Clinical trial NCT04518306
Conditions: Hypertension
Sponsor: George Medicines PTY Limited
Start date: 2021-06-14; Completion date: 2023-10-18
Enrollment: 755 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 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 placebo.

Detailed description:
TRIAL DRUG:

GMRx2: single pill combination of telmisartan/amlodipine/indapamide Dose version 1: telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg Dose version 2: telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg INDICATION: Hypertension

TRIAL TITLE:

Efficacy and safety of GMRx2 compared to placebo for the treatment of hypertension.

OBJECTIVES:

To investigate the efficacy and safety of GMRx2 compared to placebo for the treatment of hypertension.

INTERVENTION:

A 2-week single-blind placebo run-in will be followed by a 4-week double-blind period with randomization to GMRx2 dose version 1, GMRx2 dose version 2 or placebo.

Arms: arm 1: Telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg arm 2: Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg arm 3: Placebo
Interventions: intervention 1: Telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg intervention 2: Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Oral tablets intervention 2: Oral tablets intervention 3: Placebo

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 placebo for the treatment of 
hypertension: An international, multi-center, randomized, double-blind, placebo-
controlled, parallel-group trial 
 
Brief Title
Efficacy and safety of GMRx2 compared to placebo for the treatment of 
hypertension 
 
Phase of Development
Phase III
 
Trial Drug
GMRx2: Single pill combination of telmisartan/amlodipine/indapamide
Dose version 1: telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg 
Dose version 2: telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg 
 
Trial Number
GMRx2-HTN-2020-PCT1
 
Indication
Hypertension
 
Protocol Version
Version 6.0, 22 December 2023
 
Trial Registration
Clinicaltrials.gov NCT04518306
 
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 ....................................................................................................................... 19 
8.3. 
Trial Schema ................................................................................................................................. 21 
8.4. 
Intervention .................................................................................................................................. 21 
 
Single-Blind Placebo Run-In Period ........................................................................................... 21 
 
Double-Blind Treatment Period ................................................................................................ 21 
 
Optional Open-Label Extension Period ..................................................................................... 22 
8.5. 
Adherence to Trial Medication ..................................................................................................... 23 
8.6. 
Add-On Treatment for Participants with High BP ........................................................................ 23 
8.7. 
Down-Titration or Temporary Cessation of Randomized Trial Medication ................................. 23 
8.8. 
Early Permanent Discontinuation of the Trial Medication ........................................................... 24 
8.9. 
Post-Trial Medication ................................................................................................................... 24 
 
OUTCOMES ........................................................................................................................................... 24 
9.1. 
Efficacy Outcomes ........................................................................................................................ 24 
 
Primary ...................................................................................................................................... 24 
 
Secondary .................................................................................................................................. 24 
9.2. 
Safety Outcomes .......................................................................................................................... 24 
 
Primary ...................................................................................................................................... 24 
 
Secondary .................................................................................................................................. 25 


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Descriptive Safety Outcomes .................................................................................................... 25 
9.3. 
Outcomes for those participating in the Open-Label Extension Period ....................................... 25 
 
PARTICIPANT TIMELINE & ASSESSMENTS ............................................................................................ 25 
10.1. 
Schedule of Evaluations ................................................................................................................ 25 
10.2. 
Visit Procedures ............................................................................................................................ 28 
 
Written Informed Consent ........................................................................................................ 28 
 
Verbal Consent .......................................................................................................................... 28 
 
Assessment of Participant Eligibility ......................................................................................... 28 
 
Medical History ......................................................................................................................... 28 
 
Physical Examination ................................................................................................................. 28 
 
Anthropometric Measurements ............................................................................................... 28 
 
Clinic BP Measurement ............................................................................................................. 28 
 
Home BP Measurement ............................................................................................................ 29 
 
24-hour ambulatory BP measurement ..................................................................................... 29 
 Cardiovascular Risk Assessment ............................................................................................... 29 
 Electrocardiogram ..................................................................................................................... 29 
 Laboratory Investigations ......................................................................................................... 29 
 Allocation of Trial Medication ................................................................................................... 29 
 Dispensation of Trial Medication .............................................................................................. 30 
 Returning of Trial Medication ................................................................................................... 30 
 Concomitant Treatments .......................................................................................................... 30 
10.3. 
Visit details ................................................................................................................................... 30 
 
Pre-Screening Visit (as required) .............................................................................................. 30 
 
Screening Visit ........................................................................................................................... 30 
 
Re-Screening ............................................................................................................................. 31 
 
Extended Run-In ........................................................................................................................ 31 
 
Randomization Visit .................................................................................................................. 31 
 
