trials – a practical guide with flowcharts. BMC Med Res 
Methodol. 2017; 17(162).  
7. Sullivan TR, White IR, Salter AB, Ryan P, Lee KJ. Should multiple imputation be the method of choice 
for handling missing data in randomized trials? Statistical Methods in Medical Research. 2018; 27(9): 
2610-2626. 
8. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH). Addendum on estimands and sensitivity analysis in clinical trials to the guideline on 
statistical 
principles 
for 
clinical 
trials 
E9(R1); 
2019. 
Available 
from: 
https://database.ich.org/sites/default/fles/E9-R1 Step4 Guideline 2019 1203.pdf. Accessed 1 Feb 
2023. 
9. Webster R, Salam A, De Silva HA, et al. Fixed low-dose triple combination antihypertensive medication 
vs usual care for blood pressure control in patients with mild to moderate hypertension in Sri Lanka: 
a randomized clinical trial. JAMA 2018; 320(6): 566-79. 
10. Chow CK, Atkins ER, Hillis GS, et al. Initial treatment with a single pill containing quadruple 
combination of quarter doses of blood pressure medicines versus standard dose monotherapy in 
patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial. 
The Lancet 2021; 398(10305): 1043-52. 
 
 




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Appendix 2: Additional Power Calculations 
As noted in Section 2.5, the initial power calculation presented is a very conservative calculation, which is 
based on a simple comparison of mean values and a common standard deviation of the actual SBP values i.e., 
T-test of sample means with equal variances. Our modelling approach – a multivariable mixed model – is 
similar to an ANCOVA (Analysis of Covariance) type of analysis which will explicitly consider an adjustment for 
the baseline SBP values. A sample size calculation based on the ANCOVA (which would be more powerful than 
the simple and more conservative t-test approach used above) and on the same assumption as before 
(allocation ratio of 2:1 of GMRx2 vs dual, alpha 0.05, equal SD across arms of 11) would lead to the following 
power: 98% if regressing the SBP values to the specific covariate set the R2 (proportion of variance explained) 
achieved is 10%, 99% if R2 is 20%, 99.6% if R2 is 30% with overall power respectively 95%, 97% and 99%. These 
R2 values were considered to be conservative, since two similar, completed BP trials (TRIUMPH and QUARTET) 
each had R2 values over 40% in mixed models on SBP data using treatment, time, their interaction and SBP at 
baseline and compared with the null model. 
 
Supply chain and logistics issues, substantial recruitment delays related to the COVID-19 pandemic and other 
unanticipated issues caused unplanned and significant trial conduct interruptions. As a result of these delays, 
a re-supply of IMP became infeasible. In addition, there had been independent review of study power at two 
Steering Committee meetings (6 Dec 2022 and 14 Feb 2023), based on the prespecified statistical approach of 
a mixed model repeated measures and blinded standard deviation of the overall sample, that the trial likely 
would have more statistical power than the univariate approach on which initial powering was modelled, as 
detailed above. These estimates were made without any reference to unblinded data.  The Sponsor informed 
the Steering Committee of the pending IMP supply situation at their meeting on 11 April 2023, and given these 
challenges and blinded study power assessment that indicated the trial already had as much power as 
originally planned, the Steering Committee chair consulted the Data Safety Monitoring Board. Following 
deliberation between the two committees, the Steering Committee Chair wrote to the Sponsor on 21 April 
2023 recommending a premature termination of recruitment. Based on the foregoing, the Company decided 
to terminate recruitment to the study. The final number of patients randomized was over 90% of the planned 
sample size. 
 
 
 






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Appendix 4: Predictive Margins and Average Marginal Effects Macro and Implementation 
SAS documentation on the Predictive Margins and Average Marginal Effects SAS Macro is available here: 
https://support.sas.com/kb/63/038.html. 
 
Sample implementation code using simulated data: 
data test; 
 
do i = 1 to 300; 
 
trtpn = 1; 
 
week = 1; 
 
 
x1 = rand('UNIFORM'); 
 
 
if x1 > 0.3 then resp = 1;  
 
 
else resp = 0; 
 
 
output; 
 
week = 2; 
 
 
x1 = rand('UNIFORM'); 
 
 
if x1 > 0.4 then resp = 1;  
 
 
else resp = 0; 
 
 
output; 
 
 
 
end; 
 
do i = 301 to 600; 
 
trtpn = 2; 
 
week = 1; 
 
 
x1 = rand('UNIFORM'); 
 
 
if x1 > 0.4 then resp = 1;  
 
 
else resp = 0; 
 
 
output; 
 
week = 2; 
 
 
x1 = rand('UNIFORM'); 
 
 
if x1 > 0.5 then resp = 1;  
 
 
else resp = 0; 
 
 
output; 
 
 
 
end; 
 
run; 
 
proc freq data = test; 
 
table week*resp*trtpn / riskdiff; 
 
run; 
 
%include "P:\George Medicines\ACT\macros\margins.sas"; 
%Margins(data      = test, 
        class      = i trtpn week, 
        response   = RESP, 
        roptions   = event='1', 
        dist       = BINOMIAL, 
        model      = trtpn|week, 
        geesubject = i, 
        margins    = trtpn*week, 
        options    = diff cl, 
        diff       = all);