Rationale for a New Low-Dose Triple Single Pill Combination for the Treatment of Hypertension

Two recent large trials showed the potential of single pill combinations (SPCs) with ≥3 low-dose components among people with hypertension who were untreated or receiving monotherapy. In both trials, these ‘hypertension polypills’ were superior to usual care, achieving >80% BP control without increasing withdrawal due to side effects. However, there are no such products available for prescribers. To address this unmet need, George Medicines developed GMRx2 with telmisartan/amlodipine/indapamide in three strengths (mg): 10/1.25/0.625, 20/2.5/1.25; 40/5/2.5. Two pivotal trials are ongoing to support FDA submission for the treatment of hypertension, including initial treatment. These assess efficacy and safety of GMRx2 compared to: placebo, and each of the three possible dual combinations. Regulatory submissions are planned for 2024, with the aim of providing access to GMRx2 in developed and developing regions. Wider implementation of GMRx2-based treatment strategies will be guided by further research to inform access and appropriate scale up.

• Much of the BP-lowering efficacy of any drug in monotherapy is achieved at low doses and efficacy dose-response curves are typically shallow above one quarter of the standard dose [14,15].
• At low doses there are few or no adverse effects, but for many classes adverse effects rise steeply and steadily as the dose increases [14,15].
• The incidence of idiosyncratic reactions (such as anaphylaxis) to BP-lowering drugs is so low that the risks for a patient simultaneously taking three drugs is acceptably low [15].
• There is additivity of effects across drug classes that target different pathophysiological pathways [10,14,15].
• There is clear evidence of greater reduction in cardiovascular events with greater BP reduction [16,17].
Large and tolerable reductions in BP have been demonstrated in four short-term (4-12 weeks) trials of triple or quadruple low-dose SPC therapy (Table 1) [18][19][20][21].These trials provided the rationale for the triple pill vs usual care management for patients with mild-to-moderate hypertension (TRIUMPH) [20] and the quadruple ultralow dose treatment for hypertension (QUARTET) [22] trials among patients with hypertension, who were either untreated or managed with monotherapy.TRIUMPH was a six-month open label randomized controlled trial (RCT) conducted in Sri Lanka that compared initial or early low-dose triple single pill combination (SPC) (telmisartan 20 mg, amlodipine 2.5 mg, chlorthalidone 12.5 mg) with usual care in adults with uncontrolled hypertension [20].The QUARTET was a 12-week double blinded RCT in 591 Australian adults with uncontrolled hypertension that compared treatment starting with an ultra-low-dose combination (containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) to guideline-recommended treatment starting with standard dose monotherapy (irbesartan 150 mg).As shown in Figure 1, both trials showed large improvement in BP control achieved quickly and sustained over 6-12 months without usual care group 'catch-up' despite considerably higher rates of add-on BP treatment in the usual care group.Furthermore, the usual care groups had superior levels of care, with lower treatment inertia rates and higher BP control rates than are generally seen in normal clinical practice.

