A Research Study to Show the Effect of Aprocitentan in the Treatment of Difficult to Control (Resistant) High Blood Pressure (Hypertension) and Find Out More About Its Safety

Study Overview
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Brief Summary
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The goal of this clinical trial is to show the blood pressure lowering effect of aprocitentan, a new drug, when added to other anti-hypertensive drugs of patients with difficult to control (resistant) high blood pressure (hypertension), and to show that blood pressure reduction is kept for long period of time.

Detailed Description
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Participation in the study will be up to 68 weeks. The study has 4 periods: Screening period Placebo run-in period Randomized treatment period Safety follow-up period The screening period lasts between 4 and 12 weeks. It starts at the screening visit with the signing of the informed consent form (ICF) and ends the day before the participant enters the run-in period. At least 4 weeks before the start of the run-in period, the background antihypertensive medication (except beta-blockers) of participants with a diagnosis of true resistant hypertension and having a mean trough sitting systolic blood pressure of equal to or greater than 140 mmHg measured by automated AOBPM will be standardized by switching to a fixed combination of a calcium channel blocker (amlodipine), an angiotensin receptor blocker (valsartan) and a diuretic (hydrochlorothiazide). In case a beta-blocker is used as one of the background antihypertensive medications or for any other indication, this can be kept, with the provision that it has been initiated and the dose kept stable for at least 4 weeks prior to the screening visit and the dose kept stable until the end-of-treatment. Following the screening period this study has a run-in period of 4 weeks. During this period, placebo will be administered in order to exclude potential placebo responders. Following the run-in period eligible participants will enter the randomized treatment period. This period lasts for 48 weeks. It starts at randomization (i.e., Day 1 of the double-blind part) and ends at the end-of-treatment visit (i.e., at the end of the double-blind withdrawal part). The randomized treatment period consists of 3 parts: Part 1 is double-blind, randomized, parallel-group and placebo-controlled and lasts 4 weeks. Part 2 is single-blind and single-arm and lasts for 32 weeks. Part 3 is a double-blind withdrawal, randomized, parallel-group and placebo-controlled and lasts for 12 weeks. End-of treatment is at Week 48 (i.e., end of the double-blind withdrawal part). The safety follow-up starts on the day after the last dose of study treatment and ends 30 to 33 days after the last dose of study treatment.

Official Title
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Multi-center, Blinded, Randomized, Parallel-group, Phase 3 Study With Aprocitentan in Subjects With Resistant Hypertension (RHT)

Conditions
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Resistant Hypertension

