Efficacy and Safety of GMRx2 Compared to Dual Combinations for the Treatment of Hypertension (GMRx2_ACT)

Efficacy and Safety of GMRx2 (a Single Pill Combination Containing Telmisartan/Amlodipine/Indapamide) Compared to Dual Combinations 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 dual combinations.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg; Drug: telmisartan 40 mg/amlodipine 5 mg/indapamide 2.5 mg; Drug: Telmisartan 20 mg/amlodipine 2.5 mg .; Drug: telmisartan 40 mg/amlodipine 5 mg; Drug: Telmisartan 20 mg/indapamide 1.25 mg; Drug: telmisartan 40 mg/indapamide 2.5 mg; Drug: Amlodipine 2.5 mg/indapamide 1.25 mg; Drug: amlodipine 5 mg/indapamide 2.5 mg

Detailed Description

TRIAL DRUG:

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

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

INTERVENTION:

Single-Blind Active Run-In Period. Enrolled participants will be asked to discontinue their current BP-lowering drug(s) and undergo a single-blind active run-in period for 4 weeks with GMRx2 dose version 2. Participants will be advised to take the capsule once daily in the morning at the same time (± 2 hours) before home BP measurement is performed.

Double-Blind Treatment Period. Participants still eligible after the run-in period will be allocated in a double-blind fashion to one of the following 4 randomized groups: GMRx2 dose version 2, or telmisartan20mg+amlodipine2.5mg, or telmisartan 20mg+indapamide 1.25mg, or amlodipine2.5mg+indapamide 1.25mg. At week 6 all doses will be doubled.