RATIONALE FOR A NEW TRIPLE SINGLE PILL COMBINATION
Currently available triple SPCs are only indicated for substitution among patients already taking all the three-component drugs, or as an add-on/switch therapy among patients not adequately controlled on two of the component drugs [23][24][25].None of the available triple SPCs are available in low-dose strengths, nor indicated for initial treatment.Furthermore, there are no existing SPC products on the market with low-doses of an angiotensin receptor blocker (ARB), calcium channel blocker (CCB) and a thiazide-like diuretic.To address this unmet need, George Medicines (GM) developed a new SPC containing telmisartan, amlodipine and indapamide, named GMRx2, in three strengths (Table 2).The rationale for the choice of the individual drug components of GMRx2 is based on several considerations [26].Hypertension guidelines recommend use of drugs from the four following antihypertensive drug classes: ACEI, ARB, CCB, or thiazide/like diuretics for first-line therapy of adults with hypertension.ARBs are better tolerated than ACEIs and are less likely to cause angioedema among black patients [27], with direct randomized comparisons suggesting comparable efficacy in reducing CV events [28][29][30].Telmisartan has the longest half-life (~24 hours) of all ARBs [31].Among CCBs, amlodipine has been used most commonly in CV outcome trials, has little potential for drug interactions and has a long half-life (30-50 hours) [17,32].Low-doses of the thiazide-like indapamide provide good BP reduction with low side effect profiles [15,[33][34][35][36], has a half-life of 16 to 18 hours [37], and is widely available internationally.
The systolic BP (SBP)-lowering efficacy of GMRx2 strengths 1, 2 and 3 (Table 2) from a baseline SBP of 150 mmHg are expected to be approximately 13 mmHg, 18 mmHg and 25 mmHg, respectively [38].This represents a much greater and clinically important BP reduction in comparison to standard-dose monotherapy, which reduces SBP compared with placebo by only 8-9 mmHg on average, with each doubling of dose conferring only a 1-2 mmHg incremental SBP reduction [10,15].Dual combinations typically show only a 1-2 mmHg difference between neighboring drug doses and an SBP reduction of around 20 mmHg at maximal dose [10,15,38].The rationale for developing GMRx2 is, therefore, in line with USA Food & Drug Administration (FDA) observations: 'Over the last decade, the Agency has actively discouraged antihypertensive monotherapy and combination doses with effects that were very close together, considering them a nuisance to physicians seeking to get patients to goal [39]'

SUMMARY OF THE GMRX2 TRIAL PROGRAM
The main design features of the two phase III trials for FDA approval of GMRx2 are outlined in Table 3, with further details reported on clinicaltrials.gov[40,41].Both trials are expected to be completed in 2023.The overall clinical program is directed by an independent steering committee of international experts (Table 4) and an independent data and safety monitoring board (Table 5).

ACTIVE-CONTROLLED TRIAL
The main objective of this trial is to assess the contribution of each GMRx2 component drug to its overall effects, by assessing the efficacy and safety of GMRx2 compared to each of the three possible dual combinations of the component drugs.The key eligibility criteria are individuals with hypertension currently receiving 0-3 medications, for whom there is uncertainty about treatment with GMRx2 vs dual combinations.The design is summarized in Figure 2. The runin period will assess participant adherence to trial medication and trial procedures, hence maximizing the likelihood of participant follow-up and complete data collection.The doubleblind period will assess the efficacy and safety of GMRx2 dose versions 2 and 3, sequentially, compared to the corresponding three possible dual combinations of the component drugs.The duration of six weeks for each treatment period will allow comparison of the maximal effects of treatment.The safety follow-up period will assess safety over 4 weeks following switching from randomized trial medication to open label usual care treatment.
Participants who adhere to GMRx2 dose 2 during the run-in period and have an average home SBP 110-154 mmHg at the end of run-in period.Participants are being recruited from Australia, the Czech Republic, New Zealand, Poland, Sri Lanka, the United Kingdom and the USA.The primary outcome is the difference in change of home SBP from randomization to week 12 (averaged over the preceding week).Randomization was completed with 1385 participants in May 2023, which was >90% of the original 1500 planned, with the steering committee recommending a reduced sample size, without any reference to unblinded data, given the likelihood of adequate power and unexpected problems with drug supply due to pandemicrelated supply chain issues.This sample size will provide over 97% power to detect a minimum clinically significant difference of 3 mmHg in mean home seated level of SBP for each of the three comparisons of GMRx2 vs dual therapy, assuming a common standard deviation in SBP of 11 mmHg and a correlation coefficient of 0.4.The overall power for all three comparisons will therefore be > 90%.Previous trials have demonstrated an additional reduction in office SBP of approximately 5 mmHg [42].

