Endothelin-1 is the most potent endogenous vasoconstrictor currently available and is implicated in the pathogenesis of hypertension. |
Aprocitentan, the active metabolite of macitentan, is a potent, orally active, dual endothelin receptor antagonist and represents a potential novel therapy for hypertensive patients. |
Aprocitentan enhances the blood pressure-lowering effects of other antihypertensive drugs with additional potential long-term benefits. |
Blocking the actions of endothelin-1 by aprocitentan could potentially reduce blood pressure and provide broader cardiovascular protection to patients with resistant hypertension. |
Introduction
ET-1 and resistant hypertension
Pharmacodynamic and pharmacokinetics
Drug interactions
Clinical studies in hypertension
PRECISION trial (ClinicalTrials.gov Identifier: NCT03541174) | Description |
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Purpose | Evaluate blood pressure-lowering effect of aprocitentan when added to other antihypertensive drugs of patients with resistant hypertension |
Design | Multicenter, blinded, randomized, parallel-group, phase 3 study Allocation: randomized Intervention model: parallel assignment Intervention model description: Single-blind placebo run-in/randomized with 3 parts: Part 1: double-blind, randomized to aprocitentan 12.5 mg, aprocitentan 25 mg or placebo Part 2: single blind aprocitentan 25 mg Part 3: double-blind re-randomized to aprocitentan 25 mg or placebo Masking: triple (participant, care provider, investigator) |
Estimated enrollment | 600 participants treated with at least 3 antihypertensive therapies of different pharmacological classes for at least 4 weeks before the screening visit |
Primary outcome measures | Change from baseline to week 4 of double-blind treatment in trough sitting systolic blood pressure |
Exclusion criteria | Apparent/pseudo-resistant hypertension Confirmed severe hypertension Pregnant or lactating subjects Clinically significant unstable cardiac disease Severe renal insufficiency Any known factor, disease or clinically relevant medical or surgical conditions that, in the opinion of the investigator, might put the subject at risk or interfere with treatment compliance, study conduct or interpretation of the results Treatment with any medication which may affect blood pressure and/or treatment with high dose of loop diuretics |
Event | Placebo, affected/at risk (%) | Aprocitenten 5 mg, affected/at risk (%) | Aprocitenten 10 mg, affected/at risk (%) | Aprocitenten 25 mg, affected/at risk (%) | Aprocitenten 50 mg, affected/at risk (%) | Lisinopril 20 mg, affected/at risk (%) |
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Cardiac disorders | ||||||
LBBB | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 1/82 (1.22%) | 0/81 (0.00%) | 0/81 (0.00%) |
Atrioventricular block first degree | 0/82 (0.00%) | 1/82 (1.22%) | 0/82 (0.00%) | 1/82 (1.22%) | 0/81 (0.00%) | 0/81 (0.00%) |
Tachycardia | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 1/82 (1.22%) | 0/81 (0.00%) | 1/81 (1.23%) |
Fall | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 0/81 (0.00%) | 1/81 (1.23%) |
Jaw fracture | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 0/81 (0.00%) | 1/81 (1.23%) |
Neoplasm malignant | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 1/82 (1.22%) | 0/81 (0.00%) | 0/81 (0.00%) |
Anemia | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 2/82 (2.44%) | 1/81 (1.23%) | 0/81 (0.00%) |
Hyperthyroidism | 0/82 (0.00%) | 0/82 (0.00%) | 1/82 (1.22%) | 0/82 (0.00%) | 0/81 (0.00%) | 0/81 (0.00%) |
Dyspepsia | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 1/82 (1.22%) | 0/81 (0.00%) | 0/81 (0.00%) |
Abnormal hepatic function | 0/82 (0.00%) | 1/82 (1.22%) | 0/82 (0.00%) | 0/82 (0.00%) | 0/81 (0.00%) | 0/81 (0.00%) |
Headache | 1/82 (1.22%) | 1/82 (1.22%) | 2/82 (2.44%) | 2/82 (2.44%) | 2/81 (2.47%) | 4/81 (4.94%) |
Renal failure | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 0/82 (0.00%) | 0/81 (0.00%) | 1/81 (1.23%) |