ABPM Device Placement Prior to Week 4 Visit (if applicable) .................................................. 32 
 
Week 4 Visit .............................................................................................................................. 32 
 
Week 8 visit (End of Trial Visit for participants not continuing in the Open-Label Extension 
Period) ....................................................................................................................................... 32 
 
Week 4 Commence Open-Label Extension Period (selected sites only) .................................. 32 
 Week 6, 8, 16, 28, 40 (for Open-Label Extension Period only) ................................................. 33 
 Week 52 Visit (for Open-Label Extension Period only) ............................................................. 33 
 
METHODS: ASSIGNMENT OF INTERVENTION ....................................................................................... 33 
11.1. 
Allocation Sequence Generation .................................................................................................. 33 
11.2. 
Allocation Concealment ............................................................................................................... 33 
11.3. 
Blinding (Masking) ........................................................................................................................ 33 
11.4. 
Unblinding .................................................................................................................................... 33 
 
Unblinding of Trial Medication for Expedited Safety Reporting ............................................... 33 
 
Unblinding of Trial Medication in a Clinical Emergency ........................................................... 34 
 
METHODS: DATA COLLECTION, MANAGEMENT & STATISTICAL ANALYSIS ......................................... 34 
12.1. 
Data Collection ............................................................................................................................. 34 
12.2. 
Data Management ........................................................................................................................ 34 
12.3. 
Sample Size & Power Calculation ................................................................................................. 34 
12.4. 
Statistical Methods ....................................................................................................................... 34 
 
WITHDRAWAL FROM TRIAL PARTICIPATION ........................................................................................ 35 
 
TRIAL MEDICATION MANAGEMENT ..................................................................................................... 35 
14.1. 
Manufacturing .............................................................................................................................. 35 
14.2. 
Packaging, Labelling, Distribution & Storage ................................................................................ 35 


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14.3. 
Return & Destruction.................................................................................................................... 35 
 
MANAGING INTERRUPTION OF STUDY MATERIAL SUPPLY TO TRIAL CENTRES ................................... 35 
 
MONITORING........................................................................................................................................ 36 
16.1. 
Data & Safety Monitoring Board .................................................................................................. 36 
16.2. 
Data Monitoring ........................................................................................................................... 36 
 
SAFETY .................................................................................................................................................. 36 
17.1. 
Safety Definitions ......................................................................................................................... 36 
 
Adverse Event ........................................................................................................................... 36 
 
Adverse Event of Special Interest ............................................................................................. 36 
 
Serious Adverse Event ............................................................................................................... 36 
 
Intensity/Severity of an AESI/SAE ............................................................................................. 36 
 
Relationship to the Trial Medication ........................................................................................ 37 
 
Serious Unexpected Suspected Adverse Reaction.................................................................... 37 
17.2. 
Safety Reporting ........................................................................................................................... 37 
 
AESI/SAE Data Collection & Follow-Up Period .......................................................................... 37 
 
Trial Investigator Responsibilities in Reporting AESIs/SAEs ...................................................... 37 
 
Reporting of AESIs & SAEs ......................................................................................................... 37 
 
Reporting of SUSARs ................................................................................................................. 38 
 
Reporting of Pregnancy ............................................................................................................. 38 
 
Reporting of Trial Medication Use Errors or Misuse................................................................. 38 
 
ETHICAL & REGULATORY COMPLIANCE ............................................................................................... 38 
18.1. 
Ethical Approval ............................................................................................................................ 38 
18.2. 
Regulatory Approval ..................................................................................................................... 38 
18.3. 
Confidentiality .............................................................................................................................. 38 
18.4. 
Protocol Amendments .................................................................................................................. 39 
18.5. 
Adherence to the Trial Protocol ................................................................................................... 39 
 
ADMINISTRATIVE SECTION ................................................................................................................... 39 
19.1. 
Insurance ...................................................................................................................................... 39 
19.2. 
Quality Assurance ......................................................................................................................... 39 
19.3. 
Trial Documents Retention ........................................................................................................... 39 
19.4. 
Ownership, Disclosure of Data and Dissemination policy ............................................................ 39 
 
APPENDICES .......................................................................................................................................... 41 
20.1. 
Appendix 1: List of Abbreviations ................................................................................................. 41 
20.2. 
Appendix 2: Procedure for the Measurement of Clinic BP .......................................................... 43 
20.3. 
Appendix 3: Procedure for the Measurement of Home BP ......................................................... 44 
20.4. 
Appendix 4: Trial Organization ..................................................................................................... 46 
20.5. 
Appendix 5: Prohibited Drugs During the Trial ............................................................................. 47 
20.6. 
Appendix 6: Protocol Signature Page ........................................................................................... 48 
 
