Clinical trial NCT04518293: Efficacy and Safety of GMRx2 Compared to Dual Combinations for the Treatment of Hypertension
Official title: Efficacy and Safety of GMRx2 (a Single Pill Combination Containing Telmisartan/Amlodipine/Indapamide) Compared to Dual Combinations 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: 1385
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, active-controlled, parallel group.
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 (BP) 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.

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 approximately the same time each day. For days on which BP is being measured, the capsule should be taken directly after the morning home BP measurement.

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 telmisartan 20mg+amlodipine2.5mg, or telmisartan 20mg+indapamide 1.25mg, or amlodipine 2.5mg+indapamide 1.25mg. At week 6 all doses will be doubled.

Eligibility criteria: 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 systolic blood pressure (SBP) (average of last 2 measurements calculated by the device):

140-179 mmHg on 0 BP-lowering drugs, or 130-170 mmHg on 1 BP-lowering drug, or 120-160 mmHg on 2 BP-lowering drugs, or 110-150 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: in the week before randomization, at least 6 measures (e.g. ≥2 sets of triplicate measures, ≥3 sets of duplicate 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 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 (\<15-24 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.
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.

Primary outcomes:
measure: Difference in Change in Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 12
timeFrame: Week 12
Secondary outcomes:
measure: Difference in Change in Clinic Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 12
timeFrame: Week 12
measure: Difference in Change in Clinic Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 6
timeFrame: Week 6
measure: Difference in Change in Clinic Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 12
timeFrame: Week 12
measure: Difference in Change in Clinic Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 6
timeFrame: Week 6
measure: Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <140 and Diastolic Blood Pressure (DBP) <90 mmHg at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <140 and Diastolic Blood Pressure (DBP) <90 mmHg at Week 6
timeFrame: Week 6
measure: Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Clinic Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 6
timeFrame: Week 6
measure: Difference in Change in Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 6
timeFrame: Week 6
measure: Difference in Change in Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 12
timeFrame: Week 12
measure: Difference in Change in Home Seated Mean Diastolic Blood Pressure (DBP) From Randomization to Week 6
timeFrame: Week 6
measure: Difference in Change in Trough Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 12
timeFrame: Week 12
measure: Difference in Change in Trough Home Seated Mean Systolic Blood Pressure (SBP) From Randomization to Week 6
timeFrame: Week 6
measure: Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <135 and Diastolic Blood Pressure (DBP) <85 mmHg at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <135 and Diastolic Blood Pressure (DBP) <85 mmHg at Week 6
timeFrame: Week 6
measure: Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Home Seated Mean Systolic Blood Pressure (SBP) <130 and Diastolic Blood Pressure (DBP) <80 mmHg at Week 6
timeFrame: Week 6
Other outcomes:
measure: Percentage of Participants Discontinued Trial Medication Due to Adverse Event (AE)/Serious Adverse Event (SAE) From Randomization to Week 12
timeFrame: Week 12
measure: Percentage of Participants Discontinued Trial Medication Due to Adverse Event (AE)/Serious Adverse Event (SAE) From Randomization to Week 6
timeFrame: Week 6
measure: Percentage of Participants With a Serious Adverse Event (SAE) From Randomization to Week 12
timeFrame: At Week 12
measure: Percentage of Participants With Serious Adverse Event (SAE) From Randomization to Week 6
timeFrame: Week 6
measure: Percentage of Participants With Symptomatic Hypotension From Randomization to Week 12
timeFrame: Week 12
measure: Percentage of Participants With Symptomatic Hypotension From Randomization to Week 6
timeFrame: Week 6
measure: Percentage of Participants With Serum Sodium Concentration Below 135 mmol/l at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Serum Sodium Concentration Below 135 mmol/l at Week 6
timeFrame: Week 6
measure: Percentage of Participants With Serum Sodium Concentration Above 145 mmol/l at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Serum Sodium Concentration Above 145 mmol/l at Week 6
timeFrame: Week 6
measure: Percentage of Participants With Serum Potassium Concentration Below 3.5 mmol/l at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Serum Potassium Concentration Below 3.5 mmol/l at Week 6
timeFrame: Week 6
measure: Percentage of Participants With Serum Potassium Concentration Above 5.5 mmol/l at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Serum Potassium Concentration Above 5.5 mmol/l at Week 6
timeFrame: Week 6
measure: Percentage of Participants With Estimated Glomerular Filtration Rate (eGFR) Drop of Over 30% From Randomization to Week 12
timeFrame: Week 12
measure: Percentage of Participants With Estimated Glomerular Filtration Rate (eGFR) Drop of Over 30% From Randomization to Week 6
timeFrame: Week 6
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 Follow-up Week 12
timeFrame: Week 12
measure: Percentage of Participants With Serum Sodium <135 mmol/L or >145 mmol/L, and/or Serum Potassium <3.5 mmol/L or >5.5 mmol/L at Week 6
timeFrame: Week 6
measure: Percentage of Participants With Orthostatic Hypotension at Week 6
timeFrame: Week 6
