Dose-finding Study With ACT-132577 (Aprocitentan) in Participants With Essential Hypertension
- Conditions
- Essential Hypertension
- Interventions
- Registration Number
- NCT02603809
- Lead Sponsor
- Idorsia Pharmaceuticals Ltd.
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1659
-
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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Aprocitentan 10 mg 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. Placebo 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. Aprocitentan 5 mg 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. Aprocitentan 25 mg 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. Aprocitentan 50 mg 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. Lisinopril 20 mg 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.
- Primary Outcome Measures
Name Time Method Change From Baseline to End of Double-blind Treatment in Sitting Diastolic Blood Pressure at Trough Baseline (Day 1) and end of double-blind treatment (Day 56) 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.
- Secondary Outcome Measures
Name Time Method Change From Baseline to End of Double-blind Treatment in Sitting Systolic Blood Pressure at Trough Baseline (Day 1) and end of double-blind treatment (Day 56) 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.Control Rates at the End of the Double-blind Treatment Period Based on Trough Sitting Diastolic and Systolic Blood Pressure End of double-blind treatment (Day 56) 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.Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Diastolic Blood Pressure Baseline (Day 1) and end of double-blind treatment (Day 56) 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.Response Rates at End of Double-blind Treatment Period Based on Trough Sitting Systolic Blood Pressure Baseline (Day 1) and end of double-blind treatment (Day 56) 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.Change From Baseline to End of Double-blind Treatment in 24-hour Diastolic and Systolic Ambulatory Blood Pressure Monitoring (ABPM) Baseline (Day -1 to Day 1) and end of double-blind treatment (Day 55 and Day 56) 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.Ratio of Group Mean at Trough to Group Mean at Peak for Diastolic Blood Pressure Based on Ambulatory Blood Pressure Monitoring (ABPM) 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 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.
Trial Locations
- Locations (86)
LCC Medical Research Institute
🇺🇸Miami, Florida, United States
Allied Biomedical Research Institute, INC
🇺🇸Miami, Florida, United States
Midwest Institute for Clinical Research
🇺🇸Indianapolis, Indiana, United States
Artemis institute for Clinical Research
🇺🇸San Diego, California, United States
Radiant Research Inc
🇺🇸San Antonio, Texas, United States
Warner Family Practice / Radiant Research Inc
🇺🇸Chandler, Arizona, United States
Appalachian Cardiovascular Associates
🇺🇸Fort Payne, Alabama, United States
Noble Clinical Research LLC
🇺🇸Tucson, Arizona, United States
Clinical Trials Research
🇺🇸Lincoln, California, United States
Chase Medical Research LLC
🇺🇸Waterbury, Connecticut, United States
Advanced Research Center Inc
🇺🇸Anaheim, California, United States
Rochester Clinical Research Inc.
🇺🇸Rochester, New York, United States
Southeast Regional Research Group
🇺🇸Savannah, Georgia, United States
Community Clin Res CTR
🇺🇸Anderson, Indiana, United States
Heartland Research Associated LLC
🇺🇸Newton, Kansas, United States
Best Clinical Trials LLC
🇺🇸New Orleans, Louisiana, United States
Heartland Research Associates LLC
🇺🇸Wichita, Kansas, United States
Premier Research
🇺🇸Trenton, New Jersey, United States
Metrolina Internal Medicine/Internal Medicine Research
🇺🇸Charlotte, North Carolina, United States
Lillestol Research LLC
🇺🇸Fargo, North Dakota, United States
Avant Research Associates, LLC
🇺🇸Crowley, Louisiana, United States
Detweiler Family Medicine and Associates PC
🇺🇸Lansdale, Pennsylvania, United States
Trinity Hypertension & Metabolic Research Institute
🇺🇸Carrollton, Texas, United States
Soroka University Hospital - Hypertension Unit
🇮🇱Beer Sheva, Israel
Manna Research - Levis
🇨🇦Levis, Quebec, Canada
TR - Global Medical Research
🇺🇸DeSoto, Texas, United States
Coastal Bend Clinical Research
🇺🇸Corpus Christi, Texas, United States
Bandera Family Health Care
🇺🇸San Antonio, Texas, United States
Wasatch Clinical Research LLC
🇺🇸Salt Lake City, Utah, United States
Cardiology Department Barzilai
🇮🇱Ashkelon, Israel
Health Research of Hampton Roads
🇺🇸Newport News, Virginia, United States
Research & Cardiovascular Corp.
