Is GMRx2 (a single pill combination containing telmisartan/amlodipine/indapamide) effective and safe compared to placebo for the treatment of hypertension: An international, multi-center, randomized, double-blind, placebo-controlled, parallel-group trial

Study sites

National Hospital of Sri Lanka, Kandy Teaching Hospital, Colombo North Teaching Hospital, Colombo South Teaching Hospital, Teaching Hospital Kurunegala, Jaffna Teaching Hospital, Karapitiya Teaching Hospita

Single-Blind Placebo Run-In Period During the screening visit, enrolled participants will be asked to discontinue their current blood pressure (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:

Group Intervention No. of participants Treatment 1 GRMx2 Dose version 1: Triple ¼ 100 telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg 2 GRMx2 Dose version 2: Triple ½ 100 telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg 3 Placebo 50 placebo

Participants will be advised to take one capsule of trial medication once daily in the morning at approximately the same time each day, either before or after breakfast, immediately after taking morning home BP measurement.

Randomization method/allocation of Trial Medication

During the single-blind run-in period (Week -2 to Week 0) all participants will be allocated placebo. . A central, computer-based randomization sequence will be generated, stratified by trial site. During the double-blind period (Week 0 to Week 4) all participants will be allocated

• GMRx2 dose version 1(Triple ¼), 100 participants,
• GMRx2 dose version 2 (Triple ½), 100 participants
• or placebo, 50 participants.

Optional Open-Label Extension Period

In a subset of sites, participants who are still receiving study medication at Week 4 will be invited to continue on to an optional Open-Label Extension Period with the aim to assess effectiveness, safety and adherence over a 52-week period. Willing participants will enter the Open-Label Extension Period at the Week 4 visit, at which time they will be allocated to open-label GMRx2-Dose version 1.

Follow-up visits will be conducted at Week 6, 8, 16, 28, 40, and end of Open-Label Extension Period visit at week 52. Participants will continue to monitor BP at home, once per week until the Week 8 visit, and thereafter on a set day every month (e.g. 1st day of the month) until the week 52 visit. During follow-up visits, if home BP from the most recent measurement is above 130 mm Hg for SBP and/or above 80 mmHg or DBP, BP-lowering therapy will be up-titrated in the following order: GMRx2-Dose1 to GMRx2-Dose2 to GMRx2-Dose3 (telmisartan 40mg/amlodipine 5mg/indapamide 2.5mg) to GMRx2-Dose3 plus telmisartan 40 mg/amlodipine 5 mg to GMRx2-Dose3 plus telmisartan 40 mg/amlodipine 5 mg plus spironolactone 25 mg. The rationale for this regimen is based on the evidence indicating that: - About 80% of the maximum BP-lowering effects of BP-lowering regimens are achieved by 2 weeks - US hypertension guidelines recommend a home BP target of <130/80 mmHg

If necessary, participants can be stepped down to a lower dose option; or switched to other treatment or withdrawn from all BP-lowering treatment, temporarily or permanently.

At screening visit, 1. Adult aged >=18 years. 2. Male or female 3. Low calculated cardiovascular risk according to local guidelines such that pharmacological blood pressure (BP) lowering treatment is not mandatory: E.g. Pooled Cohorts Equation 10-years Atherosclerotic cardiovascular disease (ASCVD) risk <10% in the United States. 4. Likely diagnosis of hypertension, defined as: - automated Systolic blood pressure (SBP) at this clinic visit 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 Diastolic blood pressure (DBP) > >= 90mmHg on no BP lowering medicines or SBP>=130 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.

1. At randomization visit,
2. Home SBP 130-154 mmHg.
3. Adherence of 80-120% to run-in medication.
4. Tolerated run-in medication.
5. Adhered to home BP monitoring schedule.

At week 4 (for optional Open-Label Extension Period) 1. Completed randomized treatment and willing to continue GMRx2-based regimen for 12 months

At screening visit 1. Receiving 2 or more BP-lowering drugs. 2. Contraindication to placebo run-in or any of the trial medications.

At randomization visit 1. Contraindication to any of the randomized medications including placebo

At week 4 (for optional Open-Label Extension Period) 1. Contraindication to any of the open-label GMRx2-based BP-lowering treatment regimen.