Clinical trial NCT02603809: Dose-finding Study With ACT-132577 (Aprocitentan) in Participants With Essential Hypertension
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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Essential Hypertension
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2015-11-13
Enrollment: 1659
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

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