• Study Type: Interventional
• Enrollment (Actual): 1385
• Phase: Phase 3

Contacts and Locations

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

Study Locations

• Australia
  • New South Wales
    • Castle Hill, New South Wales, Australia, 2154
      • Castle Hill Medical Centre
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital - Hypertension Unit
  • 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
• Czechia
  • Kralovehradsky
    • Broumov, Kralovehradsky, Czechia, 550 01
      • EDUMED, s.r.o
    • Jaroměř, Kralovehradsky, Czechia, 551 01
      • EDUMED, s.r.o
  • Stredocesky
    • Brandýs Nad Labem, Stredocesky, Czechia, 250 01
      • Private Cardiologic Ambulance, Medicus Services s.r.o
• New Zealand
  • Gisborne, New Zealand, 4040
    • Gisborne Hospital
  • Auckland
    • Otahuhu, Auckland, New Zealand, 2025
      • Middlemore Clinical Trials
• Poland
  • Gdańsk, Poland
    • Medical University of Gdansk
  • Katowice, Poland, 40-081
    • Pratia Katowice Medical Centre
  • Katowice, Poland
    • Pratia Katowice Medical Centre
  • Nowy Dwór Mazowiecki, Poland
    • Nowodworskie Medical Center
  • Poznań, Poland
    • Medical Center Pratia Poznan
  • Skierniewice, Poland, 96-100
    • ETG Network
  • Skierniewice, Poland
    • ETG Network
  • Warsaw, Poland
    • The Medical University of Warsaw
  • Wrocław, Poland
    • EMC Instytut Medyczny S.A
  • Wrocław, Poland
    • Futuremeds
  • Gdansk
    • Gdańsk, Gdansk, Poland, 80-214
      • Medical University of Gdansk
  • Wroclaw
    • Wrocław, Wroclaw, Poland, 50-088
      • Futuremeds
• Sri Lanka
  • Colombo, Sri Lanka, 10-01000
    • Clinical Medicine Academic & Research Centre
  • 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
  • Negombo, Sri Lanka, 11500
    • Negombo District General Hospital
  • Nugegoda, Sri Lanka, 10250
    • Sri Jayawardenapura General Hospital
  • Ragama, Sri Lanka, 11010
    • Colombo North Teaching Hospital
• United Kingdom
  • London, United Kingdom, EC1M6BO
    • Bart's NHS Trust
  • Sheffield, United Kingdom, S35 9XQ
    • Ecclesfield Group Practice
  • Cambridgeshire
    • Soham, Cambridgeshire, United Kingdom, CB7 5JD
      • Steploe Medical Centre
  • Cheshire
    • Sandbach, Cheshire, United Kingdom, CW11 1EQ
      • Ashfields Primary Care Centre
  • Cornwall
    • Newquay, Cornwall, United Kingdom, TR7 1RU
      • Newquay Medical
  • Derbyshire
    • Chesterfield, Derbyshire, United Kingdom, S40 4AA
      • Royal Primary Care Ashgate
  • Durham
    • Darlington, Durham, United Kingdom, DL3 8SQ
      • Carmel Medical Practice
  • East Midlands
    • Leicester, East Midlands, United Kingdom, LE5 4PW
      • PRC Leciester
  • Herts.
    • Hitchin, Herts., United Kingdom, SG49TH
      • Portmill Surgery
  • Lancashire
    • Blackpool, Lancashire, United Kingdom, FY3 7EN
      • Layton Medical Centre
    • Blackpool, Lancashire, United Kingdom, FY4 3AD
      • Waterloo Medical Centre
  • Leicestershire
    • Hinckley, Leicestershire, United Kingdom, LE10 2SE
      • Burbage Surgery
  • London
    • Harrow, London, United Kingdom, HA3 7LT
      • Belmont Health Centre
  • Poole
    • Upton, Poole, United Kingdom, BH165PW
      • The Adam Practice
  • Somerset
    • Bath, Somerset, United Kingdom, BA2 3HT
      • Heart of Bath Medical Partnership
    • Bristol, Somerset, United Kingdom, BS37 4AX
      • West Walk Surgery
    • Nailsea, Somerset, United Kingdom, BS48 1BZ
      • Tyntesfield Medical Group
  • South Yorkshire
    • Rotherham, South Yorkshire, United Kingdom, S65 1DA
      • Clifton Medical Centre
  • Wales
    • Cardiff, Wales, United Kingdom, CV32 4RA
      • Ely Bridge
  • Warwickshire
    • Atherstone, Warwickshire, United Kingdom, CV9 1EU
      • Atherstone Surgery
  • West Midlands
    • Coventry, West Midlands, United Kingdom, CV3 6NF
      • Lakeside Surgery
    • Leamington Spa, West Midlands, United Kingdom, CV324RA
      • Sherbourne Medical Centre
  • Wiltshire
    • Chippenham, Wiltshire, United Kingdom, SN15 2SB
      • Rowden Surgery
    • Chippenham, Wiltshire, United Kingdom, SN14 6GT
      • Hathaway Surgery
    • 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 Associates
  • 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
    • Lake City, Florida, United States, 32055
      • Multi-Speciality Research Associates
    • 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
    • Saint Petersburg, Florida, United States, 33173
      • Suncoast Research Associates
    • Saint Petersburg, Florida, United States, 33709
      • Accel Research
    • Tampa, Florida, United States, 33603
      • Precision Research Center
  • Georgia
    • Savannah, Georgia, United States, 31406
      • Meridian Clinical Research
    • Snellville, Georgia, United States, 30078
      • Buckhead Primary Care Research
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Meridian Clinical Research
  • New York
    • Endwell, New York, United States, 13760
      • Meridian Clinical Research
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Javarra Research
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • The University of Tennessee Health Science Center
  • Texas
    • Austin, Texas, United States, 78735
      • ACRC Trials - Southwest Medical Village
    • Austin, Texas, United States, 78746
      • ACRC Trials - Premier Family Physicians
    • Carlton, Texas, United States, 75010
      • ACRC Trials - Family Medicine Associates of 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
    • Plano, Texas, United States, 75093
      • ACRC Trials - Village Health Partners
  • 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 of age ≥18 years.
3. Attended automated clinic seated mean SBP (average of last 2 measurements calculated by the device):

150-179 mmHg on 0 blood pressure (BP)-lowering drugs, or 140-170 mmHg on 1 BP-lowering drug, or 130-160 mmHg on 2 BP-lowering drugs, or 120-150 mmHg on 3 BP-lowering drugs.

