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

A Multi-center, Double-blind, Double-dummy, Randomized, Placebo- and Active-reference, Parallel Group, Phase 2, Dose-finding Study With ACT-132577 in Subjects With Essential Hypertension (Grade 1 and 2).

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.

Study Overview

• Status: Completed
• Conditions: Essential Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: Aprocitentan 5 mg; Drug: Aprocitentan 10 mg; Drug: Aprocitentan 25 mg; Drug: Aprocitentan 50 mg; Drug: Lisinopril 20 mg

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 1659
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6J 1S3
      • Manna Research - Vancouver
  • Ontario
    • Toronto, Ontario, Canada, M9W 4L6
      • Manna Research - Toronto
    • Toronto, Ontario, Canada, M3J 2C5
      • Canadian Phase Onwards Inc
  • Quebec
    • Levis, Quebec, Canada, G6W 0M6
      • Manna Research - Levis
    • Montreal, Quebec, Canada, H2Y 1S1
      • DIEX Recherche Montreal Inc
    • Montréal, Quebec, Canada, H2Y 1S1
      • DIEX Recherche Montreal Inc
    • Pointe-Claire, Quebec, Canada, H9R 4S3
      • Manna Research - Pointe Claire
    • Sherbrooke, Quebec, Canada, J1H 1Z1
      • Diex Reserach Sherbrooke Inc
• Israel
  • Ashkelon, Israel, 78278
    • Cardiology Department Barzilai
  • Beer Sheva, Israel, 84101
    • Soroka University Hospital - Hypertension Unit
  • Holon, Israel, 58100
    • The Hyper Unit, Edith Wolfson Medical Center
  • Jerusalem, Israel, 91240
    • Hypertension Treatment Center, Internal Dep, Hadassah
  • Kefar Sava, Israel, 44261
    • Hypertension And Nephrology Department, Meir Medical Center
  • Rehovot, Israel, 76100
    • Clinical Research Unit Kaplan Medical Center
  • Safed, Israel, 13100
    • Internal Med Department A, Ziv Medical Center
• Puerto Rico
  • Cidra, Puerto Rico, 00739
    • Advanced Medical Concepts, PSC
  • Ponce, Puerto Rico, 00717
    • Research & Cardiovascular Corp.
• United States
  • Alabama
    • Fort Payne, Alabama, United States, 35967
      • Appalachian Cardiovascular Associates
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Radiant Research Inc
    • Chandler, Arizona, United States, 85224
      • Warner Family Practice / Radiant Research Inc
    • Peoria, Arizona, United States, 85381
      • Phoenix Medical Research Institute LLC
    • Tucson, Arizona, United States, 85704
      • Advanced Arizona Clinical Research
    • Tucson, Arizona, United States, 85704
      • Noble Clinical Research Llc
    • Tucson, Arizona, United States, 85710
      • Desert Sun Clinical Research LLC
  • California
    • Anaheim, California, United States, 92805
      • Advanced Research Center Inc
    • Carmichael, California, United States, 95608
      • Med Center
    • Concord, California, United States, 94520
      • John Muir Physician Network Clinical Research Center
    • Lincoln, California, United States, 95648
      • Clinical Trials Research
    • Long Beach, California, United States, 90807
      • Long Beach Center For Clinical Research
    • Los Angeles, California, United States, 90036
      • Entertainment Medical Group Inc
    • San Diego, California, United States, 92103
      • Artemis Institute for Clinical Research
    • Tustin, California, United States, 92780
      • Memorial Research Medical Clinic / Orange County Research Center
    • Upland, California, United States, 91786
      • Empire Clinical Research
  • Connecticut
    • Milford, Connecticut, United States, 06460
      • Clinical Research Consulting LLC
    • Waterbury, Connecticut, United States, 06708
      • Chase Medical Research LLC
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfieri Cardiology
  • Florida
    • Atlantis, Florida, United States, 33462
      • ACRC - Cardiology
    • Clearwater, Florida, United States, 33756
      • Innovative Research of West Florida Inc
    • DeLand, Florida, United States, 32720
      • Avail Clinical Research LLC
    • Fort Lauderdale, Florida, United States, 33308
      • Alan Graff, MD, PA
    • Fort Myers, Florida, United States, 33912
      • Gulfcoast Clinical Research Center
    • Hialeah, Florida, United States, 33012
      • AGA Clinical Trials
    • Lake Worth, Florida, United States, 33467
      • Canvas Clinical Research, LLC
    • Miami, Florida, United States, 33126
      • LCC Medical Research Institute
    • Miami, Florida, United States, 33155
      • Allied Biomedical Research Institute, Inc
  • Georgia
    • Savannah, Georgia, United States, 31401
      • Southeast Regional Research Group
  • Indiana
    • Anderson, Indiana, United States, 46011
      • Community Clin Res CTR
    • Indianapolis, Indiana, United States, 46260
      • Midwest Institute for Clinical Research
  • Kansas
    • Newton, Kansas, United States, 67114
      • Heartland Research Associated LLC
    • Wichita, Kansas, United States, 67205
      • Heartland Research Associates LLC
    • Wichita, Kansas, United States, 67207
      • Heartland Research Associates LLC
  • Louisiana
    • Crowley, Louisiana, United States, 70526
      • Avant Research Associates, LLC
    • New Orleans, Louisiana, United States, 70115
      • Best Clinical Trials LLC
    • New Orleans, Louisiana, United States, 70119
