Investigating the endothelin receptor antagonist aprocitentan in resistant hypertension: design and baseline characteristics of the PRECISION study

Abstract

Abstract The endothelin (ET) system plays an important role in hypertension, especially in volume and salt-dependent forms, which are common in patients with resistant hypertension (RHT). Therapies targeting the ET system may provide a new treatment option. A Phase 2 dose-finding study demonstrated an effect of the dual ET receptor antagonist aprocitentan monotherapy on blood pressure (BP) [1]. PRECISION is a randomized, parallel-group, Phase 3 study assessing the short-term effect of 2 doses of aprocitentan (12.5 mg and 25 mg) and its long-term sustained effect on BP. Following randomization, patients entered a 4-week, double-blind (DB), placebo-controlled part, followed by aprocitentan 25 mg for 32 weeks, and a 12-week, placebo-controlled, randomized withdrawal part (Figure 1). The primary endpoint is the change in systolic BP (SBP) from randomization to week 4 and the key secondary endpoint is the change in SBP from re-randomization to week 40. The study enrolled 1971 patients with RHT diagnosed according to the site's medical practice, from 193 centres worldwide. Entry criteria included sitting SBP [SiSBP] ≥140 mmHg, measured by unattended automated office BP (uAOBP, reducing the white coat effect), despite the use of ≥3 antihypertensive medications. During the screening period of 4 to 12 weeks, secondary causes of hypertension were excluded by the investigator and patients still having SiSBP ≥140 mmHg were switched from their individual antihypertensive drugs to a single-tablet, triple combination of valsartan 160 mg /amlodipine 5 or 10 mg /hydrochlorothiazide 25 mg o.d. (minimizing medical inertia and improving drug adherence) for at least 4 weeks before entering the placebo run-in (RI) period. The screening failure rate of 53% is indicative of the high incidence of apparent RHT within the hypertensive population. Patients continuing having SiSBP ≥140 mmHg on triple therapy (true RHT) then entered the 4-week, single-blind placebo RI period. Of these patients, 20% failed to be randomized, most frequently because of SiSBP <140 mmHg, possibly due to a placebo effect. As of 12 March 2021, 860 patients were in the placebo RI period and 664 patients were randomized, 30% from North America, 62% from Europe, and 8% from Asia/Australia. Mean age was 61.8 years (standard deviation [SD]=10.8). 40% of patients were women, 11% were Black, 5% Asian, and 83% White. Mean body mass index (BMI) was 33.6 kg/m2 (SD=6.4) and mean estimated glomerular filtration rate (eGFR) was 76.8 mL/min/1.73 m2 (including 21% chronic kidney disease [CKD] stage 3–4 patients). Medical history included diabetes (54%), myocardial infarction (30%), stroke (23%), congestive heart failure (19%), and sleep apnoea (15%). In addition to the standardized antihypertensive medication, 59% of patients used beta-blockers. Mean baseline SiSBP/SiDBP was 153/88 mmHg. Results of the trial will be available in 2022. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): The PRECISION study is sponsored by Idorsia Pharmaceuticals Ltd.