At randomization visit

1. Home seated mean SBP 110-154 mmHg in the week prior to the randomization visit .
2. Adherence of 80-120% to run-in medication.
3. Tolerated run-in medication.
4. Adherence to home BP monitoring schedule: ≥3 days in the week before the randomization visit and ≥1 day per week during the preceding weeks, , with ≥2 measures in the specified morning and evening time periods on each day (i.e. accepting measures outside of the recommended 0600-1000 and 1800-2200 periods as long as they are in the am or pm, respectively).

At week 12 (for optional open-label extension)

1. Provided signed informed consent.
2. completed randomized treatment and willing to continue GMRx2-based regimen for up to 12 months.

Exclusion Criteria:

At screening visit

1. Receiving 4 or more BP-lowering drugs.
2. receiving any BP lowering drugs for indications other than hypertension e.g. heart failure
3. Pregnant or had a positive pregnancy test or unwilling to undertake a pregnancy test during the trial and up to 30 days after the discontinuation of the trial medication or breastfeeding or of childbearing age and not using an acceptable method of contraception. 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 the active run-in treatment or to any of the trial medication options in the four randomized groups.
6. Current/history of transient ischemic attack, stroke, or hypertensive encephalopathy.
7. Current/history of acute coronary syndrome, unstable angina, myocardial infarction, percutaneous transluminal coronary revascularization, or coronary artery bypass graft.
8. Current atrial fibrillation. Patients with a history of paroxysmal atrial fibrillation are potentially eligible as long as there has been no episode in the last 3 months, while patient with a history of persistent or permanent atrial fibrillation are not eligible.
9. Current/history of New York Heart Association class III and IV congestive heart failure.
10. Current/history of a known secondary cause of hypertension, such as primary aldosteronism, renal artery stenosis, pheochromocytoma, or Cushing's syndrome.
11. Current/history of substantially uncontrolled diabetes (HbA1c > 11.0%) within last three months.
12. Current/history of end-stage renal disease or anuria or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2.
13. Electrolyte levels that would be regarded as contraindications for any of the potential treatment arms e.g. serum sodium <132mmol/l or >148mmol/l serum potassium <3.1 mmol/l or >5.6 mmol/l.
14. Current/history of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal range within 6 months.
15. 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.
16. Arm circumference that is too large (>55 cm) or too small (<20 cm) to allow accurate measurement of BP.
17. Currently taking or might need during the trial, a concomitant treatment which is known to interact with one or more of the trial medications: digoxin, lithium, diabetics receiving aliskiren, moderate and strong CYP3A4 inhibitors (e.g. ritonavir, ketoconazole, diltiazem], simvastatin >20 mg/day, immunosuppressants.
18. 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).
19. 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.
20. Individuals working >2 nightshifts per week.
21. Participated in any investigative drug or device trial within the previous 30 days.
22. History of alcohol or drug abuse within 12 months.

At randomization visit

1. Unable to adhere to the trial procedures during the run-in treatment period.

2. Any of the following which in the investigator's judgment may compromise the safety of the participant if randomized to the trial medications:

   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 or low in clinic only; for example, the clinical relevance of 'whitecoat hypertension' is uncertain.
   2. High or low home diastolic BP (DBP) levels. The exact levels of DBP is not specified, reflecting clinical uncertainty of the implications of isolated diastolic hypertension. However, home DBP values of >99 mmHg may typically be considered as requiring treatment intensification, and such participants would not be suitable for randomization.
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.

At week 12 (for optional open-label extension)