REFERENCES.......................................................................................................................................... 49 
 
 
 
 


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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: Blood pressure over time in the QUARTET trial of quadruple quarter-dose combination as initial/early 
treatment vs initial monotherapy for hypertension ..............................................................................……………14       
Figure 3: Study design summary ....................................................................................................................................... 17 
Figure 4: Trial schema ....................................................................................................................................................... 21 
Figure 5: Schema for Open-Label Extension ..................................................................................................................... 23 
 
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 and Safety Follow-up Periods .................... 26 
Table 6: Trial visits schedule and assessments for participants in Open-Label Extension Period ................. 27 
 


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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 BP 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 1: Blood pressure over time in the TRIUMPH trial of triple low-dose combination as initial/early 
treatment vs usual care for hypertension  
Figure 2: Blood pressure over time in the QUARTET trial of quadruple quarter-dose combination as initial/early 
treatment vs initial monotherapy 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 2, 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 placebo for the treatment of hypertension in adults. 
 
To assess the longer-term efficacy and safety of GMRx2 in the optional Open-Label Extension Period.   
 
TRIAL DESIGN 
An international randomized, double-blind, placebo-controlled, parallel-group trial with a 2-week pre-
randomization placebo run-in, a 4-week randomized treatment period and a 4-week safety follow-up period 
or an optional Open-Label Extension period. The overall study design is shown in Figure 3 and 4.  
Figure 2: Study 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 placebo, i.e. the full effects of GMRx2 compared to no BP-lowering medications. The run-
in period will assess participant’s adherence to taking medication and completing trial procedures and 
therefore will enhance the power of the trial to detect difference between GMRx2 and placebo. The double-
blind period will assess the efficacy and safety of GMRx2 dose 1 and GMRx2 dose 2 compared to placebo. 
Double-blinding will avoid any performance bias by investigators and trial participants. The safety follow-up 
period will assess safety over a 30-day period after discontinuation of the trial medication. The optional Open-
Label Extension Period will assess efficacy and tolerability over a one-year period. 
7.2. 
Sub-studies 
Participants will be invited to provide venous blood and urine specimens at baseline, 4 weeks and if applicable 
at 8 weeks visits for use in planned substudy analyses. These samples will be analysed for renal biomarkers60 
and drug metabolite levels.61, 62 The samples will be immediately processed and stored at −80°C ± 10°C and 
shipped during or at the end of the study to designated central laboratories for storage until analyses have 
been completed. In addition, some centers will participate in a sub-study of ambulatory BP measurement and 
provide participants the option of joining this substudy. 


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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 poster or flyer, via 
social media etc. 
8.2. 
Participant Eligibility 
The guiding principle of participant eligibility is patients with hypertension who could appropriately be treated 
with GMRx2 dose version 1 or GMRx2 dose version 2 or placebo. 
 Inclusion Criteria 
At screening visit 
1. Provided signed consent to participate in the trial. 
2. Adult aged ≥18 years. 
3. Low calculated CV risk according to local guidelines such that pharmacological BP-lowering treatment 
is not mandatory: e.g. Pooled Cohorts Equation 10-years ASCVD risk <10% in the USA. 
4.  Likely diagnosis of hypertension, defined as one or more of: 
 
automated SBP at this clinic visit according to trial methods (see Appendix 2) of ≥130mmHg on no 
BP lowering medicines or ≥120mmHg on 1 BP lowering medicine that will be stopped at this visit, 
OR 
 
documentation in last 6 months of office SBP ≥ 140 mmHg and/or DBP ≥ 90mmHg on no BP 
lowering medicines or SBP ≥ 130 mmHg and/or DBP ≥ 85mmHg on 1 BP lowering medicine that 
will be stopped at this visit, OR 
 
documentation in last 6 months of home SBP ≥ 130 mmHg and/or DBP ≥ 80mmHg on no BP 
lowering medicines or SBP ≥ 120 mmHg and/or DBP ≥ 75mmHg on 1 BP lowering medicine that 
will be stopped at this visit, OR  
 
documentation in last 6 months of ambulatory daytime SBP ≥ 130 mmHg and/or DBP ≥ 80mmHg 
on no BP lowering medicines or SBP ≥ 120 mmHg and/or DBP ≥ 75mmHg on 1 BP lowering 
medicine that will be stopped at this visit 
5. No contraindication to trial medications, including 2-weeks placebo run-in and 4-weeks randomized 
treatment period with GMRx2 (dose version 1 or 2) or placebo. 
 