🇵🇷Ponce, Puerto Rico
Canadian Phase Onwards Inc
🇨🇦Toronto, Ontario, Canada
National Clinical Research Inc
🇺🇸Richmond, Virginia, United States
Manna Research - Toronto
🇨🇦Toronto, Ontario, Canada
Diex Recherche Montreal Inc
🇨🇦Montréal, Quebec, Canada
Manna Research - Pointe Claire
🇨🇦Pointe-Claire, Quebec, Canada
Primecare Research Associates, LLC
🇺🇸Florissant, Missouri, United States
Clinical Research Advantage, Inc. / Oklahoma City Clinic - Midwest City
🇺🇸Midwest City, Oklahoma, United States
Pharmquest LLC
🇺🇸Greensboro, North Carolina, United States
Advanced Arizona Clinical Research
🇺🇸Tucson, Arizona, United States
Phoenix Medical Research Institute LLC
🇺🇸Peoria, Arizona, United States
New Orleans Center for Clinical Research - Nola
🇺🇸New Orleans, Louisiana, United States
Diex Reserach Sherbrooke Inc
🇨🇦Sherbrooke, Quebec, Canada
Med Center
🇺🇸Carmichael, California, United States
John Muir Physician Network Clinical Research Center
🇺🇸Concord, California, United States
Desert Sun Clinical Research LLc
🇺🇸Tucson, Arizona, United States
Empire Clinical Research
🇺🇸Upland, California, United States
Entertainment Medical Group Inc
🇺🇸Los Angeles, California, United States
Long Beach Center for Clinical Research
🇺🇸Long Beach, California, United States
Memorial Research Medical Clinic / Orange County Research Center
🇺🇸Tustin, California, United States
Alan Graff, MD, PA
🇺🇸Fort Lauderdale, Florida, United States
ACRC - Cardiology
🇺🇸Atlantis, Florida, United States
Innovative Research of West Florida INC
🇺🇸Clearwater, Florida, United States
Alfieri Cardiology
🇺🇸Wilmington, Delaware, United States
Clinical Research Consulting LLC
🇺🇸Milford, Connecticut, United States
Avail Clinical Research LLC
🇺🇸DeLand, Florida, United States
Gulfcoast Clinical Research Center
🇺🇸Fort Myers, Florida, United States
AGA Clinical Trials
🇺🇸Hialeah, Florida, United States
Canvas Clinical Research, LLC
🇺🇸Lake Worth, Florida, United States
Clinical Research Advantage, Inc. / Diagnostic Center Of Medicine - Durango
🇺🇸Las Vegas, Nevada, United States
Peters Medical Research
🇺🇸High Point, North Carolina, United States
Wake Research Associates
🇺🇸Raleigh, North Carolina, United States
Aventiv Research Inc.
🇺🇸Dublin, Ohio, United States
Sterling Research Group Ltd.
🇺🇸Cincinnati, Ohio, United States
Dayton Clinical Research
🇺🇸Dayton, Ohio, United States
Oklahoma City Clinic - Edmond / Radiant Research Inc
🇺🇸Edmond, Oklahoma, United States
Willamette Valley Clinical Studies
🇺🇸Eugene, Oregon, United States
Volunteer Research Group
🇺🇸Knoxville, Tennessee, United States
Suburban Research Center
🇺🇸Media, Pennsylvania, United States
Tekton Research Inc
🇺🇸Austin, Texas, United States
Degarmo Institute of Medical Research
🇺🇸Greer, South Carolina, United States
Texas Diabetes & Endocrinology
🇺🇸Round Rock, Texas, United States
Family Medicine Associates of Texas - ACRC Trials
🇺🇸Carrollton, Texas, United States
Ventavia Research Group, LLC
🇺🇸Fort Worth, Texas, United States
Clinical Investigations of Texas
🇺🇸Plano, Texas, United States
Avant Research Associates LLC
🇺🇸Port Arthur, Texas, United States
Northwest Clinical Research Center
🇺🇸Bellevue, Washington, United States
Manna Research - Vancouver
🇨🇦Vancouver, British Columbia, Canada
The Hyper Unit, Edith Wolfson Medical Center
🇮🇱Holon, Israel
Hypertension And Nephrology Department, Meir Medical Center
🇮🇱Kefar Sava, Israel
Clinical Research Unit Kaplan Medical Center
🇮🇱Rehovot, Israel
Hypertension Treatment Center, Internal Dep, Hadassah
🇮🇱Jerusalem, Israel
Internal Med Department A, Ziv Medical Center
🇮🇱Safed, Israel
Clinsite LLC
🇺🇸Ann Arbor, Michigan, United States
Advanced Medical Concepts, PSC
🇵🇷Cidra, Puerto Rico