ID-080A301

Idorsia Pharmaceuticals Ltd

Hegenheimermattweg 91, Allschwil, Switzerland, 4123

Idorsia Clinical Trial Information, Idorsia Pharmaceuticals Ltd, +41 58 844 1977, idorsiaclinicaltrials@idorsia.com

Idorsia Clinical Trial Information, Idorsia Pharmaceuticals Ltd, +41 58 844 1977, idorsiaclinicaltrials@idorsia.com

No

No

No

Final

12 May 2022

Yes

25 Apr 2022

Yes

25 Apr 2022

No

To demonstrate the blood pressure (BP) lowering effect of aprocitentan when added to standard of care in true resistant hypertension (RHT) subjects.

Prior to the start of the study, each study site consulted an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), i.e., a review panel that was responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation. The protocol and any material provided to the subject (such as a subject information sheet or description of the study used to obtain informed consent) were reviewed and approved by the appropriate IEC or IRB before the study was started. Sponsor personnel and the investigators were required to conduct the study in full compliance with ICH-GCP Guidelines, the principles of the Declaration of Helsinki, and with the laws and regulations of the countries in which the study is conducted. Both the sponsor and the investigators had the right to terminate the study at any time, and in such a case, were responsible for protecting the subjects’ interests. The investigators were responsible for maintaining the subjects’ identities in strictest confidence. Written informed consent was required to be obtained from each individual participating in the study prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study. It was made clear to each subject that he or she was completely free to refuse to enter the study, or to withdraw from it at any time for any reason.

18 Jun 2018

No

Yes

Netherlands: 8

Poland: 51

Spain: 18

United Kingdom: 3

Belgium: 8

Czechia: 28

Finland: 16

France: 7

Germany: 18

Greece: 8

Hungary: 6

Italy: 5

Lithuania: 10

Australia: 23

Canada: 21

China: 27

Israel: 10

Russian Federation: 166

Ukraine: 86

United States: 211

730

183

0

0

0

0

0

0

409

321

0

Double-blind Part 1

Randomised - controlled

Yes

Aprocitentan

ACT-132577

Tablet

Oral use

Subjects received aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks.

Aprocitentan

ACT-132577

Tablet

Oral use

Subjects received aprocitentan 25 mg, orally, once daily in the morning for 4 weeks.

Placebo

Tablet

Oral use

Subjects received placebo (matching aprocitentan), orally, once daily in the morning for 4 weeks.

Single-blind single-arm Part 2

Non-randomised - controlled

Aprocitentan

ACT-132577

Tablet

Oral use

Participants received aprocitentan 25 mg, orally, once daily in the morning for 4 weeks.

Double-blind Withdrawal Part 3

Randomised - controlled

No

Aprocitentan

ACT-132577

Tablet

Oral use

Participants received aprocitentan 25 mg, orally, once daily in the morning for 12 weeks.

Placebo in Part 3

Tablet

Oral use

Participants received placebo (matching aprocitentan), orally, once daily in the morning for 12 weeks.

Aprocitentan 12.5 mg in Part 1 (Double-blind)

Aprocitentan 25 mg in Part 1 (Double-blind)

Placebo in Part 1 (Double-blind)

Aprocitentan 12.5 mg in Part 1 (Double-blind)

Aprocitentan 25 mg in Part 1 (Double-blind)

Placebo in Part 1 (Double-blind)

Aprocitentan 25 mg in Part 2 (single-blind, single arm)

Aprocitentan 25 mg in Part 3 (double-blind withdrawal)

Placebo in Part 3 (double-blind withdrawal)

Changes from baseline to Week 4 in mean trough SiSBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). A negative change indicates a decrease in SiSBP from baseline.

Primary

Pre-dose Day 1 (Part 1 double-blind randomized baseline) up to Week 4 (End of double-blind randomized part 1).

The analysis was performed on the Full Analysis Set (FAS). The FAS included all participants who were randomized and had a baseline sitting systolic blood pressure, measured by automated office blood pressure measurement. Baseline was defined as the last measurement before randomization.

Aprocitentan 12.5 mg in Part 1 (Double-blind) v Placebo in Part 1 (Double-blind)

487

Pre-specified

-3.79

2-sided

The analysis was performed on the Full Analysis Set (FAS). The FAS included all participants who were randomized and had a baseline sitting systolic blood pressure, measured by automated office blood pressure measurement. Baseline was defined as the last measurement before randomization.

Aprocitentan 25 mg in Part 1 (Double-blind) v Placebo in Part 1 (Double-blind)

487

Pre-specified

-3.73

2-sided

Changes from double-blind withdrawal baseline (Week 36) to Week 40 in mean trough SiSBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). A negative change indicates a decrease in SiSBP from baseline.

Secondary

Pre-dose Week 36 (Part 3 double-blind-withdrawal baseline) up to Week 40.

Mixed effects model for Repeated Measures: Change from DB-WD baseline in SiSBP = DB-WD baseline SiSBP + stratum (randomized treatment in DB part) + treatment + visit + treatment x visit + DB-WD baseline x visit.

Aprocitentan 25 mg in Part 3 (double-blind withdrawal) v Placebo in Part 3 (double-blind withdrawal)

614

Pre-specified

-5.82

2-sided

Changes from baseline to Week 4 in mean trough SiDBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. A negative change indicates a decrease in SiDBP from baseline.

Secondary

Pre-dose Day 1 (Part 1 double-blind randomized baseline) up to Week 4 (End of double-blind randomized part 1).

Mixed effects model for Repeated Measures: Change from baseline in SiDBP = baseline SiDBP + treatment + visit + treatment x visit + baseline x visit.

Aprocitentan 12.5 mg in Part 1 (Double-blind) v Placebo in Part 1 (Double-blind)

487

Pre-specified

-3.94

2-sided

Mixed effects model for Repeated Measures: Change from baseline in SiDBP = baseline SiDBP + treatment + visit + treatment x visit + baseline x visit.

Aprocitentan 25 mg in Part 1 (Double-blind) v Placebo in Part 1 (Double-blind)

487

Pre-specified

-4.47

2-sided

ABPM devices were provided to each site by the central blood pressure laboratory. On the first day after all visit assessments were performed, the ABPM device (Mobil-O-Graph NG) was fitted to the participant. The following day (i.e., second day), the participant came back to site to have the ABPM device removed. ABPM data collected over the 24-hours was electronically transferred to the central BP laboratory. Systolic blood pressure and diastolic blood pressure were measured at predetermined times every 20 minutes from 06:00 to 21:59, and every 30 minutes from 22:00 to 05:59. For each participant and at each visit (baseline and Week 4) the 24-hour mean SBP (or DBP) was calculated from the area under the SBP (or DBP) time curve and divided by the time span. A negative change indicates a decrease in 24-hour mean systolic / diastolic blood pressure from baseline.

Secondary

Pre-dose Day 1 (Part 1 double-blind randomized baseline) and Week 4 (End of double-blind randomized part 1).

Aprocitentan 12.5 mg in Part 1 (Double-blind) v Placebo in Part 1 (Double-blind)

426

Pre-specified

-4.18

2-sided

Aprocitentan 25 mg in Part 1 (Double-blind) v Placebo in Part 1 (Double-blind)

427

Pre-specified

-5.9

2-sided

Aprocitentan 12.5 mg in Part 1 (Double-blind) v Placebo in Part 1 (Double-blind)

426

Pre-specified

-4.32

2-sided

Aprocitentan 25 mg in Part 1 (Double-blind) v Placebo in Part 1 (Double-blind)

427

Pre-specified

-5.81

2-sided

Changes from double-blind withdrawal (Week 36) to Week 40 in mean trough SiDBP were analyzed using a mixed model. Participants had their blood pressure (BP) measured at the study site using the automated oscillometric sphygmomanometer (Microlife WatchBP® Office) which was provided to each site. BP was to be measured at trough (before taking the study treatment and SBAT). The BP assessment, participant preparation (e.g., arm selection, arm position, cuff size) was standardized and followed the American Heart Association guidelines / Canadian Education Program on Hypertension. The participant was resting undisturbed, alone (unattended) in a quiet place for 5 minutes at each visit. BP was measured at each visit with the same device, which recorded five sitting blood pressure readings (one per minute, the first value was excluded from the average). A negative change indicates a decrease in SiDBP from baseline.

Secondary

Pre-dose Week 36 (Part 3 double-blind-withdrawal baseline) up to Week 40.

Aprocitentan 25 mg in Part 3 (double-blind withdrawal) v Placebo in Part 3 (double-blind withdrawal)

614

Pre-specified

-5.19

2-sided

ABPM devices were provided to each site by the central blood pressure laboratory. On the first day after all visit assessments were performed, the ABPM device (Mobil-O-Graph NG) was fitted to the participant. The following day (i.e., second day), the participant came back to site to have the ABPM device removed. ABPM data collected over the 24-hours was electronically transferred to the central BP laboratory. Systolic blood pressure and diastolic blood pressure were measured at predetermined times every 20 minutes from 06:00 to 21:59, and every 30 minutes from 22:00 to 05:59. For each participant and at each visit (the double-blind withdrawal baseline [Week 36] and the week 40) the 24-hour mean SBP (or DBP) was calculated from the area under the SBP (or DBP) time curve. A negative change indicates a decrease in 24-hour mean systolic / diastolic blood pressure from baseline.

Secondary

From Week 36 (Part 3 double-blind-withdrawal baseline) and Week 40.

Aprocitentan 25 mg in Part 3 (double-blind withdrawal) v Placebo in Part 3 (double-blind withdrawal)

478

Pre-specified

-6.53

2-sided

Placebo in Part 3 (double-blind withdrawal) v Aprocitentan 25 mg in Part 3 (double-blind withdrawal)

478

Pre-specified

-6.75

2-sided

AE were considered treatment-emergent, if the onset date is between the first intake of treatment up to 30 days after the stop of study treatment. Study treatment was up to 48 weeks. The length of treatment in each part is described in each treatment arm.

Only participants entering the randomized treatment period were considered enrolled for the study and are included in the AE analysis. The Run-in period was designed to exclude potential placebo responders and is not part of the statistical analysis of the study.

24.1

Aprocitentan 12.5 mg in Part 1 (Double-blind)

Aprocitentan 25 mg in Part 1 (Double-blind)

Placebo in Part 1 (Double-blind)

Aprocitentan 25 mg in Part 2 (Single-blind, single arm)

Aprocitentan 25 mg in Part 3 (Double-blind withdrawal)

Placebo in Part 3 (Double-blind withdrawal)