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

Essential Hypertension Clinical Trial

Official title:

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).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02603809
• Other study ID #: AC-080A201
• Status: Completed
• Phase: Phase 2
• Start date: December 14, 2015
• Est. completion date: April 7, 2017

Study information

• Verified date: November 2022
• Source: Idorsia Pharmaceuticals Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 1659
• Est. completion date: April 7, 2017
• Est. primary completion date: February 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Essential Hypertension
• Hypertension

Intervention

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.
• Aprocitentan 10 mg
Two capsules of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks.
• Aprocitentan 25 mg
One capsule of 25 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.
• Aprocitentan 50 mg
One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril.
• Lisinopril 20 mg
One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan
• Placebo
One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.

Locations

Country	Name	City	State
Canada	Manna Research - Levis	Levis	Quebec
Canada	Diex Recherche Montreal Inc	Montreal	Quebec
Canada	Diex Recherche Montreal Inc	Montréal	Quebec
Canada	Manna Research - Pointe Claire	Pointe-Claire	Quebec
Canada	Diex Reserach Sherbrooke Inc	Sherbrooke	Quebec
Canada	Canadian Phase Onwards Inc	Toronto	Ontario
Canada	Manna Research - Toronto	Toronto	Ontario
Canada	Manna Research - Vancouver	Vancouver	British Columbia
Israel	Cardiology Department Barzilai	Ashkelon
Israel	Soroka University Hospital - Hypertension Unit	Beer Sheva
Israel	The Hyper Unit, Edith Wolfson Medical Center	Holon
Israel	Hypertension Treatment Center, Internal Dep, Hadassah	Jerusalem
Israel	Hypertension And Nephrology Department, Meir Medical Center	Kefar Sava
Israel	Clinical Research Unit Kaplan Medical Center	Rehovot
Israel	Internal Med Department A, Ziv Medical Center	Safed
Puerto Rico	Advanced Medical Concepts, PSC	Cidra
Puerto Rico	Research & Cardiovascular Corp.	Ponce
United States	Advanced Research Center Inc	Anaheim	California
United States	Community Clin Res CTR	Anderson	Indiana
United States	Clinsite LLC	Ann Arbor	Michigan
United States	ACRC - Cardiology	Atlantis	Florida
United States	Tekton Research Inc	Austin	Texas
United States	Texas Diabetes & Endocrinology	Austin	Texas
United States	Northwest Clinical Research Center	Bellevue	Washington
United States	Med Center	Carmichael	California
United States	Family Medicine Associates of Texas - ACRC Trials	Carrollton	Texas
United States	Trinity Hypertension & Metabolic Research Institute	Carrollton	Texas
United States	Radiant Research Inc	Chandler	Arizona
United States	Warner Family Practice / Radiant Research Inc	Chandler	Arizona
United States	Metrolina Internal Medicine/Internal Medicine Research	Charlotte	North Carolina
United States	Sterling Research Group Ltd.	Cincinnati	Ohio
United States	Innovative Research of West Florida INC	Clearwater	Florida
United States	Aventiv Research Inc.	Columbus	Ohio
United States	John Muir Physician Network Clinical Research Center	Concord	California
United States	Coastal Bend Clinical Research	Corpus Christi	Texas
United States	Avant Research Associates, LLC	Crowley	Louisiana
United States	Dayton Clinical Research	Dayton	Ohio
United States	Avail Clinical Research LLC	DeLand	Florida
United States	TR - Global Medical Research	DeSoto	Texas
United States	Aventiv Research Inc.	Dublin	Ohio
United States	Oklahoma City Clinic - Edmond / Radiant Research Inc	Edmond	Oklahoma
United States	Willamette Valley Clinical Studies	Eugene	Oregon
United States	Lillestol Research LLC	Fargo	North Dakota
United States	Primecare Research Associates, LLC	Florissant	Missouri
United States	Alan Graff, MD, PA	Fort Lauderdale	Florida
United States	Gulfcoast Clinical Research Center	Fort Myers	Florida
United States	Appalachian Cardiovascular Associates	Fort Payne	Alabama
United States	Ventavia Research Group, LLC	Fort Worth	Texas
United States	Pharmquest LLC	Greensboro	North Carolina
United States	Degarmo Institute of Medical Research	Greer	South Carolina
United States	AGA Clinical Trials	Hialeah	Florida
United States	Peters Medical Research	High Point	North Carolina
United States	Midwest Institute for Clinical Research	Indianapolis	Indiana
United States	Volunteer Research Group	Knoxville	Tennessee
United States	Canvas Clinical Research, LLC	Lake Worth	Florida
United States	Detweiler Family Medicine and Associates PC	Lansdale	Pennsylvania
United States	Clinical Research Advantage, Inc. / Diagnostic Center Of Medicine - Durango	Las Vegas	Nevada
United States	Clinical Trials Research	Lincoln	California
United States	Long Beach Center for Clinical Research	Long Beach	California
United States	Entertainment Medical Group Inc	Los Angeles	California
United States	Suburban Research Center	Media	Pennsylvania
United States	Allied Biomedical Research Institute, INC	Miami	Florida
United States	LCC Medical Research Institute	Miami	Florida
United States	Clinical Research Advantage, Inc. / Oklahoma City Clinic - Midwest City	Midwest City	Oklahoma
United States	Clinical Research Consulting LLC	Milford	Connecticut
United States	Best Clinical Trials LLC	New Orleans	Louisiana
United States	New Orleans Center for Clinical Research - Nola	New Orleans	Louisiana
United States	Health Research of Hampton Roads	Newport News	Virginia
United States	Heartland Research Associated LLC	Newton	Kansas
United States	Phoenix Medical Research Institute LLC	Peoria	Arizona
United States	Clinical Investigations of Texas	Plano	Texas
United States	Avant Research Associates LLC	Port Arthur	Texas
United States	Wake Research Associates	Raleigh	North Carolina
United States	National Clinical Research Inc	Richmond	Virginia
United States	Rochester Clinical Research Inc.	Rochester	New York
United States	Texas Diabetes & Endocrinology	Round Rock	Texas
United States	Wasatch Clinical Research LLC	Salt Lake City	Utah
United States	Bandera Family Health Care	San Antonio	Texas
United States	Radiant Research Inc	San Antonio	Texas
United States	Artemis institute for Clinical Research	San Diego	California
United States	Southeast Regional Research Group	Savannah	Georgia
United States	Premier Research	Trenton	New Jersey
United States	Advanced Arizona Clinical Research	Tucson	Arizona
United States	Desert Sun Clinical Research LLc	Tucson	Arizona
United States	Noble Clinical Research LLC	Tucson	Arizona
United States	Memorial Research Medical Clinic / Orange County Research Center	Tustin	California
United States	Empire Clinical Research	Upland	California
United States	Chase Medical Research LLC	Waterbury	Connecticut
United States	Heartland Research Associates LLC	Wichita	Kansas
United States	Heartland Research Associates LLC	Wichita	Kansas
United States	Alfieri Cardiology	Wilmington	Delaware

Sponsors (1)

Lead Sponsor	Collaborator
Idorsia Pharmaceuticals Ltd.

Countries where clinical trial is conducted

United States,  Canada,  Israel,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)