Clinical trial NCT04518306: Efficacy and Safety of GMRx2 Compared to Placebo for the Treatment of Hypertension
Official title: Efficacy and Safety of GMRx2 (a Single Pill Combination Containing Telmisartan/Amlodipine/Indapamide) Compared to Placebo for the Treatment of Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypertension
Lead sponsor: George Medicines PTY Limited
Sponsor class: INDUSTRY
First posted: 2020-08-19
Enrollment: 755
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: International, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Difference in Change in Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4
timeFrame: Randomization to Week 4
Secondary outcomes:
measure: Difference in Change in Clinic Seated Mean Mean Systolic Blood Pressure (SBP) From Randomization to Week 4
timeFrame: Randomization to Week 4
measure: Difference in Change in Clinic Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4
timeFrame: Randomization to Week 4
measure: Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <140 and DBP <90 mmHg at Week 4
timeFrame: At Week 4
measure: Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4
timeFrame: At Week 4
measure: Difference in Change in Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4
timeFrame: Randomization to Week 4
measure: Difference in Change in Trough Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 4
timeFrame: Randomization to Week 4
measure: Difference in Change in Trough Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 4
timeFrame: Randomization to Week 4
measure: Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <135 and Diastolic Blood Pressure (DBP) <85 mmHg at Week 4
timeFrame: At Week 4
measure: Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 4
timeFrame: Randomization to Week 4
Other outcomes:
measure: Percentage of Participants Discontinued Trial Medication Due to Adverse Event (AE) or a Serious Adverse Event (SAE) From Randomization to Week 4
timeFrame: Randomization to Week 4
measure: Percentage of Participants With an Serious Adverse Event (SAE) From Randomization to Week 4
timeFrame: Randomization to Week 4
measure: Percentage of Participants With Symptomatic Hypotension From Randomization to Week 4
timeFrame: Randomization to Week 4
measure: Percentage of Participants With Serum Sodium Concentration Below 135 mmol/l at Week 4
timeFrame: At Week 4
measure: Percentage of Participants With Serum Sodium Concentration Above 145 mmol/l at Week 4
timeFrame: At Week 4
measure: The Percentage of Participants With Serum Potassium Concentration Below 3.5 mmol/l at Week 4
timeFrame: At Week 4
measure: Percentage of Participants With Serum Potassium Concentration Above 5.5 mmol/l at Week 4
timeFrame: At Week 4
measure: Percentage of Participants With eGFR Drop of Over 30% From Randomization to Week 4
timeFrame: Randomization to Week 4
measure: 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
timeFrame: At Week 4
measure: Percentage of Participants With Postural Hypotension at Week 4
timeFrame: At Week 4
measure: Percentage of Participants With Postural Hypertension at Week 4
timeFrame: At Week 4
Locations:
city: Phoenix
country: United States
facility: Elite Clinical Studies
state: Arizona
city: Scottsdale
country: United States
facility: Headlands Research
state: Arizona
city: Tucson
country: United States
facility: Quality of Life Medical & Research Centers, LLC
state: Arizona
city: S. Gate
country: United States
facility: Valiance Clinical Research
state: California
city: Tarzana
country: United States
facility: Valiance Clinical Research
state: California
city: Brandon
country: United States
facility: Clinical Research of Brandon
state: Florida
city: Hialeah
country: United States
facility: Inpatient Research Clinic
state: Florida
city: Miami
country: United States
facility: Suncoast Research Group
state: Florida
city: Miami
country: United States
facility: New Horizon Research Center
state: Florida
city: Ocala
country: United States
facility: Ocala Research Institute
state: Florida
city: Palm Beach
country: United States
facility: Altus Research, Inc
state: Florida
city: Saint Petersburg
country: United States
facility: Suncoast Research Associates
state: Florida
city: Saint Petersburg
country: United States
facility: Accel Research
state: Florida
city: Sunrise
country: United States
facility: Precision Clinical Research
state: Florida
city: Tampa
country: United States
facility: Precision Research Center
state: Florida
city: Snellville
country: United States
facility: Buckhead Primary Care Research
state: Georgia
city: Baton Rouge
country: United States
facility: Meridian Clinical Research
state: Louisiana
city: Memphis
country: United States
facility: The University of Tennessee Health Science Center
state: Tennessee
city: Houston
country: United States
facility: Synergy Groups Medical
state: Texas
city: Houston
country: United States
facility: Synergy Groups Medical
state: Texas
city: Missouri City
country: United States
facility: Synergy Groups Medical
state: Texas
city: North Richland Hills
country: United States
facility: North Hills Medical Research
state: Texas
city: Portsmouth
country: United States
facility: Meridian Clinical Research
state: Virginia
city: Castle Hill
country: Australia
facility: Castle Hill Medical Centre
state: New South Wales
city: Clayton
country: Australia
facility: Hudson Institute of Medical Research
state: Victoria
city: Geelong
country: Australia
facility: Barwon Health, Geelong University Hospital
state: Victoria
city: Bentley
country: Australia
facility: Curtin University
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Gwagwalada
country: Nigeria
facility: University of Abuja Teaching Hospital
state: Federal Capital Territory
city: Kano
country: Nigeria
facility: Aminu Kano Teaching Hospital
city: Colombo
country: Sri Lanka
facility: Institute of Cardiology, National Hospital of Sri Lanka
city: Dehiwala
country: Sri Lanka
facility: Colombo South Teaching Hospital
city: Galle
country: Sri Lanka
facility: Karapitiya Teaching Hospital
city: Jaffna
country: Sri Lanka
facility: Jafna Teaching Hospital
city: Kandy
country: Sri Lanka
facility: Kandy National Hospital
city: Kurunegala
country: Sri Lanka
facility: Kurunegala Teaching Hospital
city: Ragama
country: Sri Lanka
facility: Colombo North Teaching Hospital
city: Soham
country: United Kingdom
facility: Steploe Medical Centre
state: Cambridgeshire
city: Newquay
country: United Kingdom
facility: Newquay Medical
state: Cornwall
city: Hinckley
country: United Kingdom
facility: Burbage Surgery
state: Leicestershire
city: Harrow
country: United Kingdom
facility: Belmont Health Centre
state: London
city: Bristol
country: United Kingdom
facility: West Walk Surgery
state: Somerset
city: Betchworth
country: United Kingdom
facility: Brockwood Medical Practice
state: Surrey
city: Coventry
country: United Kingdom
facility: Lakeside Surgery
state: West Midlands
city: Trowbridge
country: United Kingdom
facility: Trowbridge Health Centre
state: Wiltshire
city: Romsey
country: United Kingdom
facility: Abbeywell Surgery
city: Wellingborough
country: United Kingdom
facility: Albany House Medical Centre
Study officials:
affiliation: The George Institute
name: Anthony Rodgers, Professor
role: PRINCIPAL_INVESTIGATOR
References: