Table 1
Short-term RCTs of triple or quadruple low-dose combination therapy.
| TRIAL | COMPARISON | BP REDUCTION | TOLERABILITY |
|---|---|---|---|
| Mahmud et al 2007 [18] | 4 × ¼ dose (amlodipine 1.25 mg, atenolol 12.5 mg, bendroflumethiazide 0.625 mg, captopril 25 mg, n = 22) vs each at standard dose (n = 86) | 13/8 mmHg (p < 0.001) | No SAEs or treatment withdrawals |
| Wald et al 2012 [19] | 3 × ½ dose (amlodipine 2.5 mg, losartan 25 mg, hydrochlorothiazide 12.5 mg) vs. placebo (n = 86 crossover) | 18/10 mmHg (P < 0.001) | No SAEs or treatment withdrawals |
| Chow et al 2017 [21] | 4 × ¼ dose (irbesartan 37.5 mg, amlodipine 1.25 mg, HCTZ 6.25 mg and atenolol 12.5 mg) vs. placebo (n = 21 crossover) | 22/13 mmHg p < 0.001 | No SAEs or treatment withdrawals |
| Hong et al 2020 [54] | amlodipine, losartan and chlorthalidone at 3 × ½ dose, 3 × ⅓ dose and 3 × ¼ dose (n = 107) vs. placebo (n = 36) for 8 weeks | 17/9, 20/10 and 14/8 mmHg, respectively (all p < 0.01) | No SAEs, 1 treatment-related withdrawal |
Figure 1
Summary of the QUARTET [22] and TRIUMPH [20] trials of low-dose combination vs usual care for initial/early treatment of hypertension.
Table 2
GMRx2 strengths.
| GMRx2 DOSE VERSION | STANDARD DOSES OF COMPONENT DRUGS | TELMISARTAN/AMLODIPINE/INDAPAMIDE DOSES (MG) |
|---|---|---|
| 1 | ¼ | 10/1.25/0.625 |
| 2 | ½ | 20/2.5/1.25 |
| 3 | 1 | 40/5/2.5 |
Table 3
Summary of characteristics of the phase III efficacy and safety trials of GRMx2.
| TRIAL | DESIGN | PARTICIPANT KEY ELIGIBILITY FOR RANDOMIZATION | KEY EXCLUSION CRITERIA | RANDOMIZED ALLOCATION | INTERVENTION, COMPARATOR | DURATION OF RANDOMIZED TREATMENT AND FOLLOW UP | PRIMARY OUTCOME | PRIMARY SAFETY OUTCOME | SAMPLE SIZE, POWER |
|---|---|---|---|---|---|---|---|---|---|
| GMRx2 ACT | Randomized, double-blind, active-controlled, parallel-group, international multi-center | Adults on ≤3 BP-lowering drugs, adhering to and tolerating GMRx2 dose 2 run-in and post run-in home SBP 110-154 mmHg | Receiving 4 or more BP-lowering drugs. Contraindication to the individual components of the GMRx2 | 2:1:1:1 ratio to GMRx2 or one of the three comparators of dual combinations | Intervention: GMRx2 dose 2 Comparators: telmisartan 20 + amlodipine 2.5, Or telmisartan 20 + indapamide 1.25, Or amlodipine 2.5 + indapamide 1.25 for 6 weeks, forced uptitration to double dose for 6 weeks | 12 weeks + 4 weeks safety follow up | Difference in change in home mean SBP from randomization to week 12 | Adverse events (AEs) leading to discontinuation of trial medication from baseline to week 12 | 1500, ≥95% for each of the three comparisons |
| GMRx2 PCT | Randomized, double-blind, placebo-controlled, parallel-group, international multi-center | Adults on ≤2 BP-lowering drugs, adhering to and tolerating placebo run-in and post run-in home SBP 130-154 mmHg | Receiving 2 or more BP-lowering drugs. Contraindication to placebo run-in or any of the randomized medications | 2:2:1 ratio to GMRx2 dose 1, GMRx2 dose 2 or placebo | Intervention 1: GMRx2 dose 1 for 4 weeks Intervention 2: GMRx2 dose 2 for 4 weeks Comparator: Placebo for 4 weeks | 4 weeks + 4 weeks safety follow up | Difference in change in home mean SBP from randomization to week 4 | AEs leading to discontinuation of trial medication from baseline to week 4 | 250, >90% for GMRx2 vs placebo, and >80% for GMRx2 dose 1 vs GMRx2 dose2 |
Table 4
GMRx2 Program Steering Committee.
| NAME | AFFILIATION | ROLE |
|---|---|---|
| Professor Paul Whelton | Tulane University, New Orleans, USA | Steering Committee Member (Chair) |
| Professor William Cushman | University of Tennessee Health Science Center, USA | Steering Committee Member |
| Professor Asita de Silva | University of Kelaniya, Sri Lanka | Steering Committee Member |
| Professor Diederick Grobbee | University Medical Center Utrecht, Utrecht University, The Netherlands | Steering Committee Member |
| Professor Krzysztof Narkiewicz | Medical University of Gdańsk, Poland | Steering Committee Member |
| A/Professor Dike Ojji | University of Abuja, Nigeria | Steering Committee Member |
| Professor Suzanne Oparil | University of Alabama at Birmingham, USA | Steering Committee Member |
| Professor Neil Poulter | Imperial College, London, UK | Steering Committee Member |
| Professor Markus Schlaich | The University of Western Australia, Australia | Steering Committee Member |
| A/Professor Wilko Spiering | University Medical Center Utrecht, Utrecht University, The Netherlands | Steering Committee Member |
| Professor Bryan Williams | University College, London, UK | Steering Committee Member |
| Professor Jackson T Wright Jr | University Hospitals Cleveland Medical Center, Case Western Reserve University, USA | Steering Committee Member |
| Professor Anthony Rodgers* | The George Institute for Global Health, University of New South Wales, Australia | Steering Committee Member, Academic Coordinating Center |
| Dr Abdul Salam* | The George Institute for Global Health, University of New South Wales, India | Steering Committee Member, Academic Coordinating Center |
| Professor Aletta E Schutte* | The George Institute for Global Health, University of New South Wales, Australia | Steering Committee Member, Academic Coordinating Center |
| Professor Gian Luca Di Tanna* | The George Institute for Global Health, University of New South Wales, Australia | Academic Coordinating Center |
[i] * Non-voting members.
Table 5
GMRx2 Data and Safety Monitoring Board.
| NAME | AFFILIATION | ROLE |
|---|---|---|
| Professor Lawrence Appel | Johns Hopkins University, Bal, USA | Chair |
| Professor Mark Espeland | Wake Forest University, NC, USA | Member |
| Professor Michael Weber | State University of New York, NY, USA | Member |
| Professor Gian Luca Di Tanna | University of Applied Sciences and Arts of Southern Switzerland, Lugano, Switzerland | Blinded statistician |
| Chris Gianacas | The George Institute for Global Health, Sydney, Australia | Blinded statistician |
| Xiaoqiu (Julia) Liu | The George Institute for Global Health, Sydney, Australia | Unblinded statistician |
| Michelle Leroux | Toronto, Canada | Executive Secretary |
Figure 2
Schema for trial comparing GMRx2 with each dual combination (GMRx2 ACT).
Figure 3
Schema for trial comparing GMRx2 with placebo (GMRx2 PCT).