At randomization visit 
1. Home seated mean SBP 130-154 mmHg in the week before the randomization visit. 
2. Adherence of 80-120% to placebo run-in. 
3. Tolerated placebo run-in.  
4. 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. 
At week 4 (for optional Open-Label Extension Period) 
1. Provided signed informed consent.  
2. Completed randomized treatment and willing to continue GMRx2-based treatment regimen for 12 
months. 
 


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 Exclusion Criteria 
At screening visit 
1. Receiving 2 or more 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. 
2. Clinic seated mean SBP ≥160 mmHg and/or DBP ≥100 mmHg.  
3. 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. 
4. Contraindication, including hypersensitivity (e.g. anaphylaxis or angioedema), to the placebo run-in 
treatment or to any of the trial medications in the three randomized groups. 
5. Current/history of transient ischemic attack, stroke, or hypertensive encephalopathy. 
6. Current/history of acute coronary syndrome, unstable angina, myocardial infarction, percutaneous 
transluminal coronary revascularization, or coronary artery bypass graft  
7. 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. 
8. Current/history of New York Heart Association class III and IV congestive heart failure 
9. Current/history of cardiomyopathy or any other cardiovascular condition of sufficient severity to 
contraindicate the trial medications or require a contraindicated medication.   
10. Current/history of a known secondary cause of hypertension, such as primary aldosteronism, renal 
artery stenosis, pheochromocytoma, or Cushing's syndrome. 
11. Current/history of severe uncontrolled diabetes (HbA1c > 11.0% (> 97 mmol/mol)) within the last three 
months. 
12. Current/history of end-stage renal disease or anuria. 
13. 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.  
14. 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. 
15. Currently taking or might need during the trial, a concomitant treatment which is known to interact 
significantly with the trial medication: digoxin, lithium, diabetics receiving aliskiren, moderate and strong 
CYP3A4 
inhibitors 
(e.g. 
ritonavir, 
ketoconazole, 
diltiazem], 
simvastatin 
>20 
mg/day, 
immunosuppressants. 
16. 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). 
17. 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. 
18. Individuals working >2-night shifts per week. 
19. 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.  
20. History of alcohol or drug abuse within 12 months. 
 
At randomization visit 
1. Unable to adhere to the trial procedures during the run-in period. 
2. Any of the following which in the investigator’s judgment may compromise the safety or wellbeing 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 


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the relevance of BP levels which are high/low in clinic only; for example, the clinical relevance 
of ‘whitecoat hypertension’ is uncertain. 
b. High or low home DBP levels. The exact levels of DBP are 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. 
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 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 Randomization visit and until the end of trial participation. 
4. Current estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m.2 
5. 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.  
6. Current/history of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the 
upper limit of normal range within 6 months. 
7. 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’ safety or well-being.  
8. Fulfilling any of the exclusion criteria mentioned for the screening visit, when verified again at the 
randomization visit. 
 
At week 4 (for optional Open-Label Extension Period)  
1. 
Contraindication to open-label GMRx2-based BP-lowering treatment.  


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8.3. 
Trial Schema 
Figure 43: Trial schema 
 
   
8.4. 
Intervention 
 Single-Blind Placebo Run-In Period 
During the screening visit, enrolled participants will be asked to discontinue their current BP-lowering drug if 
applicable and undergo a single-blind placebo run-in period for 2 weeks. 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 2-week single-blind placebo run-in will be followed by a 4-week double-blind period with randomization 
to one of the following three treatment groups: 




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Figure 4: Schema for Open-Label Extension 
 
 
8.5. 
Adherence to Trial Medication  
Adherence to trial medication will be assessed during all scheduled trial follow-up visits by counting trial 
medication capsules returned. Participants in all the groups will be advised of the importance of adhering to 
BP-lowering drugs for improving BP control and preventing CV events. 
8.6. 
Add-On Treatment for Participants with High BP  
The following situations will prompt an urgent clinic visit in an asymptomatic participant for remeasurement 
of BP in clinic and consideration by the trial investigator of the need to initiate open-label add-on treatment:  
1. home seated mean SBP >170 mmHg and/or DBP >105 mmHg on any single day; 
2. home seated mean SBP>160 mmHg and/or DBP >100 mmHg on 2 consecutive BP measurement days. 
 
During the randomized treatment period, if the trial investigator decides that non-trial BP-lowering medication 
is warranted after assessment at the site, then they should prescribe the supplied open-label telmisartan 40 
mg and/or amlodipine 5 mg on top of existing trial medication, without the need to stop and/or unblind trial 
medication.  
 