PLACEBO-CONTROLLED TRIAL
The main objective of this trial is to investigate the efficacy and safety of GMRx2 compared to placebo.Placebo controlled trials provide important evidence on the full effects of treatment, including both efficacy and safety.Without such evidence it would be difficult to assess the full degree of efficacy, or to reliably attribute the causality of any adverse effects observed.The key eligibility criteria are individuals with hypertension currently receiving 0-1 medications and low estimated cardiovascular risk (e.g., Pooled Cohorts Equation <10% ten-year risk), for whom there is uncertainty about treatment with GMRx2 vs. placebo.The design is summarized in Figure 3.The placebo run-in period will assess each participant's adherence to trial procedures and allow confirmation of untreated mean BP levels, hence enhancing the power of the trial to detect a difference between GMRx2 and placebo.The double-blind period will assess the efficacy and safety of GMRx2 dose 1 and GMRx2 dose 2 compared to placebo.The safety follow-up period will assess safety over four weeks following switching from randomized trial medication to open label usual care treatment.
Participants who tolerate placebo and whose average home SBP is between 130-154 mmHg after a two-week run-in period on placebo are eligible for randomization.Participants were recruited from Australia, Nigeria, Sri Lanka and the USA.The primary outcome is difference in change in home SBP from randomization to week 4 (averaged over the week preceding the final clinic visit).The trial sample size of 250 randomized participants (100 each to GMRx2 strength 1 and 2, and 50 to placebo) is expected to provide 90% power to detect a difference of at least 9 mmHg in mean home SBP for each of the active drug comparisons vs placebo, assuming a common standard deviation of 11 mmHg.

Open-label extension of active and placebo-controlled trial
An open-label extension period of the above two trials will be conducted in some sites, to assess the efficacy and safety of GMRx2 over a one-year period.Willing participants on ≤3 BP-lowering drugs, being adherent to the trial procedures will be consented to be switched at the end of the double-blind period to open label GMRx2.Follow-up visits for the open-label extension study will be scheduled at weeks 2 and 4, given the evidence that almost all the BP-lowering effects of treatment will accrue within two weeks [43], hence providing an opportunity for the study to assess the effects of an evidence-based, accelerated titration schedule.Subsequent follow-up visits will be conducted at week 12, 28, and 40.Participants will continue to monitor home BP, with uptitration for those with home BP > 130/80 mmHg: GMRx2 strength 1 à GMRx2 strength 2 → GMRx2 strength 3 → GMRx2 strength 3 plus telmisartan 40 mg/amlodipine five mg → GMRx2 strength 3 plus telmisartan 40 mg/amlodipine 5 mg plus spironolactone 25 mg.Each titration step was chosen to provide an estimated additional SBP reduction of at least 5 mmHg, in keeping with the strategy of avoiding titration steps that only confer additional average SBP reductions of 1-3 mmHg, such as doubling the dose of a single drug [10,15,42].