Intervention / Treatment
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* Drug: Aprocitentan 12.5 mg
* Drug: Aprocitentan 25 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Screening period: Signed and dated informed consent form (ICF) prior to any study-mandated procedure; Male and female participants; 18 years (or year of country specific majority) or older; Historical documentation in the participant's medical records on uncontrolled blood pressure despite at least 3 background antihypertensive medications within 1 year before screening visit; Treated with at least 3 antihypertensive therapies of different pharmacological classes for at least 4 weeks before the screening visit (Visit 1); Mean Sitting Systolic Blood Pressure (SiSBP) greater or equal to 140 mmHg measured by Automated Office Blood Pressure Measurement (AOBPM); Women of childbearing potential are eligible only if the following applies: Negative pregnancy test at screening and at baseline (i.e., before randomization); Agreement to undertake pregnancy tests during the study and up to 30 days after randomized study treatment discontinuation; Agreement to use methods of birth control from Screening up to at least 30 days after randomized study treatment discontinuation. Run-in period (RI): Switched to the standardized background antihypertensive therapy at least 4 weeks before the first RI visit; Mean trough SiSBP greater than or equal to140 mmHg as measured by AOBPM. Randomization period: Stable dose of the standardized background antihypertensive therapy for at least 1 week before the end of the RI period; Mean trough SiSBP greater than or equal to 140 mmHg measured by AOBPM. Exclusion Criteria: Apparent/pseudo Resistant Hypertension (RHT) due to white coat effect, medical inertia, poor therapeutic adherence, or secondary causes of hypertension (except sleep apnea); Confirmed severe hypertension (grade 3) defined as SiSBP greater than or equal to 180 mmHg and/or Sitting Diastolic Blood Pressure (SiDBP) greater than or equal to 110 mmHg as measured by AOBPM at two different timepoints; Pregnant or lactating participants; Clinically significant unstable cardiac disease at screening or in the past in the opinion of the investigator (exclusion of participants with significant or potential 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 participant at risk, interfere with treatment compliance, study conduct or interpretation of the results. Treatment with any medication which may affect blood pressure (BP) and/or treatment with high dose of loop diuretics (i.e., furosemide greater than 80 mg/day, or equivalent dosage of other loop diuretics).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study with multiple periods and parts. Once eligibility is confirmed during screening and the run-in period, the individuals entered the randomized treatment period consisting of 3 parts: Part 1: double-blind (DB), randomized to aprocitentan 12.5 mg, aprocitentan 25 mg or placebo; Part 2 single-blind (SB) aprocitentan 25 mg; Part 3: double-blind withdrawal (DB-WD) re-randomized to aprocitentan 25 mg or placebo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aprocitentan 25 mg in Part 1 (double-blind)<br>Participants will receive aprocitentan 25 mg, orally, once daily in the morning for 4 weeks. | Drug: Aprocitentan 25 mg<br>* Tablet, oral use<br>* Other names: ACT-132577;|
| Experimental: Aprocitentan 12.5 mg in Part 1 (double-blind)<br>Participants will receive aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks. | Drug: Aprocitentan 12.5 mg<br>* Tablet, oral use<br>* Other names: ACT-132577;|
| Placebo Comparator: Placebo in Part 1 (double-blind)<br>Participants will receive placebo (matching aprocitentan), orally, once daily in the morning for 4 weeks. | Drug: Placebo<br>* Matching placebo tablet<br>|
| Experimental: Aprocitentan 25 mg in Part 2 (single-blind, single arm)<br>After 4-weeks in the double-blind randomized part (Part 1), participants will received 25 mg aprocitentan, orally, once daily in the morning for 32 weeks. | Drug: Aprocitentan 25 mg<br>* Tablet, oral use<br>* Other names: ACT-132577;|
| Experimental: Aprocitentan 25 mg in Part 3 (double-blind withdrawal)<br>After 32-weeks in the single-blind, single-arm part (Part 2), participants will be re-randomized and receive aprocitentan 25 mg, orally, once daily in the morning for 12 weeks. | Drug: Aprocitentan 25 mg<br>* Tablet, oral use<br>* Other names: ACT-132577;|
| Placebo Comparator: Placebo in Part 3 (double-blind withdrawal)<br>After 32-weeks in the single-blind, single-arm part (Part 2), participants will be re-randomized and receive placebo (matching aprocitentan), orally, once daily in the morning for 12 weeks. | Drug: Placebo<br>* Matching placebo tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Automated Office Blood Pressure Measurement | 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. | Pre-dose Day 1 (Part 1 double-blind randomized baseline) up to Week 4 (End of double-blind randomized part 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 in Mean Trough Sitting Systolic Blood Pressure (SiSBP) Measured by Unattended Automated Office Blood Pressure Measurement | 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. | Pre-dose Week 36 (Part 3 double-blind-withdrawal baseline) up to Week 40 | 
| Change From Baseline to Week 4 of Double-blind Treatment in Mean Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure Measurement | 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. | Pre-dose Day 1 (Part 1 double-blind randomized baseline) up to Week 4 (End of double-blind randomized part 1) | 
| Changes From Baseline to Week 4 of Double-blind Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 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. | Pre-dose Day 1 (Part 1 double-blind randomized baseline) and Week 4 (End of double-blind randomized part 1) | 
| Change From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in Trough Sitting Diastolic Blood Pressure (SiDBP) Measured by Unattended Automated Office Blood Pressure | 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. | Pre-dose Week 36 (Part 3 double-blind-withdrawal baseline) up to Week 40 | 
| Changes From Double-blind Withdrawal Baseline (Week 36) to Week 40 of Double-blind-withdrawal (DB-WD) Treatment in 24-hour Mean Systolic (SBP) and Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring | 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. | From Week 36 (Part 3 double-blind-withdrawal baseline) and Week 40 |