Participants who require add-on treatment during the run-in period are not eligible for randomization, since 
there is no longer eligibility for randomization to any of the three possible treatment groups. Such participants 
should therefore cease run-in.  
8.7. 
Down-Titration or Temporary Cessation of Randomized Trial Medication  
If, during the randomized period a participant develops a condition or symptom likely to be related to the trial 
medication (e.g. due to possible hypotension) that is severe enough to warrant discontinuation of the trial 
medication, then the Investigator can choose to discontinue the trial medication temporarily. The reason for 
discontinuation will be recorded. There is no need to unblind trial medication in this situation. Consideration 
should also be given to restarting trial 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 


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medication.  
8.8. 
Early Permanent Discontinuation of the Trial Medication 
Discontinuation of trial medication occurs when a randomized participant permanently ceases taking the trial 
medication, regardless of the circumstances, before the Week 4 visit. Early discontinuation must be reported 
immediately to the CRO and recorded in the study database, including the reason for discontinuation.  
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 8. For withdrawal from trial participation, see Section 13, 
page 35. 
8.9. 
Post-Trial Medication  
At either the Week 4 visit or after the Open-Label Extension Period, 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 4. 
  Secondary 
 
Difference in change in clinic seated mean SBP from randomization to Week 4. 
 
Difference in change in home seated mean DBP from randomization to Week 4. 
 
Difference in change in clinic seated mean DBP from randomization to Week 4. 
 
Percentage of participants with clinic seated mean SBP <140 and DBP <90 mmHg at Week 4. 
 
Percentage of participants with clinic seated mean SBP <130 and DBP <80 mmHg at Week 4. 
 
Difference in change in trough home seated mean SBP from randomization to week 4. 
 
Difference in change in trough home seated mean DBP from randomization to week 4. 
 
Percentage of participants with home seated mean SBP <135 and DBP <85 mmHg at Week 4. 
 
Percentage of participants with home seated mean SBP <130 and DBP <80 mmHg at Week 4. 
9.2. 
Safety Outcomes 
  Primary 
 
Percentage of participants discontinued trial medication due to AEs/SAEs from randomization to 
Week 4. 


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 Secondary 
 
Percentage of participants with an SAE from randomization to Week 4. 
 
Percentage of participants with symptomatic hypotension from randomization to Week 4. 
 
Percentage of participants with serum sodium concentration below 135 mmol/l at Week 4. 
 
Percentage of participants with serum sodium concentration above 145 mmol/l at Week 4. 
 
Percentage of participants with serum potassium concentration below 3.5 mmol/l at Week 4. 
 
Percentage of participants with serum potassium concentration above 5.5 mmol/l at Week 4. 
 
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 4.  
 
Percentage of participants with eGFR drop of over 30% from randomization to Week 4. 
 
Percentage of participants with postural hypotension at Week 4 
 
Percentage of participants with postural hypertension at Week 4 
 Descriptive Safety Outcomes 
In addition, descriptive safety data will be reported on: 
 
 
Percentage of participants discontinued trial medication due to AE/SAE during the placebo run-in 
period. 
 
All AESI and SAEs, by severity and by System Organ Class (SOC) criteria during the run-in period, by 
trial medication group during the randomized treatment period, and safety follow-up period or Open-
Label Extension Period. 
9.3. 
Outcomes for those participating in the Open-Label Extension Period  
 
Descriptive, 
non-comparative 
data on mean 
BP, 
BP 
control and the safety 
outcome 
measures outlined in Sections 9.1 and 9.2 will be reported on the cohort of participants entering the 
Open-Label Extension Period.  
 
PARTICIPANT TIMELINE & ASSESSMENTS 
10.1. 
Schedule of Evaluations 
Table 5 outlines the trial visits schedule and assessments for participants in the trial who do not enter the 
optional Open-Label extension period; for those who do enter the Open-Label Extension period, Table 6 
outlines the visits schedule from Week 4 onwards. It should be noted that there is flexibility in the timing of 
blood and urine collection tests before randomization as noted in Table 5, to suit participant preferences and 
local clinic feasibility and ease of scheduling, with the proviso that all of the requirements for eligibility at 
Screening and Randomization are met, as outlined in Section 8.2. 
 