      • New Orleans Center for Clinical Research - Nola
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • ClinSite LLC
  • Missouri
    • Florissant, Missouri, United States, 63031
      • Primecare Research Associates, LLC
  • Nevada
    • Las Vegas, Nevada, United States, 89117
      • Clinical Research Advantage, Inc. / Diagnostic Center Of Medicine - Durango
  • New Jersey
    • Trenton, New Jersey, United States, 08611
      • Premier Research
  • New York
    • Rochester, New York, United States, 14609
      • Rochester Clinical Research Inc.
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Metrolina Internal Medicine/Internal Medicine Research
    • Greensboro, North Carolina, United States, 27408
      • PharmQuest LLC
    • High Point, North Carolina, United States, 27262
      • Peters Medical Research
    • Raleigh, North Carolina, United States, 27604-1547
      • Wake Research Associates
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Lillestol Research LLC
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Sterling Research Group Ltd.
    • Columbus, Ohio, United States, 43213
      • Aventiv Research Inc.
    • Dayton, Ohio, United States, 45406
      • Dayton Clinical Research
    • Dublin, Ohio, United States, 43016
      • Aventiv Research Inc.
  • Oklahoma
    • Edmond, Oklahoma, United States, 73034
      • Oklahoma City Clinic - Edmond / Radiant Research Inc
    • Midwest City, Oklahoma, United States, 73110
      • Clinical Research Advantage, Inc. / Oklahoma City Clinic - Midwest City
  • Oregon
    • Eugene, Oregon, United States, 97404
      • Willamette Valley Clinical Studies
  • Pennsylvania
    • Lansdale, Pennsylvania, United States, 19446
      • Detweiler Family Medicine and Associates PC
    • Media, Pennsylvania, United States, 19063
      • Suburban Research Center
  • South Carolina
    • Greer, South Carolina, United States, 29651
      • DeGarmo Institute of Medical Research
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Volunteer Research Group
  • Texas
    • Austin, Texas, United States, 78745
      • Tekton Research Inc
    • Austin, Texas, United States, 78749
      • Texas Diabetes & Endocrinology
    • Carrollton, Texas, United States, 75006
      • Trinity Hypertension & Metabolic Research Institute
    • Carrollton, Texas, United States, 75010
      • Family Medicine Associates of Texas - ACRC Trials
    • Corpus Christi, Texas, United States, 78413
      • Coastal Bend Clinical Research
    • DeSoto, Texas, United States, 75115
      • TR - Global Medical Research
    • Fort Worth, Texas, United States, 76104
      • Ventavia Research Group, LLC
    • Plano, Texas, United States, 75075
      • Clinical Investigations of Texas
    • Port Arthur, Texas, United States, 77640
      • Avant Research Associates LLC
    • Round Rock, Texas, United States, 78681
      • Texas Diabetes & Endocrinology
    • San Antonio, Texas, United States, 78229
      • Radiant Research Inc
    • San Antonio, Texas, United States, 78249
      • Bandera Family Health Care
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • Wasatch Clinical Research LLC
  • Virginia
    • Newport News, Virginia, United States, 23606
      • Health Research of Hampton Roads
    • Richmond, Virginia, United States, 23294
      • National Clinical Research inc
  • Washington
    • Bellevue, Washington, United States, 98007
      • Northwest Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 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.	Drug: Placebo; One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.
Experimental: Aprocitentan 5 mg; 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.	Drug: Aprocitentan 5 mg; One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.; Other Names: ACT-132577
Experimental: Aprocitentan 10 mg; 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.	Drug: Aprocitentan 10 mg; Two capsules of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks.; Other Names: ACT-132577
Experimental: Aprocitentan 25 mg; 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.	Drug: Aprocitentan 25 mg; One capsule of 25 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.; Other Names: ACT-132577
Experimental: Aprocitentan 50 mg; 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.	Drug: Aprocitentan 50 mg; One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.; Other Names: ACT-132577
Active Comparator: Lisinopril 20 mg; 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.	Drug: Lisinopril 20 mg; One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough	Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The absolute change in mean trough sitting diastolic blood pressure (SiDBP) measured by from baseline (i.e., at randomization) to week 8 (Day 56). A negative change indicates a decrease in the diastolic blood pressure from the start of treatment.	Baseline (Day 1) and end of double-blind treatment (Day 56)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough	Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The absolute change in mean trough sitting systolic blood pressure (SiSBP) measured by from baseline (i.e., at randomization) to week 8 (Day 56). A negative change indicates a decrease in the systolic blood pressure from the start of treatment.	Baseline (Day 1) and end of double-blind treatment (Day 56)
Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure	Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The Canadian Hypertension Education Program (CHEP) issued guidelines proposing cut-offs of 85 mmHg for diastolic blood pressure and 135 mmHg for systolic blood pressure specifically focusing on measurement by automated office blood pressure measurement. The number of participants at the end of the 8-week treatment period that had values below the protocol and CHEP cut-off values are reported. The initial protocol control rates at Week 8 (Day 56) on trough SiDBP are also reported and were defined as a SiDBP of less than 90 mmHg and a SiSBP of less than 140 mmHg.	End of double-blind treatment (Day 56)
Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure	Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. A participant was a responder if the reduction from baseline in mean trough sitting diastolic blood pressure (SiDBP) was 10 mmHg or greater-than 10 mmHg.	Baseline (Day 1) and end of double-blind treatment (Day 56)
Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure	Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. A participant was a responder if the reduction from baseline in mean trough sitting systolic blood pressure (SiSBP) was 20 mmHg or greater-than 20 mmHg.	Baseline (Day 1) and end of double-blind treatment (Day 56)
Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM)	Diastolic and systolic ambulatory blood pressure monitoring was performed over a 24-hour period with the ABPM device (Mobil-o-Graph) set to record diastolic and systolic blood pressure at a pre-defined time. Over a 24-hour period 3 measurements per hour during the day and 2 per hour during the night were made. The blood pressure measurements were derived from the area under the diastolic and systolic blood pressure curves and divided by the time span and averaged. For ambulatory blood pressure monitoring the baseline was the period from the time of last run-in placebo intake up to the time of the first double-blind treatment intake.	Baseline (Day -1 to Day 1) and end of double-blind treatment (Day 55 and Day 56)
Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM)	Ratio of group mean at trough to group mean at peak was calculated from the diastolic ambulatory blood pressure monitoring performed over a 24-hour period with the ABPM device. The trough (the smallest blood pressure reduction) and the peak (the highest blood pressure reduction) ratio show the extent of blood pressure lowering throughout the 24-hour dosing interval in the group. The group mean trough (at 20-24 hours) to group mean (at 2-6 hours) peak of diastolic blood pressure were examined to evaluate the extent to which once-daily dosing criteria were met (trough-to-peak values greater than 0.5). The ratio is positive if there was a decrease in diastolic blood pressure at both the trough and peak times at the end of treatment (Day 55 to Day 56) when compared to baseline (Day -1 to Day 1). For ambulatory blood pressure monitoring the baseline was the period from the time of last run-in placebo intake up to the time of the first double-blind treatment intake.	Baseline (Day -1 to Day 1) and end of double-blind treatment (Day 55 and Day 56)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Supportive Analysis of Primary Endpoint: Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough	Participants had their blood pressure measured at the study site using the BpTRU® device. The BpTRU® is an automatic unattended office blood pressure measurement device. Six measurements, at rest, per participant per visit were performed. The mean of the last 5 measurements was used for the analysis. The absolute change in mean trough sitting diastolic blood pressure (SiDBP) measured by from baseline (i.e., at randomization) to week 8 (Day 56). A negative change indicates a decrease in the diastolic blood pressure from the start of treatment.	Baseline (Day -1 to Day 1) and end of double-blind treatment (Day 55 and Day 56)

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.
• Investigators: Study Director: ClinicalTrials, Idorsia Pharmaceuticals

Publications and helpful links

General Publications

• Verweij P, Danaietash P, Flamion B, Menard J, Bellet M. Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension. Hypertension. 2020 Apr;75(4):956-965. doi: 10.1161/HYPERTENSIONAHA.119.14504. Epub 2020 Feb 17.

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2015
• Primary Completion (Actual): February 28, 2017
• Study Completion (Actual): April 7, 2017

Study Registration Dates

• First Submitted: November 9, 2015
• First Submitted That Met QC Criteria: November 11, 2015
• First Posted (Estimate): November 13, 2015

Study Record Updates

• Last Update Posted (Actual): November 23, 2022
• Last Update Submitted That Met QC Criteria: November 22, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Protective Agents; Cardiotonic Agents; Angiotensin-Converting Enzyme Inhibitors; Lisinopril
• Other Study ID Numbers: AC-080A201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No