Home » Trials » SLCTR/2021/007


Efficacy and safety of GMRx2 (a single pill combination containing telmisartan/amlodipine/indapamide) compared to dual combinations for the treatment of hypertension: An international, multi-center, randomized, double-blind, active-controlled, parallel-group trial.

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SLCTR Registration Number

SLCTR/2021/007


Date of Registration

05 Mar 2021

The date of last modification

Mar 05, 2021



Application Summary


Scientific Title of Trial

Efficacy and safety of GMRx2 (a single pill combination containing telmisartan/amlodipine/indapamide) compared to dual combinations for the treatment of hypertension: An international, multi-center, randomized, double-blind, active-controlled, parallel-group trial.


Public Title of Trial

Efficacy and safety of GMRx2 (a single pill combination containing telmisartan/amlodipine/indapamide) compared to dual combinations for the treatment of hypertension: An international, multi-center, randomized, double-blind, active-controlled, parallel-group trial.


Disease or Health Condition(s) Studied

Hypertension


Scientific Acronym

GMRx2-HTN-2020-ACT1


Public Acronym

GMRx2-HTN-2020-ACT1


Brief title

Efficacy and safety of GMRx2 compared to dual combinations for the treatment of hypertension


Universal Trial Number

U1111-1262-2089


Any other number(s) assigned to the trial and issuing authority

Registered with clinicaltrials.gov. Trial registration no : NCT04518293 ERC Number - P/134/10/2020


Trial Details


What is the research question being addressed?

What is the efficacy and safety of GMRx2 for lowering BP compared to each of the three dual combinations of component drugs of GMRx2 at equivalent doses?


Type of study

Interventional


Study design

Allocation

Randomized controlled trial


Masking

Double blinded : Participants, Investigators, Data analysts, Healthcare providers, Outcome assessors


Control

Active


Assignment

Parallel


Purpose

Treatment


Study Phase

Phase 3


Intervention(s) planned

Study setting:

  1. National Hospital of Sri Lanka
  2. Colombo North Teaching Hospital
  3. Negombo District General Hospital
  4. Sri Jayewardenepura General Hospital
  5. Colombo South Teaching Hospital
  6. Kandy National Hospital
  7. Kurunegala Teaching Hospital
  8. Jaffna Teaching Hospital
  9. Karapitiya Teaching Hospital

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.

Single-Blind Active Run-In Period: During the screening visit, 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) after home BP measurement is performed.

Double-Blind Treatment Period: Following randomization, participants will be allocated in a double-blind fashion to one of 4 randomized group. 1. Group 1 (Triple therapy - TAI (GMRx2))-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. (N= 600) 2. Group 2 (dual therapy)- Telmisartan 20 mg/amlodipine 2.5 mg. At Week 6 visit, forced up-titration to telmisartan 40 mg/amlodipine 5 mg (N= 300) 3. Group 3 (dual therapy)- Telmisartan 20 mg/indapamide 1.25 mg. At Week 6 visit, forced up-titration to telmisartan 40 mg/indapamide 2.5 mg (N= 300) 4. Group 4 (dual therapy)- Amlodipine 2.5 mg/indapamide 1.25 mg. At Week 6 visit, forced up-titration to amlodipine 5 mg/indapamide 2.5 mg (N=300)

Randomisation method: A central computer based randomization sequence will be generated. Stratification will be by trial site. Participants will be randomised in the ratio of 2:1:1:1.

On the day of randomization visit, all participants will be prescribed and dispensed trial medication to be taken between the randomization and Week 6 visit (period 2). On the day of the Week 6 visit, all participants will be prescribed and dispensed trial medication (the same initial treatment but at double dose) to be taken between Week 6 and Week 12 visit (period 3). All participants will be up-titrated at Week 6, unless the investigator believes there is a specific contraindication for a particular participant, such as symptomatic hypotension or is asymptomatic with very low home or clinical BP levels (i.e. SBP <100 mmHg). If a participant is asymptomatic but is judged to be not suitable for dose doubling, then they should be continued on existing trial medication for the remaining 6 weeks. Participants should take trial medication once daily in the morning either before or after breakfast immediately after taking home BP measurement.


Inclusion criteria

At screening visit 1. Adults of age ?18 years (both male and female) 2. Clinic SBP: 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 120-154 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.


Exclusion criteria

At screening visit 1. Receiving 4 or more BP-lowering drugs. 2. 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. 3. 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). 4. 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. 5. Current/history of transient ischemic attack, stroke, or hypertensive encephalopathy. 6. Current/history of acute coronary syndrome, unstable angina, myocardial infarction, percutaneous transluminal coronary revascularization, or coronary artery bypass graft. 7. Current/history of New York Heart Association class III and IV congestive heart failure. 8. Current/history of a known secondary cause of hypertension, such as primary aldosteronism, renal artery stenosis, pheochromocytoma, or Cushing's syndrome. 9. Current/history of substantially uncontrolled diabetes (HbA1c > 11.0%) within last three months. 10. Current/history of end-stage renal disease or anuria or estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2. 11. Current/history of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper limit of normal range within 6 months. 12. 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. 13. Arm circumference that is too large (>55 cm) or too small (<20 cm) to allow accurate measurement of BP. 14. 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. 15. 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). 16. 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. 17. Individuals working >2 nightshifts per week. 18. Participated in any investigative drug or device trial within the previous 30 days. 19. 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: a. 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. b. 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 outcome(s)

1.

Difference in change in home SBP

[

0 and at 12 Weeks

]
2.

Percentage of participants discontinued trial medication due to an Adverse Event (AE) or a Serious Adverse Event (SAE)

[

0 and at 12 Weeks

]

Secondary outcome(s)

1.