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* All laboratory investigations will be performed at the trial site based local laboratory. Local practice can be followed whether the blood 
draws are done before, at or following each clinic visit. Any other investigations at discretion of site investigator    
EOT=End of trial; FU=Follow up  
10.2. 
Visit Procedures 
 
 Written Informed Consent 
No trial procedures are to be carried out until participants have provided written informed consent except 
where the IRB/IEC has approved verbal consent as the first step in the consent process (See Section 10.2.2). 
Participants willing to take part in the trial will be consented by trial sites as per the local regulatory and ethical 
requirements. In brief, participants will be given the PISCF to read and adequate explanation about the trial 
and will be given ample time to consider their trial participation. They will be given the opportunity to ask 
questions about the trial and what their participation involves and will receive full answers from the trial site 
staff. Before a participant participates in the trial, a written informed consent form (ICF) (using translated 
versions where appropriate) approved by the relevant IRB/IEC should be signed and personally dated by the 
participant or by the participant's legally acceptable representative, and by the person who conducted the 
informed consent discussion. If a participant is unable to read or if a legally acceptable representative is unable 
to read, an impartial witness should be present during the entire informed consent discussion and must attest 
an ICF. A copy of the signed ICF will be given to the participant.  
 Verbal Consent 
To enable participants to attend the screening visit in the fasting state for blood sample collection, verbal 
consent to fast may be obtained. Participants will be provided with a copy of the PISCF to read and an adequate 
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. 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. 


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  Home BP Measurement 
For the days on which home BP is measured, BP measurements measurement should be at the same time in 
the morning and evening on each measurement day and 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 and Week 4 trial visits, BP measurements should be taken on the 4 days 
immediately prior to the day of the on-site Randomization visit. In other weeks, measurements should 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 44. Telemonitored BP values will be 
monitored for adherence with measurement schedules and high values (as noted in Section 8.6, page 23), with 
reporting to the clinic 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 continue to use the same home BP monitor. 
 24-hour ambulatory BP measurement 
24-hour ABPM will be performed prior to Week 4 visit for participants in the ABPM substudy. Accordingly, 
participants will be asked to visit trial site 1 to 7 days before the end of trial medication visit for the placement 
of ABPM device on the participant for 24-hours.   
Cardiovascular Risk Assessment 
Cardiovascular risk assessment will be conducted by the study investigator, in accordance with the local 
guideline recommended algorithm or estimator. For example, the ACC/AHA Pooled Cohort Equations 
(http://tools.acc.org/ASCVD-Risk-Estimator/) to estimate 10-year risk of atherosclerotic CVD (ASCVD) 
recommended by the 2017 ACC/AHA hypertension guideline. Note if a patient input value is out of range for 
the calculator, use the nearest value and clinical judgement eg. when using the ACC/AHA calculator for an 18 
year old, enter age 20 years and use clinical judgement that this will be a slight overestimate of absolute risk. 
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.     
 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. 
Blood and urine sample collected for urinary biomarkers and adherence will be stored and shipped to a central 
laboratory for analysis. 
Allocation of Trial Medication  
During the single-blind run-in period (Week -2 and Week -1, inclusive) all participants will be allocated placebo. 
During the double-blind period (Week 1 to Week 4, inclusive) all participants will be allocated GMRx2 dose 
version 1(Triple ¼), GMRx2 dose version 2 (Triple ½) or placebo. 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 4, participants not entering the Open Label Extension Period will be switched to 
non-trial medication as per local guidelines/practice. 


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Dispensation of Trial Medication 
Starting at the screening visit (Week -2), participants will receive sufficient quantities of the trial medication 
until the next scheduled trial visit. In the case of dispensed treatment lost/damaged, 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 the two 
scheduled trial visits, trial medication delivery will be arranged to the participant’s location. Delivery of trial 
medication to the participant’s location may also occur in other circumstances and where feasible e.g. if blood 
test results are not available at the time of the randomization visit 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 randomized trial medication to the sites at Week 4 (or prior in some 
circumstances – e.g. discontinuation of treatment) and at respective visits for the open label extension period. 
Sites will collect all the returned trial medication and keep an accurate record 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. Prescription of non-trial BP-lowering drugs will only be allowed as noted in Section 
8.6, page 23. 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 over the phone. 
 
Assess potential participant’s interest for participation and eligibility for the trial. 
 
Discuss the trial with the potential participant, including using the PISCF, and obtain signed informed 
consent. Potential participants may be provided time to consider their participation, with a follow-up 
visit arranged as needed. 
 
Consider stopping current BP monotherapy to facilitate trial eligibility, if clinically appropriate and 
considered safe. Informed consent must be obtained before the modification of medication.  
 
If locally preferred and/or feasible, blood tests can be pre-arranged following informed consent. 
 
 The pre-screening visit can be repeated up to 3 times, as needed 
 Screening Visit 
 
Assess the potential participant’s interest and eligibility for the trial. 
 
Discuss the trial with the potential participant, including using the PISCF, and obtain signed informed 
consent. This can also be done before the screening visit. The potential 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.  
 