measure: Percentage of Participants With Orthostatic Hypotension at Week 12
timeFrame: Week 12
measure: Percentage of Participants With Orthostatic Hypertension at Week 6
timeFrame: Week 6
measure: Percentage of Participants With Orthostatic Hypertension at Week 12
timeFrame: Week 12
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 Associates
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: Lake City
country: United States
facility: Multi-Speciality Research Associates
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: Saint Petersburg
country: United States
facility: Suncoast Research Associates
state: Florida
city: Saint Petersburg
country: United States
facility: Accel Research
state: Florida
city: Tampa
country: United States
facility: Precision Research Center
state: Florida
city: Savannah
country: United States
facility: Meridian Clinical Research
state: Georgia
city: Snellville
country: United States
facility: Buckhead Primary Care Research
state: Georgia
city: Maywood
country: United States
facility: Loyola University
state: Illinois
city: Baton Rouge
country: United States
facility: Meridian Clinical Research
state: Louisiana
city: Endwell
country: United States
facility: Meridian Clinical Research
state: New York
city: Charlotte
country: United States
facility: Javarra Research
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Memphis
country: United States
facility: The University of Tennessee Health Science Center
state: Tennessee
city: Austin
country: United States
facility: ACRC Trials - Southwest Medical Village
state: Texas
city: Austin
country: United States
facility: ACRC Trials - Premier Family Physicians
state: Texas
city: Carlton
country: United States
facility: ACRC Trials - Family Medicine Associates of Texas
state: Texas
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: Plano
country: United States
facility: ACRC Trials - Village Health Partners
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: Brisbane
country: Australia
facility: Princess Alexandra Hospital - Hypertension Unit
state: Queensland
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: Broumov
country: Czechia
facility: EDUMED, s.r.o
state: Kralovehradsky
city: Jaroměř
country: Czechia
facility: EDUMED, s.r.o
state: Kralovehradsky
city: Brandýs Nad Labem
country: Czechia
facility: Private Cardiologic Ambulance, Medicus Services s.r.o
state: Stredocesky
city: Otahuhu
country: New Zealand
facility: Middlemore Clinical Trials
state: Auckland
city: Gisborne
country: New Zealand
facility: Gisborne Hospital
city: Gdańsk
country: Poland
facility: Medical University of Gdansk
state: Gdansk
city: Wrocław
country: Poland
facility: Futuremeds
state: Wroclaw
city: Gdańsk
country: Poland
facility: Medical University of Gdansk
city: Katowice
country: Poland
facility: Pratia Katowice Medical Centre
city: Katowice
country: Poland
facility: Pratia Katowice Medical Centre
city: Nowy Dwór Mazowiecki
country: Poland
facility: Nowodworskie Medical Center
city: Poznań
country: Poland
facility: Medical Center Pratia Poznan
city: Skierniewice
country: Poland
facility: ETG Network
city: Skierniewice
country: Poland
facility: ETG Network
city: Warsaw
country: Poland
facility: The Medical University of Warsaw
city: Wrocław
country: Poland
facility: EMC Instytut Medyczny S.A
city: Wrocław
country: Poland
facility: Futuremeds
city: Colombo
country: Sri Lanka
facility: Clinical Medicine Academic & Research Centre
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: Negombo
country: Sri Lanka
facility: Negombo District General Hospital
city: Nugegoda
country: Sri Lanka
facility: Sri Jayawardenapura General Hospital
city: Ragama
country: Sri Lanka
facility: Colombo North Teaching Hospital
city: Soham
country: United Kingdom
facility: Steploe Medical Centre
state: Cambridgeshire
city: Sandbach
country: United Kingdom
facility: Ashfields Primary Care Centre
state: Cheshire
city: Newquay
country: United Kingdom
facility: Newquay Medical
state: Cornwall
city: Chesterfield
country: United Kingdom
facility: Royal Primary care Ashgate
state: Derbyshire
city: Darlington
country: United Kingdom
facility: Carmel Medical Practice
state: Durham
city: Leicester
country: United Kingdom
facility: PRC Leciester
state: East Midlands
city: Hitchin
country: United Kingdom
facility: Portmill Surgery
state: Herts.
city: Blackpool
country: United Kingdom
facility: Layton Medical Centre
state: Lancashire
city: Blackpool
country: United Kingdom
facility: Waterloo Medical Centre
state: Lancashire
city: Hinckley
country: United Kingdom
facility: Burbage Surgery
state: Leicestershire
city: Harrow
country: United Kingdom
facility: Belmont Health Centre
state: London
city: Upton
country: United Kingdom
facility: The Adam Practice
state: Poole
city: Bath
country: United Kingdom
facility: Heart of bath Medical Partnership
state: Somerset
city: Bristol
country: United Kingdom
facility: West Walk Surgery
state: Somerset
city: Nailsea
country: United Kingdom
facility: Tyntesfield Medical Group
state: Somerset
city: Rotherham
country: United Kingdom
facility: Clifton Medical centre
state: South Yorkshire
city: Cardiff
country: United Kingdom
facility: Ely Bridge
state: Wales
city: Atherstone
country: United Kingdom
facility: Atherstone Surgery
state: Warwickshire
city: Coventry
country: United Kingdom
facility: Lakeside Surgery
state: West Midlands
city: Leamington Spa
country: United Kingdom
facility: Sherbourne Medical Centre
state: West Midlands
city: Chippenham
country: United Kingdom
facility: Hathaway Surgery
state: Wiltshire
city: Chippenham
country: United Kingdom
facility: Rowden Surgery
state: Wiltshire
city: Trowbridge
country: United Kingdom
facility: Trowbridge Health Centre
state: Wiltshire
city: London
country: United Kingdom
facility: Bart's NHS Trust
city: Sheffield
country: United Kingdom
facility: Ecclesfield group Practice
Study officials:
affiliation: The George Institute
name: Anthony Rodgers, Professor
role: PRINCIPAL_INVESTIGATOR
References: