Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension.

Verweij P ，Danaietash P ，Flamion B ，Ménard J ，Bellet M ... -  《-》

Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial.

Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was -15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, -15·2 (0·9) mm Hg for aprocitentan 25 mg, and -11·5 (0·9) mm Hg for placebo, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was -4·2 mm Hg (95% CI -6·2 to -2·1) and -5·9 mm Hg (-7·9 to -3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p<0·0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment. In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40. Idorsia Pharmaceuticals and Janssen Biotech.

Schlaich MP ，Bellet M ，Weber MA ，Danaietash P ，Bakris GL ，Flack JM ，Dreier RF ，Sassi-Sayadi M ，Haskell LP ，Narkiewicz K ，Wang JG ，PRECISION investigators ... -  《-》

Identifying and treating resistant hypertension in PRECISION: A randomized long-term clinical trial with aprocitentan.

The design and baseline data of the PRECISION study, which evaluates the effect of the dual endothelin receptor antagonist aprocitentan on blood pressure (BP) in patients with resistant hypertension (RHT) are presented. The study is a blinded, randomized, parallel-group Phase 3 study and its three-part design assesses the short-term and sustained long-term effects of aprocitentan on BP. Results are expected in 2022. Patients with uncontrolled BP (measured as unattended automated office BP) despite the use of three or more antihypertensive medications for at least 1 year were screened. They were switched to a single-tablet triple fixed combination antihypertensive therapy for at least 4 weeks before entering a single-blind placebo run-in period. The 4-week placebo run-in period further excluded placebo responders. The randomization period consisted of three sequential parts: (1) a 4-week double-blind part with aprocitentan 12.5 mg, 25 mg, or placebo (1:1:1 ratio); (2) a 32-week single-blind part with aprocitentan 25 mg; and (3) a 12-week randomized withdrawal part with aprocitentan 25 mg or placebo (1:1 ratio). The purpose was to demonstrate the BP lowering effect of aprocitentan in RHT (Part 1) and the persistence of this effect (Parts 2 and 3). Out of 1965 screened patients, 730 were randomized resulting in an overall inclusion failure rate of 62.8%. The most common reason for exclusion (44.4% of all screened patients) was failure to meet the BP inclusion criteria. These results underline the high proportion of pseudoresistant hypertension among patients referred for RHT.

Danaietash P ，Verweij P ，Wang JG ，Dresser G ，Kantola I ，Lawrence MK ，Narkiewicz K ，Schlaich M ，Bellet M ，PRECISION investigators ... -  《-》

A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of four doses of tasosartan in patients with essential hypertension. Tasosartan Investigator's Group.

Lacourcière Y ，Pool JL ，Svetkey L ，Gradman AH ，Larochelle P ，de Champlain J ，Smith WB ... -  《AMERICAN JOURNAL OF HYPERTENSION》

Efficacy and tolerability of once-daily oral fimasartan 20 to 240 mg/d in Korean Patients with hypertension: findings from Two Phase II, randomized, double-blind, placebo-controlled studies.

Fimasartan is a selective angiotensin II receptor blocker developed for once-daily dosing. To meet the regulatory requirements for approval of an antihypertensive treatment in Korea, this pair of studies was conducted to evaluate the efficacy and tolerability of fimasartan, to determine its dose-response relationship and minimum effective dose, and to characterize its blood pressure (BP)-reduction profile over the dosing interval. These 2 Phase II, randomized, double-blind, placebo-controlled, parallel-group, and dose-response studies enrolled male or nonchildbearing female Korean patients aged 18 to 65 years (study 1) or 18 to 70 years (study 2) with essential hypertension (sitting diastolic BP [DBP] 95-<115 mm Hg [study 1] or 90-<110 mm Hg [study 2]). Patients were randomly assigned to receive fimasartan 20, 60, 120, or 180 mg (study 1) or 20, 60, 120, or 240 mg (study 2) or placebo in the same ratio, once daily for 4 weeks (study 1) or 8 weeks (study 2). Clinic BP was measured at trough, and change from baseline in DBP at week 4 (study 1) or 8 (study 2) was the primary efficacy end point. In study 1, 24-hour ambulatory BP monitoring (ABPM) was conducted. Treatment-emergent adverse events (TEAEs) were assessed using a structured questionnaire, laboratory testing, physical examination, and ECG readings. Totals of 61 and 195 patients participated in studies 1 and 2, respectively (68% male; mean age, 50.1 and 55.1 years; DBP, 98.7 and 103.6 mm Hg; systolic BP, 147.0 and 158.1 mm Hg), of whom 52 (85.2%) and 169 (86.7%) completed each study. Data from ABPM were obtained from 45 patients (73.8%), and safety profile was evaluated in 225 participants. Four-week treatment with fimasartan 180 mg once daily was associated with a significantly greater mean reduction in DBP compared with placebo in study 1 (-16.4 vs -5.5 mm Hg; P = 0.022). In study 2, fimasartan 60, 120, and 240 mg once daily were associated with significantly greater reductions in DBP after 8 weeks of treatment compared with placebo (-14.4, -14.1, and -12.7 vs -5.8 mm Hg, respectively; P < 0.0001-< 0.005). Fimasartan 60 mg once daily was the minimum effective dose, and the dose-response relationship was flat at doses >60 mg once daily. BP reduction was maintained over the full 24-hour dosing interval (trough-to-peak ratios: 0.41-0.98). The proportions of patients who experienced TEAEs were comparable among the treatment groups in both studies, with headache (9.8%) and dizziness (4.4%) being most commonly reported. No serious AEs were reported. Once-daily oral administration of fimasartan was well tolerated and efficacious in reducing BP in these hypertensive Korean patient populations. ClinicalTrials.gov identifiers: NCT00937651 and NCT00923611.

Lee H ，Yang HM ，Lee HY ，Kim JJ ，Choi DJ ，Seung KB ，Jeon ES ，Ha JW ，Rim SJ ，Park JB ，Shin JH ，Oh BH ... -  《-》