Review all medication currently being taken. 
 
Measure height and weight. 
 
Measure BP and pulse. 


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 
Perform 12-lead ECG. 
 
Collect blood and urine samples, including for pregnancy, (if applicable) or arrange for these tests to 
be completed during the run-in period. Results must be reviewed and eligibility confirmed prior to 
randomization, but are not required for review prior to the beginning of the placebo run-in. 
 
Collect sub-study blood and urine samples (if applicable) – these can also be collected during run-in or 
at the randomization visit if preferred. 
 
Assess eligibility as per the trial inclusion and exclusion criteria. 
 
Consider stopping current BP monotherapy to facilitate trial eligibility, if clinically appropriate and 
considered safe. Informed consent must be obtained before the modification of medication. If 
medication is altered, a period of at least 14 days is required between alteration of BP 
treatment and trial randomization (ie the minimum placebo run-in duration is 14 days). In situations 
in which it is not deemed clinically appropriate to stop BP monotherapy for the trial duration, such 
participants should be regarded as ineligible. 
 
Demonstrate home BP measurement and dispense home BP monitor (record serial number) to 
participant.  
 
Dispense run-in medication as soon as possible. 
 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 randomization. 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 
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. 
 Randomization Visit 
 
Measure BP and pulse. 
 
Record any AESIs/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 laboratory results. If laboratory results are not available for review prior to or on the same day 
end of the 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 by courier to the 
participant’s home. 


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 
Collect sub-study urine and blood for storage (if applicable and not collected during the run-in 
period). 
 
Review home BP measurement technique. 
 
Assess eligibility as per the trial inclusion and exclusion criteria. 
 
Confirm that participant is suitable to be randomized. If not, collect home BP monitor and thank for 
participation. If suitable, randomize participant. 
 
Dispense treatment according to the allocated kit number selected by IBM database (eCRF). 
 
Advise participant to visit the site 1 or 7 days before the Week 4 visit for the placement of the ABPM 
device, if participating in ABPM substudy.  
 ABPM Device Placement Prior to Week 4 Visit (if applicable) 
 
To be conducted 1-7 days prior to Week 4 Visit 
 
Initialize and program the ABPM device, place on the participant and provide instructions on use. 
 
Instruct the participant to return the device to the site after completing 24 hours of ABPM. 
 Week 4 Visit 
All participants 
 
If applicable, collect the ABPM device, download the data, check if 24-hour ABPM was successful. If 
unsuccessful, repeat within 48 hours and delay the Week 4 visit. 
 
Measure BP and pulse. 
 
Record AESIs/SAEs since the previous visit. 
 
Collect fasting blood and urine samples. 
 
Collect sub-study urine and blood for storage (if applicable) 
 
Review all medications being taken by the participant and update concomitant medications.  
 
Collect unused trial medication and review medication adherence 
If 
the 
site 
is 
participating in Open-Label extension, 
invite 
all 
participants still 
receiving 
trial 
medication to participate.   
Participants continuing in the Open-Label Extension period – go to Section 10.3.9 
Participants not continuing in the Open-Label Extension period:  
 
Collect home BP monitor. 
 
Ask participants to report any AEs during the next 4 weeks after the end of trial medication.  
 
Record AESIs/SAEs since the previous visit. 
 
Collect blood and urine sample  
 
Review all medications being taken by the participant and update concomitant medications.  
 
Stop trial medication and prescribe alternate BP-lowering treatment in line with local 
guidelines/practice.  
 
Explain that the trial follow-up is now completed and thank participant. 
 Week 8 visit (End of Trial Visit for participants not continuing in the Open-Label Extension Period)  
 
Contact participant by telephone.  
 
Record AESIs or SAEs since the previous visit.  
 
Review all medications being taken by the participant and update medications.  
 
Arrange blood and urine for participants who have had ≥30% reduction in eGFR and/or ≥30% increase 
in serum creatinine between baseline and week 4 visits 
 
Explain that the trial follow-up is now completed and thank participant.  
 Week 4 Commence Open-Label Extension Period (selected sites only)  
 
Obtain consent for Open-Label Extension Period  
 
Switch from randomized treatment to Open-Label GMRx2 Dose1, as outlined in 8.4.3, page 22.   


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 
Fora device will be collected and new BP monitor will be issued  
Week 6, 8, 16, 28, 40 (for Open-Label Extension Period only)  
 
Measure clinic BP and pulse.  
 
Record AESIs/SAEs since the previous visit.  
 
Arrange blood and urine for participants who have had ≥30% reduction in eGFR and/or ≥30% increase 
in serum creatinine between baseline and week 4 visits (Week 8 only) 
 
Collect blood sample (Week 16, 28).  
 
