Dose-finding Study With ACT-132577 (Aprocitentan) in Participants With Essential Hypertension

Idorsia Pharmaceuticals

Status and phase: Completed; Phase 2

Conditions: Essential Hypertension

Treatments: Drug: Aprocitentan 5 mg; Drug: Aprocitentan 25 mg; Drug: Placebo; Drug: Aprocitentan 50 mg; Drug: Aprocitentan 10 mg; Drug: Lisinopril 20 mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT02603809

AC-080A201

Details and patient eligibility

About

The main objective will be to evaluate the dose-response of ACT-132577 (aprocitentan) on diastolic blood pressure (DBP) in participants with grade 1 or 2 essential hypertension.

Secondary objectives will be to evaluate the dose-response of ACT-132577 on: systolic blood pressure (SBP); control and response rate of blood pressure; 24-hour ambulatory blood pressure monitoring (ABPM) and to evaluate the safety and tolerability of a once daily oral regimen of 4 doses of ACT-132577.

Full description

Participation in the study is planned to last up to 18 weeks. A single-blind placebo run-in period of 4 to 6 weeks after which participants will be randomized into a double-blind treatment period of 8 weeks and a washout and follow-up period ending with an end-of-study visit approximately 12 weeks after randomization.

Enrollment: 1,659 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Signed informed consent prior to any study-mandated procedure

• No contra-indication to stop (according to label) anti-hypertensive treatment(s) at screening

• Mild-to-moderate essential hypertension with or without ongoing anti-hypertensive treatment(s):

  -- Mean (of 5 measurements) sitting diastolic blood pressure (SiDBP) ≥ 90 to < 110 mmHg measured by office blood pressure measurements (OBPM).

• Women of childbearing potential must have a negative pregnancy test and use of reliable methods of contraception

Exclusion criteria

• Severe hypertension (grade 3): mean sitting systolic/diastolic BP (SiSBP/SiDBP; measured by OBPM) ≥ 180/110 mmHg, respectively.
• Secondary hypertension
• Known hypertensive retinopathy greater than Keith-Wagener Grade 2
• Myocardial infarction, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft within 12 months prior to randomization
• Unstable angina within 6 months prior to randomization
• Heart failure New York Heart Association class III and IV
• Valvular defects (such as severe aortic or mitral valve disease) and/or hemodynamically relevant rhythm disturbances
• Clinical evidence of cerebrovascular insufficiency or a cerebrovascular accident within 6 months prior to randomization.
• Subjects working night shifts
• Body mass index < 20 kg/m2 or > 40 kg/m2
• Treatment with any medication which may affect BP (e.g., treatment of psychiatric diseases, ophthalmic preparations)
• Treatment with strong cytochrome P450 3A4 (CYP3A4) isoenzyme inhibitors or inducers
• Treatment with guanethidine and/or mineralocorticoid receptor antagonists within 1 month prior to Screening (Visit 1)
• Treatment with another investigational treatment within 1 month prior to Screening (Visit 1)
• Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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1,659 participants in 6 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received placebo orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.

Treatment:

Drug: Placebo

Aprocitentan 5 mg

Experimental group

Description:

After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.

Treatment:

Drug: Aprocitentan 5 mg

Aprocitentan 10 mg

Experimental group

Description:

After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan 10 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.

Treatment:

Drug: Aprocitentan 10 mg

Aprocitentan 25 mg

Experimental group

Description:

After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan 25 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.

Treatment:

Drug: Aprocitentan 25 mg

Aprocitentan 50 mg

Experimental group

Description:

After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan 50 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.

Treatment:

Drug: Aprocitentan 50 mg

Lisinopril 20 mg

Active Comparator group

Description:

After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received lisinopril 20 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.

Treatment:

Drug: Lisinopril 20 mg