1. contraindication to open-label GMRx2-ased BP-lowering treatment.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Triple - TAI; Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg. At week 6 visit, forced up-titration to telmisartan 40 mg/amlodipine 5 mg/indapamide 2.5 mg	Drug: Telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg; Single pill; Drug: telmisartan 40 mg/amlodipine 5 mg/indapamide 2.5 mg; Signle pill
Active Comparator: Dual - TA; Telmisartan 20 mg/amlodipine 2.5 mg . At week 6 visit, forced up-titration to telmisartan 40 mg/amlodipine 5 mg	Drug: Telmisartan 20 mg/amlodipine 2.5 mg .; oral tablet; Drug: telmisartan 40 mg/amlodipine 5 mg; oral tablet
Active Comparator: Dual - TI; Telmisartan 20 mg/indapamide 1.25 mg. At week 6 visit, forced up-titration to telmisartan 40 mg/indapamide 2.5 mg	Drug: Telmisartan 20 mg/indapamide 1.25 mg; oral tablet; Drug: telmisartan 40 mg/indapamide 2.5 mg; oral tablet
Active Comparator: Dual - AI; Amlodipine 2.5 mg/indapamide 1.25 mg. At week 6 visit, forced up-titration to amlodipine 5 mg/indapamide 2.5 mg	Drug: Amlodipine 2.5 mg/indapamide 1.25 mg; oral tablet; Drug: amlodipine 5 mg/indapamide 2.5 mg; oral tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Difference in change in home SBP from baseline to week 12	12 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Difference in change in clinic seated mean SBP from baseline to Week 12	12 weeks
Difference in change in clinic seated mean SBP from baseline to Week 6	6 weeks
Difference in change in clinic seated mean DBP from baseline to Week 12	12 weeks
Difference in change in clinic seated mean DBP from baseline to Week 6	6 weeks
Percentage of participants with clinic seated mean SBP <140 and DBP <90 mmHg at Week 12	12 weeks
Percentage of participants with clinic seated mean SBP <140 and DBP <90 mmHg at Week 6	6 weeks
Percentage of participants with clinic seated mean SBP <130 and DBP <80 mmHg at Week 12	12 weeks
Percentage of participants with clinic seated mean SBP <130 and DBP <80 mmHg at Week 6	6 weeks
Difference in change in home seated mean SBP from baseline to Week 6	6 weeks
Difference in change in home seated mean DBP from baseline to Week 12	12 weeks
Difference in change in home seated mean DBP from baseline to Week 6	6 weeks
Difference in change in trough home seated mean SBP from baseline to week 12	12 weeks
Difference in change in trough home seated mean SBP from baseline to Week 6	6 weeks
Percentage of participants with home seated mean SBP <135 and DBP <85 mmHg at Week 12	12 weeks
Percentage of participants with home seated mean SBP <135 and DBP <85 mmHg at Week 6	6 weeks
Percentage of participants with home seated mean SBP <130 and DBP <80 mmHg at Week 12	12 weeks
Percentage of participants with home seated mean SBP <130 and DBP <80 mmHg at Week 6	6 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of participants discontinued trial medication due to AE/SAE from baseline to week 12	Safety Outcomes	12 weeks
Percentage of participants discontinued trial medication due to AE/SAE from baseline to Week 6	Safety Outcomes	6 weeks
Percentage of participants with an SAE from baseline to Week 12	Safety Outcomes	12 weeks
Percentage of participants with SAE from baseline to Week 6	Safety Outcomes	6 weeks
Percentage of participants with symptomatic hypotension from baseline to Week 12	Safety Outcomes	12 weeks
Percentage of participants with symptomatic hypotension from baseline to Week 6	Safety Outcomes	6 weeks
Percentage of participants with serum sodium concentration below 135 mmol/l at Week 12	Safety Outcomes	12 weeks
Percentage of participants with serum sodium concentration below 135 mmol/l at Week 6	Safety Outcomes	6 weeks
Percentage of participants with serum sodium concentration above 145 mmol/l at Week 12	Safety Outcomes	12 weeks
Percentage of participants with serum sodium concentration above 145 mmol/l at Week 6	Safety Outcomes	6 weeks
Percentage of participants with serum potassium concentration below 3.5 mmol/l at Week 12	Safety Outcomes	12 weeks
Percentage of participants with serum potassium concentration below 3.5 mmol/l at Week 6	Safety Outcomes	6 weeks
Percentage of participants with serum potassium concentration above 5.5 mmol/l at Week 12	Safety Outcomes	12 weeks
Percentage of participants with serum potassium concentration above 5.5 mmol/l at Week 6	Safety Outcomes	6 weeks
Percentage of participants with eGFR drop of over 30% from baseline to Week 12	Safety Outcomes	12 weeks
Percentage of participants with eGFR drop of over 30% from baseline to Week 6	Safety Outcomes	6 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 26, 2021
• Primary Completion (Actual): August 1, 2023
• Study Completion (Actual): September 1, 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 13, 2023
• Last Update Submitted That Met QC Criteria: December 6, 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-ACT1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: 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