Review all medications being taken by the participant.  
 
Collect unused study medication (if applicable).   
 
Continue medication as is or titrate according to GMRx2 treatment regimen  
 
Dispense study medication (if applicable).  
Week 52 Visit (for Open-Label Extension Period only)  
 
Measure clinic BP and pulse.  
 
Record AESIs/SAEs since the previous visit.  
 
Collect blood and urine samples.  
 
Review all medications being taken by the participant.   
 
Collect unused study medication (if applicable).  
 
Stop study medication and prescribe alternate BP-lowering treatment in line with local 
guidelines/practice.  
 
Ask participants to report any AESIs/SAEs during 14 days after the end of study medication  
 
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.  


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 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.  
 
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.63  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.63 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 total of 250 participants will be randomized, with a 2:2:1 ratio of triple ¼: triple ½ : placebo, which is likely 
to necessitate over 300 entering the placebo run-in treatment period. Assuming a common standard deviation 
of 11 mmHg, this sample size will provide >90% power to detect differences in mean home SBP of 9 mmHg 
and 13 mmHg respectively for the comparisons of triple ¼ vs placebo and triple ½ vs placebo, respectively. For 
the comparison of triple ¼ vs triple ½ there will be >80% power to detect a difference of at least 4.5 mmHg in 
mean home SBP. 
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 4 will be analyzed using a mixed model with baseline BP and treatment group as fixed effect 
and accounting for clustering at the site level. Other continuous outcomes of difference in change in BP will 


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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 4 will be summarized 
descriptively and analyzed using a generalized estimating equation to account for clustering at the site level. 
Percentages by treatment groups with 95% CI will be presented along with the associated estimated RR 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 8-week follow-up visit. 
 
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 (Period 1 (Run-in) or Period 2 as in 
Figure 3) is not available at the centre, the participant should delay the start of Run-in, which may necessitate 
rescreening. If a participant is on Run-in but Period 2 study treatment is not available, then randomization 
should be delayed, which may necessitate extending or repeating run-in. 


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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 


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judgment and the following guidance: 
 
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 8 EOT visit for the double-blind period.  For participants continuing in the Open-Label Extension 
Period, AESIs/SAEs will be collected up to and including the Week 52 visit.  Follow-up information on ongoing 
AESIs/SAEs obtained after the participant’s respective EOT visit (as applies) will not be collected in the eCRF.  
 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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All SAEs will be reported by the site staff to the sponsor via the eCRF within 24-hours of first becoming aware 
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. 


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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. 
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 monitored by the Sponsor, including 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; and input by the Steering Committee. 
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 
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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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SC 
Steering Committee 
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 recommendations64 and will be performed using a 
supplied FORA D40g BP machine (also known as Medisanté BP800 machine),65, 66 which is a validated, 
electronic, automatic, digital upper-arm cuff monitor,67 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 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.  
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, available only in 
some 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 at all clinic visits) 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 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 recommendations64 with reference to recent trials 
and clinical use.68, 69  During the run-in and randomised treatment periods, 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. During 
the OLE period, BP measurements will be performed using a supplied validated, electronic, digital upper-arm 
cuff, with measurements recorded in a home BP diary. 
 
During the run-in and randomised treatment periods, home BP will be measured according to the following 
schedule: 
 
on four consecutive days immediately prior to the trial visit (i.e. Weeks -1, and 3), 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. 
 
During the OLE period, home BP will be measured according to the following schedule: 
 
once per week until the Week 16 visit, and thereafter on a set day every month (e.g., 1st day of the 
month) until the Week 52 visit. 
 
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 BP measurements should be immediately before the next trial medication dose. 
 
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. 


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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 23. Past use does not contraindicate eligibility as long as a period 
of at least 2 weeks or 5 half-lives (whichever is longer) has elapsed 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 (e.g. 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-PCT1 
Indication: Hypertension 
 
 
 
 
 
 
GEORGE MEDICINES CHIEF INVESTIGATOR 
 
 
 
Signature  
____
________________________________________________ 
 
 
Date  
 
_______________________________________________________________________ 
 
 
Name  
____________________________________________ 
 
 
Title  
 
_______________________________________________________________________ 
 
 
 
 
 
 
TRIAL SITE INVESTIGATOR 
 
 
Trial Site Name   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature  
_______________________________________________________________________ 
 
 
Date  
 
_______________________________________________________________________ 
 
 
Name  
_______________________________________________________________________ 
 
 
Title  
 
_______________________________________________________________________ 
3 Jan 2024


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