Pharmacokinetic studies
The GMRx2 development program also includes pharmacokinetic studies [44,45].The first trial aimed to evaluate pharmacokinetic drug interactions between telmisartan, amlodipine and indapamide and GMRx2.The trial design was a single center, open, randomized, single-dose, twoperiod, four-treatment, two-sequence, crossover study with a washout period between doses of at least 14 days for Cohort 1 (telmisartan) and Cohort 3 (indapamide), and 28 days for Cohort 2 (amlodipine).In total, 122 healthy volunteers were enrolled and randomized.The second trial aims to evaluate the effect of food on bioavailability (AUC and Cmax) of GMRx2.It is a single center, open, randomized, single-dose, two-period, two-treatment (fed vs. fasting), two-sequence, crossover study with a washout period between doses of at least 28 days.Performed where?
The delivery of optimal blood pressure control in Africa (VERONICA) -Nigeria trial VERONICA-Nigeria is an investigator-initiated trial being conducted in Black Africans that is comparing a triple therapy SPC-based treatment protocol with treatment based on the Nigeria hypertension guidelines to determine the effectiveness, safety, and feasibility of the SPC for control of high BP in Nigeria.Eligibility is restricted to Black African adults who are untreated or on one BP-lowering medication for ≥2 weeks with clinic BP 140-179 mmHg and/or DBP 90-109 mmHg.The trial compares treatment with an accelerated, simplified, GMRx2-based regimen to the Nigeria hypertension treatment protocol, and the primary outcome is difference in change in home SBP from randomization to month 6.A total of 300 participants are planned, with outcomes expected in late 2023.
Triple therapy prevention of recurrent intracerebral disease events trial (TRIDENT) TRIDENT is an investigator initiated and conducted, multicenter, international, double-blinded, placebo-controlled, parallel-group, randomized trial designed to determine the efficacy of more intensive BP control with a low-dose SPC (GMRx2 dose 2) strategy in addition to standard of care, on stroke recurrence in patients with a history of acute stroke due to intracerebral hemorrhage [46].Eligible participants are adults with a history primary intracerebral hemorrhage, SBP of 130-160 mmHg, and no contraindication to the randomization of GMRx2-dose version 2 or placebo in addition to any existing BP lowering regimen.The primary outcome is time to first occurrence of recurrent stroke.A total of 1500 randomized participants are planned with a mean duration of 3 years follow-up.

DISCUSSION
Low-dose triple SPCs have the potential to significantly improve BP control by providing improved efficacy and adherence, and reduced therapeutic inertia with fewer adverse effects compared to current approaches.However, to date there is limited clinical research in this area, and no low-dose triple SPCs on the market globally.The GMRx2 clinical development aims to address these gaps, assessing efficacy and tolerability, with two pivotal regulatory approval trials, and a series of investigator-initiated studies.The phase III and pharmacokinetics trial program described in this manuscript has been approved by the FDA to potentially support an indication for the treatment of hypertension, including initial treatment.Regulatory approval will also be sought in other markets globally, including importantly low-and middle-income countries (LMICs).Globally there is a dearth in availability and affordability of SPCs in LMICs, where more effective treatment is most needed [47,48].For example, BP levels are now among the highest globally in Sub-Saharan Africa, where over 200 million people are projected to have hypertension by 2030.Furthermore, hypertension is the leading cause of the rapidly increasing burden of noncommunicable diseases, and less than one in seven with hypertension achieve adequate control [2,49,50].Market access is also planned in high income settings outside of the USA, but this may be delayed in Europe, given the current requirements for additional studies [51].The majority of SPC products in Europe are approved only on the basis of bioequivalence studies, and such approvals lead to a 'straight substitution' indication (i.e., for use only in people already stabilized on the same drugs at the same doses).This is not possible or appropriate for novel low-dose combinations, developed to help address poor adherence and treatment inertia.
Following regulatory approval of GMRx2, additional studies and implementation research will be required to further delineate the role and cost-effectiveness of GMRx2 compared to current usual care modalities in different patient populations and geographies.Further indications will also be explored such as the prevention of stroke in people with intracerebral hemorrhage [46] and the prevention of dementia [52].A key issue will be reimbursement in HIC markets, availability and affordability.Most importantly research will be conducted to inform access and appropriate scale-up in disadvantaged populations, where the burden of high BP is highest, and reliable access to affordable, effective therapies is lowest [53].

ACEI:
Angiotensin converting enzyme inhibitor ARB: angiotensin receptor blocker BP: blood pressure CCB: calcium channel blocker FDA: United States Food and Drug Administration LMIC: low-and middle-income country RCT: randomized controlled trial SPC: single pill combination SBP: systolic blood pressure USA: United States of America

Table 1
Short-term RCTs of triple or quadruple low-dose combination therapy.

Table 3
Summary of characteristics of the phase III efficacy and safety trials of GRMx2.Rodgers et al.

Table 4
GMRx2 Program Steering Committee.Rodgers et al.

Table 5
GMRx2 Data and Safety Monitoring Board.
Rodgers et al.