Efficacy and Safety of GMRx2 Compared to Placebo for the Treatment of Hypertension (GMRx2_PCT)

Efficacy and Safety of GMRx2 (a Single Pill Combination Containing Telmisartan/Amlodipine/Indapamide) Compared to Placebo for the Treatment of Hypertension

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.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: Telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg; Drug: Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg

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 I NDICATION: 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.

• Study Type: Interventional
• Enrollment (Actual): 295
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Erin Corstanje; Phone Number: +44 (0)7879192633; Email: ecorstanje@george-medicines.com
• Study Contact Backup: Name: Suzanne Milne; Phone Number: +19013900306; Email: gmrx2gpm@georgeclinical.com

Study Locations

• Australia
  • New South Wales
    • Castle Hill, New South Wales, Australia, 2154
      • Castle Hill Medical Centre
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Hudson Institute of Medical Research
    • Geelong, Victoria, Australia, 3220
      • Barwon Health, Geelong University Hospital
  • Western Australia
    • Bentley, Western Australia, Australia, 6102
      • Curtin University
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital
• Nigeria
  • Kano, Nigeria
    • Aminu Kano Teaching Hospital
  • Federal Capital Territory
    • Gwagwalada, Federal Capital Territory, Nigeria, 902101
      • University of Abuja Teaching Hospital
• Sri Lanka
  • Colombo, Sri Lanka, 10-01000
    • Institute of Cardiology, National Hospital of Sri Lanka
  • Dehiwala, Sri Lanka, 10350
    • Colombo South Teaching Hospital
  • Galle, Sri Lanka, 80000
    • Karapitiya Teaching Hospital
  • Jaffna, Sri Lanka, 40000
    • Jafna Teaching Hospital
  • Kandy, Sri Lanka, 20000
    • Kandy National Hospital
  • Kurunegala, Sri Lanka, 60000
    • Kurunegala Teaching Hospital
  • Ragama, Sri Lanka, 11010
    • Colombo North Teaching Hospital
• United Kingdom
  • Romsey, United Kingdom, SO51 8EN
    • Abbeywell Surgery
  • Wellingborough, United Kingdom, NN8 4RW
    • Albany House Medical Centre
  • Cambridgeshire
    • Soham, Cambridgeshire, United Kingdom, CB7 5JD
      • Steploe Medical Centre
  • Cornwall
    • Newquay, Cornwall, United Kingdom, TR7 1RU
      • Newquay Medical
  • Leicestershire
    • Hinckley, Leicestershire, United Kingdom, LE10 2SE
      • Burbage Surgery
  • London
    • Harrow, London, United Kingdom, HA3 7LT
      • Belmont Health Centre
  • Somerset
    • Bristol, Somerset, United Kingdom, BS37 4AX
      • West Walk Surgery
  • Surrey
    • Betchworth, Surrey, United Kingdom, RH3 7NJ
      • Brockwood Medical Practice
  • West Midlands
    • Coventry, West Midlands, United Kingdom, CV3 6NF
      • Lakeside Surgery
  • Wiltshire
    • Trowbridge, Wiltshire, United Kingdom, BA14 8LW
      • Trowbridge Health Centre
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Elite Clinical Studies
    • Scottsdale, Arizona, United States, 85260
      • Headlands Research
    • Tucson, Arizona, United States, 85712
      • Quality of Life Medical & Research Centers, LLC
  • California
    • S. Gate, California, United States, 90280
      • Valiance Clinical Research
    • Tarzana, California, United States, 91356
      • Valiance Clinical Research
  • Florida
    • Brandon, Florida, United States, 33511
      • Clinical Research of Brandon
    • Hialeah, Florida, United States, 33013
      • Inpatient Research Clinic
    • Miami, Florida, United States, 33165
      • New Horizon Research Center
    • Miami, Florida, United States, 33135
      • Suncoast Research Group
    • Ocala, Florida, United States, 34471
      • Ocala Research Institute
    • Palm Beach, Florida, United States, 33461
      • Altus Research, Inc
    • Saint Petersburg, Florida, United States, 33173
      • Suncoast Research Associates
    • Saint Petersburg, Florida, United States, 33709
      • Accel Research
    • Sunrise, Florida, United States, 33351
      • Precision Clinical Research
    • Tampa, Florida, United States, 33603
      • Precision Research Center
  • Georgia
    • Snellville, Georgia, United States, 30078
      • Buckhead Primary Care Research
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Meridian Clinical Research
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • The University of Tennessee Health Science Center
  • Texas
    • Houston, Texas, United States, 77036
      • Synergy Groups Medical
    • Houston, Texas, United States, 77087
      • Synergy Groups Medical
    • Missouri City, Texas, United States, 77459
      • Synergy Groups Medical
    • North Richland Hills, Texas, United States, 76180
      • North Hills Medical Research
  • Virginia
    • Portsmouth, Virginia, United States, 23703
      • Meridian Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Exclusion Criteria:

At screening visit:

1. Receiving 2 or more BP-lowering drugs.
2. Clinic seated mean SBP ≥160 mmHg and/or DBP ≥100 mmHg.
3. Pregnant or had a positive pregnancy test or unwilling to undertake a pregnancy test during the trial and up to 30 days after the discontinuation of the trial medication or breastfeeding or of childbearing age and not using an acceptable method of contraception. Acceptable methods of birth control include hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double-barrier method (e.g. condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), or male partner sterilization. Contraception should be used for at least 1 month before the screening visit and until the end of trial participation.
4. Not suitable for participation in a clinical trial according to local ethical or regulatory requirements related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
5. Contraindication, including hypersensitivity (e.g. anaphylaxis or angioedema), to any of the 3 trial medications.
6. Current/history of transient ischemic attack, stroke, or hypertensive encephalopathy.
7. Current/history of acute coronary syndrome, unstable angina, myocardial infarction, percutaneous transluminal coronary revascularization, or coronary artery bypass graft.
8. Current/history of New York Heart Association class III and IV congestive heart failure.
9. Current/history of a known secondary cause of hypertension, such as primary aldosteronism, renal artery stenosis, pheochromocytoma, or Cushing's syndrome.
10. Current/history of substantially uncontrolled diabetes (HbA1c > 11.0%) within last three months.
11. Current/history of end-stage renal disease or anuria or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2.
12. Current/history of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal range within 6 months.
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' well-being.
14. Arm circumference that is too large (>55 cm) or too small (<20 cm) to allow accurate measurement of BP.
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 Error! Reference source not found.).
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.
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 of the participant if randomized to the trial medications:

   1. High or low clinic BP levels even in the light of the values for home BP that are available for that participant. The exact levels of BP are not specified, since there is clinical uncertainty as to the relevance of BP levels which are high/low in clinic only; for example the clinical relevance of 'whitecoat hypertension' is uncertain.
   2. High or low home DBP levels. The exact levels of DBP are not specified, reflecting clinical uncertainty of for example 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. Any abnormal laboratory value which in the judgment of the investigator could interfere with the effective conduct of the trial or constitutes a significant risk to the participants' well-being.
4. Fulfilling any of the exclusion criteria mentioned for the screening visit, when verified again at randomization visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo
Experimental: Triple ¼ (GMRx2); Telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg	Drug: Telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg; Oral tablets
Active Comparator: Triple ½ (GMRx2); Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg	Drug: Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg; Oral tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Difference in change in home seated SBP from baseline to Week 4	4 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Difference in change in clinic seated mean SBP from baseline to Week 4	4 weeks
Difference in change in clinic seated mean DBP from baseline to Week 4	4 weeks
Percentage of participants with clinic seated mean SBP <140 and DBP <90 mmHg at Week 4	4 weeks
Percentage of participants with clinic seated mean SBP <130 and DBP <80 mmHg at Week 4	4 weeks
Difference in change in home seated mean DBP from baseline to Week 4	4 weeks
Difference in change in trough home seated mean SBP from baseline to week 4	4 weeks
Difference in change in trough home seated mean DBP from baseline to week 4	4 weeks
Percentage of participants with home seated mean SBP <135 and DBP <85 mmHg at Week 4	4 weeks
Percentage of participants with home seated mean SBP <130 and DBP <80 mmHg at Week 4	4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Safety Outcome	Percentage of participants discontinued trial medication due to AE/SAE from baseline to Week 4	4 weeks
Secondary Safety Outcome 1	Percentage of participants with an SAE from baseline to Week 4	4 weeks
Secondary Safety Outcome 2	Percentage of participants with symptomatic hypotension from baseline to Week 4	4 weeks
Secondary Safety Outcome 3	Percentage of participants with serum sodium concentration below 135 mmol/l at Week 4	4 weeks
Secondary Safety Outcome 4	Percentage of participants with serum sodium concentration above 145 mmol/l at Week 4	4 weeks
Secondary Safety Outcome 5	Percentage of participants with serum potassium concentration below 3.5 mmol/l at Week 4	4 weeks
Secondary Safety Outcome 6	Percentage of participants with serum potassium concentration above 5.5 mmol/l at Week 4	4 weeks
Secondary Safety Outcome 7	Percentage of participants with eGFR drop of over 30% from baseline to Week 4	4 weeks
Secondary Safety Outcome 8	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	4 weeks
Secondary Safety Outcome 9	Percentage of participants with postural hypotension at Week 4	4 weeks
Secondary Safety Outcome 10	Percentage of participants with postural hypertension at Week 4	4 weeks

Collaborators and Investigators

• Sponsor: George Medicines PTY Limited
• Investigators: Principal Investigator: Anthony Rodgers, Professor, The George Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2021
• Primary Completion (Actual): September 18, 2023
• Study Completion (Actual): October 18, 2023

Study Registration Dates

• First Submitted: August 15, 2020
• First Submitted That Met QC Criteria: August 15, 2020
• First Posted (Actual): August 19, 2020

Study Record Updates

• Last Update Posted (Estimated): December 19, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Sodium Chloride Symporter Inhibitors; Amlodipine; Telmisartan; Indapamide
• Other Study ID Numbers: GMRx2-HTN-2020-PCT1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No If the sponsor receives a request for study data, then such requests will be reviewed by sponsor following completion of regulatory submissions and review, and with support from members of the GMRX2 steering committee who will advise on the scientific merit and integrity of the proposed analysis.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No