Difference in change in clinic seated mean SBP from baseline to Week 12

[

12 weeks

]
2.

Difference in change in clinic seated mean SBP from baseline to Week 6

[

6 weeks

]
3.

Difference in change in clinic seated mean DBP from baseline to Week 12

[

12 weeks

]
4.

Difference in change in clinic seated mean DBP from baseline to Week 6

[

6 weeks

]
5.

Percentage of participants with clinic seated mean SBP <140 and DBP <90 mmHg at Week 12

[

12 weeks

]
6.

Percentage of participants with clinic seated mean SBP <140 and DBP <90 mmHg at Week 6

[

6 weeks

]
7.

Percentage of participants with clinic seated mean SBP <130 and DBP <80 mmHg at Week 12

[

12 weeks

]
8.

Percentage of participants with clinic seated mean SBP <130 and DBP <80 mmHg at Week 6

[

6 weeks

]
9.

Difference in change in home seated mean SBP from baseline to Week 6

[

6 weeks

]
10.

Difference in change in home seated mean DBP from baseline to Week 12

[

12 weeks

]
11.

Difference in change in home seated mean DBP from baseline to Week 6

[

6 weeks

]
12.

Difference in change in trough home seated mean SBP from baseline to week 12

[

12 weeks

]
13.

Difference in change in trough home seated mean SBP from baseline to Week 6

[

6 weeks

]
14.

Percentage of participants with home seated mean SBP <135 and DBP <85 mmHg at Week 12

[

12 weeks

]
15.

Percentage of participants with home seated mean SBP <135 and DBP <85 mmHg at Week 6

[

6 weeks

]
16.

Percentage of participants with home seated mean SBP <130 and DBP <80 mmHg at Week 12

[

12 weeks

]
17.

Percentage of participants with home seated mean SBP <130 and DBP <80 mmHg at Week 6

[

6 weeks

]
18.

Percentage of participants discontinued trial medication due to AE/SAE from baseline to Week 6.

[

6 weeks

]
19.

Percentage of participants with an SAE from baseline to Week 12.

[

12 weeks

]
20.

Percentage of participants with SAE from baseline to Week 6.

[

6 weeks

]
21.

Percentage of participants with symptomatic hypotension from baseline to Week 12.

[

12 weeks

]
22.

Percentage of participants with symptomatic hypotension from baseline to Week 6.

[

6 weeks

]
23.

Percentage of participants with serum sodium concentration below 135 mmol/l at Week 12.

[

12 weeks

]
24.

Percentage of participants with serum sodium concentration below 135 mmol/l at Week 6.

[

6 weeks

]
25.

Percentage of participants with serum sodium concentration above 145 mmol/l at Week 12.

[

12 weeks

]
26.

Percentage of participants with serum sodium concentration above 145 mmol/l at Week 12.

[

12 weeks

]
27.

Percentage of participants with serum sodium concentration above 145 mmol/l at Week 6.

[

6 weeks

]
28.

Percentage of participants with serum potassium concentration below 3.5 mmol/l at Week 12.

[

12 weeks

]
29.

Percentage of participants with serum potassium concentration below 3.5 mmol/l at Week 6.

[

6 weeks

]
30.

Percentage of participants with serum potassium concentration above 5.5 mmol/l at Week 12.

[

12 weeks

]
31.

Percentage of participants with serum potassium concentration above 5.5 mmol/l at Week 6.

[

6 weeks

]
32.

Percentage of participants with eGFR drop of over 30% from baseline to Week 12.

[

12 weeks

]
33.

Percentage of participants with eGFR drop of over 30% from baseline to Week 6.

[

6 weeks

]

Target number/sample size

1500 participants (600/300/300/300 in each arm)


Countries of recruitment

Sri Lanka


Anticipated start date

2021-03-06


Anticipated end date

2021-09-27


Date of first enrollment


Date of study completion


Recruitment status

Pending


Funding source

Rose Anne McErlane Global Project Manager Centrum House, 36 Station Road Egham, Surrey, TW20 9LF United Kingdom Phone: +44(0) 7901 613 680 Email: gmrx2gpm@georgeclinical.com


Regulatory approvals

Pending



State of Ethics Review Approval


Status

Approved


Date of Approval

2020-12-08


Approval number

P/134/10/2020


Details of Ethics Review Committee

Name: Ethics Review Committee of the Faculty of Medicine, University of Kelaniya.
Institutional Address:P.O Box 6, Thalagolla Road, Ragama, Sri Lanka
Telephone:+94 11 2961267
Email: ercmed@kln.ac.lk

Contact & Sponsor Information


Contact person for Scientific Queries/Principal Investigator

Dr. Gotabhaya Ranasinghe
Consultant Cardiologist
Institute of Cardiology, National Hospital of Sri Lanka, Colombo 10 – 01000, Sri Lanka

+94777319143

gotabhayar@gmail.com

Contact Person for Public Queries

Dr. Gotabhaya Ranasinghe
Consultant Cardiologist
Institute of Cardiology, National Hospital of Sri Lanka, Colombo 10 – 01000, Sri Lanka

+94777319143

gotabhayar@gmail.com


Primary study sponsor/organization

Dr. Karl Roberts
Chief Business Officer
9 Dallington St, Clerkenwell London EC1V 0LN United Kingdom
+44 7983 578 290

kroberts@george-health.com

Secondary study sponsor (If any)







Trial Completion details


Do the investigators plan to share identified individual clinical trial participant-level data (IPD)?

No


IPD sharing plan description


Study protocol available

No


Protocol version and date

Not Available


Protocol URL

Not Available


Results summary available

No


Date of posting results


Date of study completion


Final sample size


Date of first publication


Link to results


Brief summary of results