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 (PRECISION)

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

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.

Study Overview

• Status: Completed
• Conditions: Resistant Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: Aprocitentan 25 mg; Drug: Aprocitentan 12.5 mg

Detailed Description

Participation in the study will be up to 68 weeks.

The study has 4 periods:

1. Screening period
2. Placebo run-in period
3. Randomized treatment period
4. 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.

• Study Type: Interventional
• Enrollment (Actual): 730
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Gosford, New South Wales, Australia, 2250
      • Renal Research
    • Sydney, New South Wales, Australia, 2145
      • Westmead Hospital Department of Renal Medicine
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Baker Heart and Diabetes Institute
    • Melbourne, Victoria, Australia, 3004
      • Hypertension & Kidney Disease / Huma Neurotransmitter Laboratory
  • Western Australia
    • Bentley, Western Australia, Australia, 6102
      • Curtin University, Faculty of Health Sciences, School of Public Health
    • Perth, Western Australia, Australia, 6000
      • Royal Perth Hospital Unit - The University of Western Australia
• Belgium
  • Brussels, Belgium, 1200
    • Clinique Universitaires de Saint Luc, Departement cardio-vasculaires intensives
  • Brussels, Belgium, 1070
    • Hospital Erasme - Cardiology department
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent Cardiologie
  • Liège, Belgium, 4000
    • Centre Hospitalier Universitaire du Sart-Tilman
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8J 3W2
      • Manna Research Inc (North Burlington)
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre - Victoria Hospital
    • Toronto, Ontario, Canada, M3J 2C5
      • Canadian Phase Onward Inc.
    • Toronto, Ontario, Canada, M4C 5T2
      • Stephen S. Chow Medicine Professional Corporation
    • Waterloo, Ontario, Canada, N2J 3Z4
      • Clinical Research Solutions Inc.
• China
  • Baotou, China, 014010
    • The First Affiliated Hospital of Baotou Medical College of Inner Mongolia
  • Changsha, China, 410000
    • The Third Xiangya Hospital of Central South University
  • Guangzhou, China, 510080
    • Guangdong General Hospital
  • Hangzhou, China, 310014
    • Zhejiang Province People's Hospital
  • Sanya, China, 572000
    • Hainan NO.3 Provincial people's Hospital
  • Shanghai, China, 200000
    • Ruijin Hospital Shanghai Jiaotong University School of Medicine
  • Xi'an, China, 710061
    • The First Affiliated Hospital of Xi'an Jiaotong University
• Czechia
  • Brno, Czechia, 656 91
    • FN U Sv.Anny Brno, kardiologická klinika
  • Prague, Czechia, 16000
    • Interni oddeleni, Nefrologie
  • Praha 2, Czechia, 128 08
    • Všeobecní fakultní nemocnice Praha
  • Praha 4, Czechia, 140 59
    • Thomayerova nemocnice
  • Přerov, Czechia, 750 02
    • Kardio Václavík s.r.o
• Finland
  • Oulu, Finland, 90220
    • University of Oulu, Medical Research Center
  • Tampere, Finland, 33520
    • TAYS RDI center (Tampere University Hospital,Specialist Internal Medicine, Rare Diseases)
  • Turku, Finland, 20520
    • Turku University Central Hospital - Turun yliopistollinen keskussairaala Sisätautien klinikka
• France
  • Grenoble cedex 9, France, 38043
    • CHU Grenoble - Alpes
  • Lyon, France, 69317
    • Hôpital de la Croix-Rousse - Rhône
  • Paris, France, 75015
    • Hôpital Européen Georges Pompidou- Centre d' Investigation Clinique
  • Toulon, France, 83100
    • Centre Hospitalier Intercommunal Toulon La Seyne sur Mer
• Germany
  • Berlin, Germany, 13347
    • Jewish Hospital Berlin
  • Düsseldorf, Germany, 40225
    • Universitätsklinikum Düsseldorf Klinik für Nephrologie
  • Erlangen, Germany, 91054
    • Universitätsklinikum Erlangen Klinische Forschungsstation (CRC)
  • Homburg/Saar, Germany, 66421
    • Universitätsklinikum des Saarlandes
  • Leipzig, Germany, 04289
    • Herzzentrum Leipzig Universitätsklinik für Kardiologie
  • Nürnberg, Germany, 90471
    • Universitätsklinikum Nürnberg Süd
• Greece
  • Athens, Greece, 11527
    • General Hospital of Athens, Ippokrateio
  • Athens, Greece, 15669
    • General Hospital of Athens Georgios Gennimatas
  • Athens, Greece, 16673
    • Asklepeion General Hospital
  • Nea Ionia, Greece, 14233
    • General Hospital Konstantopouleio-Patision
• Hungary
  • Balatonfüred, Hungary, 8230
    • DRC Gyogyszervizsgalo Kozpont Kft.
  • Budapest, Hungary, 1096
    • Gottsegen György Országos Kardiológiai Intézet
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem - Klinikai Kozpont
  • Szombathely, Hungary, 9700
    • Markusovszky Egyetemi Oktatokorhaz
• Israel
  • Afula, Israel, 1834111
    • Haemek Medical Center
  • Ashkelon, Israel, 7830604
    • Barzilai Medical Center, Cardiovascular Institute
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center
  • Nahariya, Israel, 2210001
    • Galilee Medical Center
  • Tel HaShomer, Israel, 5265601
    • Sheba Medical Center
• Italy
  • Brescia, Italy, 25121
    • University Brescia Department Clinical and Experimental Science
  • Monza, Italy, 20835
    • Ospedale San Gerardo, Clinica Medica
  • Pisa, Italy, 56126
    • Azienda Ospedaliero Universitaria Pisana - Department Clinical and Experimental Medicine
  • Roma, Italy, 00189
    • Azienda Ospedaliera S. Andrea di Roma - Division of Cardiology and of Cardiothoracic and Vascular Science Department -
  • Torino, Italy, 10126
    • SCU Medicina Interna e Centro Ipertensione arteriosa. Dipartimento di Scienze Mediche Università di Torino, Aou Citta' Salute E Scienza Torino
• Lithuania
  • Kaunas, Lithuania, LT-50177
    • JSC "InMedica"
  • Klaipeda, Lithuania, LT-91131
    • Clinic of Cardiology and Rehabilitation
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academic Medical Center Amsterdam
  • Geleen, Netherlands, 6162 BG
    • Zuyderland Medical Center
  • Maastricht, Netherlands, 6229 HX
    • Maastricht University Medical Center, Dept. of Medicine
  • Nijmegen, Netherlands, 6500 HB
    • Radboud University Medical Center
• Poland
  • Gdańsk, Poland, 80-214
    • Uniwersyteckie Centrum Kliniczne Centrum Kardiologii
  • Katowice, Poland, 40-027
    • Samodzielny Publiczny Szpital Kliniczny im. Andrzeja Mielęckiego Slaskiego Uniwersytetu Medycznego w Katowicach
  • Kraków, Poland, 31-559
    • Diamond Clinic
  • Lodz, Poland, 92-213
    • SPZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego w Łodzi
  • Lublin, Poland, 20-412
    • ETG Lublin
  • Lublin, Poland, 20-362
    • KO-MED. CentraKliniczne Sp. Z o.o. Ośrodek Badań Klinicznych w Lublinie II
  • Olsztyn, Poland, 10-117
    • ETYKA Osrodek Badan Klinicznych
  • Puławy, Poland, 24-100
    • KO-MED. Centra Kliniczne Sp. Z o.o. Ośrodek Badań Klinicznych w Puławach
  • Skierniewice, Poland, 96-100
    • ETG Skierniewice
  • Warszawa, Poland, 00-874
    • Medycyna Kliniczna
  • Warszawa, Poland, 02-777
    • ETG Warszawa
  • Warszawa, Poland, 02-097
    • Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie
  • Warszawa, Poland, 04-628
    • Klinika Wad Wrodzonych Serca Instytut Kardiologii im. Kardynala Wyszynskiego
  • Zamość, Poland, 22-400
    • Samodzielny Publiczny Szpital Wojewódzki im. Papieża Jana Pawła II w Zamościu
  • Zgierz, Poland, 95-100
    • ETG Zgierz
• Russian Federation
  • Arkhangelsk, Russian Federation, 163001
    • State Budgetary Healthcare Institution of Arkhangelsk Region "First City Clinical Hospital n.a. E.E. Volosevich"
  • Kazan, Russian Federation, 420043
    • Federal State Autonomous Institution of Higher Education "Kazan (Volga Region) Federal University"
  • Kemerovo, Russian Federation, 650002
    • Federal State Budget Scientific Institution "Scientific Research Institute for Complex Issues of Cardiovascular Diseases"
  • Krasnodar, Russian Federation, 350086
    • Scientific Research Institute - Regional Clinical Hospital №1
  • Moscow, Russian Federation, 101990
    • National Medical Research Center for Preventive Medicine
  • Novosibirsk, Russian Federation, 630054
    • State budget healthcare institution of Novosibirsk region "City clinical hospital #34"
  • Novosibirsk, Russian Federation, 630089
    • Federal State Budget Scientific Institution "Federal Research Center Institute of Cytology and Genetics of Siberian Department of Russian Academy of Sciences"
  • Saint Petersburg, Russian Federation, 194044
    • Federal State Military Educational Institution of Higher Professional Education, Military Medical Academy named for S. M. Kirov of the Ministry of Defense of the Russian Federation
  • Saint Petersburg, Russian Federation, 197341
    • Federal State Budget Institution National Medical Research Center n.a. V.A. Almazov of the Ministry of Healthcare of the Russia
  • Saratov, Russian Federation, 410028
    • State Healthcare Institution "Regional Clinical Cardiology Dispensary"
  • Saratov, Russian Federation, 410054
    • Federal State Budget Educational Institution of Higher Education "Saratov State Medical University n.a. V.I. Razumovskiy" of the Ministry of Healthcare of the Russian Federation
  • Smolensk, Russian Federation, 214018
    • State Budgetary Educational Institution of Higher Professional Education Smolensk State Medical Academy
  • St. Petersburg, Russian Federation, 197341
    • Federal State Budget Institution "National Medical Research Center n.a. V.A. Almazov" of the Ministry of healthcare of the Russian Federation
  • Tomsk, Russian Federation, 634012
    • Federal State Budget Scientific Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences"
  • Tyumen, Russian Federation, 625026
    • Tyumen Cardiology Research Center, Tomsk National Research Medical Center, Russian Academy of Science
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Barcelona, Spain, 08025
    • Fundacio Puigvert
  • Barcelona, Spain, 08907
    • Hospital Universitari de Bellvitge
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron de Barcelona
  • Granada, Spain, 18014
    • Hospital Virgen de las Nieves - Internal Medicine Department
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos - Istituto de Investigacion Sanitaria San Carlos (IdISSC)
  • Sevilla, Spain, 41013
    • Hospital Virgen del Rocio Departamento de Medicina Interna
  • Valencia, Spain, 46010
    • Hospital Clinic Universitari de Valencia
  • Valencia, Spain, 46010
    • Hypertension Clinic, Internal Medicine, Hospital Clinico, University of Valencia, Valencia
• Ukraine
  • Kharkiv, Ukraine, 61039
    • State Institution "L.T. Malaya Therapy National Institute of the NAMS of Ukraine"
  • Kharkiv, Ukraine, 61176
    • Municipal non-profit enterprise "Clinical Hospital # 8"of Kharkiv City Council
  • Kyiv, Ukraine, 02091
    • Kyiv City Clinical Hospital # 1
  • Kyiv, Ukraine, 02116
    • Kyiv Municipal Clinical Emergency Hospital
  • Kyiv, Ukraine, 03680
    • State Institution "National Scientific Center "M.D. Strazhesko Institute of Cardiology" of the National Academy of Medical Sciences of Ukraine"
  • Kyiv, Ukraine, 04114
    • State Institution "D.F. Chebotarev Institute of Gerontology, National Academy of Medical Science of Ukraine"
  • Kyiv, Ukraine, 04114
    • State Institution "Institute of Gerontology named after D.F. Chebotarev of National Academy of Medical Sciences of Ukraine"
  • Lutsk, Ukraine, 43024
    • Volyn Regional Center for Cardiovascular Pathology, Rehabilitation Department
  • Lviv, Ukraine, 79013
    • Danylo Halytsky Lviv National Medical University
  • Vinnytsya, Ukraine, 21028
    • Communal Non-profit Enterprise "Vinnytsya regional Clinical Hospital named after. N.I. Pirogov Vinnytsia Regional Council"/ National Pirogov Memorial Medical University, Vinnytsya
  • Zhytomyr, Ukraine, 10002
    • O.F. Herbachevsky Zhytomyr Regional Clinical Hospital, Cardiology department
• United Kingdom
  • Aberdeen, United Kingdom, AB24 2ZN
    • Aberdeen Royal Infirmary, Clinical Pharmacology Unit
  • Edinburgh, United Kingdom, EH4 2XU
    • Clinical Research Centre The University of Edinburgh Centre for Cardiovascular Science
  • London, United Kingdom, EC1M 6BQ
    • Queen Mary University of London
• United States
  • Alabama
    • Alexander City, Alabama, United States, 35010
      • Advanced Cardiovascular, LLC
  • California
    • Inglewood, California, United States, 90301
      • Chrishard Medical Group
    • Lincoln, California, United States, 95648
      • Clinical Trials Research
    • Los Angeles, California, United States, 90022
      • Academic Medical Research Institute Inc
    • Northridge, California, United States, 91324
      • Amicis Research Center
    • San Dimas, California, United States, 91773
      • California Kidney Specialists
  • Florida
    • Brandon, Florida, United States, 33511
      • Bay Area Cardiology Associates, P.A.
    • Daytona Beach, Florida, United States, 32117
      • Century Clinical Research, Inc
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Lake Worth, Florida, United States, 33467
      • Canvas Clinical Research, LLC
    • Saint Augustine, Florida, United States, 32086
      • East Coast Institute For Research
    • The Villages, Florida, United States, 32159
      • Premier Medical Associates
  • Illinois
    • Springfield, Illinois, United States, 62702
      • SIU School of Medicine Center for Clinical Research
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Midwest Institute for Clinical Research
    • Munster, Indiana, United States, 46231
      • Cardiovascular Research of Northwest Indiana, L.L.C.
    • Richmond, Indiana, United States, 47374
      • Reid Physician Associates
  • Louisiana
    • Bossier City, Louisiana, United States, 71111
      • Grace Research, LLC
  • Maryland
    • Hyattsville, Maryland, United States, 20782
      • Medstar Health Research Institute
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Clinical Research Consultants, LLC
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Hypertension and Nephrology Association PA
  • New Mexico
    • Albuquerque, New Mexico, United States, 87109
      • Renal Medicine Associates
  • New York
    • Albany, New York, United States, 12206
      • Albany Medical College
    • Laurelton, New York, United States, 11413
      • Scott Research Inc
    • Westfield, New York, United States, 14787
      • Great Lakes Medical Research LLC
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Metrolina Internal Medicine/Internal Medicine Research
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
    • Greenville, North Carolina, United States, 27834
      • Physician's East Endocrinology
    • Morehead City, North Carolina, United States, 28557
      • Carteret Medical Group
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center - Neurological Institute
  • Oregon
    • Eugene, Oregon, United States, 97404
      • Willamette Valley Clinical Studies
  • South Carolina
    • Columbia, South Carolina, United States, 29204
      • TLM Medical Services LLC
    • Greer, South Carolina, United States, 29650
      • DeGarmo Institute of Medical Research
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Stern Cardiovascular Foundation, Inc
    • Memphis, Tennessee, United States, 38119
      • LifeDOC Research PLLC
  • Texas
    • Amarillo, Texas, United States, 79106
      • Amarillo Heart Clinical Research Institute, Inc.
    • Pearland, Texas, United States, 77584
      • LinQ Research, LLC
    • Webster, Texas, United States, 77598
      • Mercury Clinical Research
  • Utah
    • Saint George, Utah, United States, 84790
      • St. George Kidney Care LLC dba Southern Utah Kidney and Hypertension Center
  • Virginia
    • Burke, Virginia, United States, 22015
      • Burke Internal Medicine & Research
    • Manassas, Virginia, United States, 20110
      • Manassas Clinical Research Center
  • Wisconsin
    • Wauwatosa, Wisconsin, United States, 53226
      • Milwaukee Nephrologists, Sc

Participation Criteria

Eligibility Criteria

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

Description

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).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aprocitentan 25 mg in Part 1 (double-blind); Participants will receive aprocitentan 25 mg, orally, once daily in the morning for 4 weeks.	Drug: Aprocitentan 25 mg; Tablet, oral use; Other Names: ACT-132577
Experimental: Aprocitentan 12.5 mg in Part 1 (double-blind); Participants will receive aprocitentan 12.5 mg, orally, once daily in the morning for 4 weeks.	Drug: Aprocitentan 12.5 mg; Tablet, oral use; Other Names: ACT-132577
Placebo Comparator: Placebo in Part 1 (double-blind); Participants will receive placebo (matching aprocitentan), orally, once daily in the morning for 4 weeks.	Drug: Placebo; Matching placebo tablet
Experimental: Aprocitentan 25 mg in Part 2 (single-blind, single arm); 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; Tablet, oral use; Other Names: ACT-132577
Experimental: Aprocitentan 25 mg in Part 3 (double-blind withdrawal); 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; Tablet, oral use; Other Names: ACT-132577
Placebo Comparator: Placebo in Part 3 (double-blind withdrawal); 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; Matching placebo tablet

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Idorsia Pharmaceuticals Ltd.
• Collaborators: Janssen Biotech, Inc.

Publications and helpful links

General Publications

• Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ. Recommendations for blood pressure measurement in humans and experimental animals: part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation. 2005 Feb 8;111(5):697-716. doi: 10.1161/01.CIR.0000154900.76284.F6.
• Daskalopoulou SS, Khan NA, Quinn RR, Ruzicka M, McKay DW, Hackam DG, Rabkin SW, Rabi DM, Gilbert RE, Padwal RS, Dawes M, Touyz RM, Campbell TS, Cloutier L, Grover S, Honos G, Herman RJ, Schiffrin EL, Bolli P, Wilson T, Feldman RD, Lindsay MP, Hemmelgarn BR, Hill MD, Gelfer M, Burns KD, Vallee M, Prasad GV, Lebel M, McLean D, Arnold JM, Moe GW, Howlett JG, Boulanger JM, Larochelle P, Leiter LA, Jones C, Ogilvie RI, Woo V, Kaczorowski J, Trudeau L, Bacon SL, Petrella RJ, Milot A, Stone JA, Drouin D, Lamarre-Cliche M, Godwin M, Tremblay G, Hamet P, Fodor G, Carruthers SG, Pylypchuk G, Burgess E, Lewanczuk R, Dresser GK, Penner B, Hegele RA, McFarlane PA, Sharma M, Campbell NR, Reid D, Poirier L, Tobe SW; Canadian Hypertension Education Program. The 2012 Canadian hypertension education program recommendations for the management of hypertension: blood pressure measurement, diagnosis, assessment of risk, and therapy. Can J Cardiol. 2012 May;28(3):270-87. doi: 10.1016/j.cjca.2012.02.018.
• Danaietash P, Verweij P, Wang JG, Dresser G, Kantola I, Lawrence MK, Narkiewicz K, Schlaich M, Bellet M; PRECISION investigators. Identifying and treating resistant hypertension in PRECISION: A randomized long-term clinical trial with aprocitentan. J Clin Hypertens (Greenwich). 2022 Jul;24(7):804-813. doi: 10.1111/jch.14517. Epub 2022 Jun 9.
• Schlaich MP, Bellet M, Weber MA, Danaietash P, Bakris GL, Flack JM, Dreier RF, Sassi-Sayadi M, Haskell LP, Narkiewicz K, Wang JG; PRECISION investigators. Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet. 2022 Dec 3;400(10367):1927-1937. doi: 10.1016/S0140-6736(22)02034-7. Epub 2022 Nov 7. Erratum In: Lancet. 2023 Jan 28;401(10373):268.

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2018
• Primary Completion (Actual): May 14, 2021
• Study Completion (Actual): April 25, 2022

Study Registration Dates

• First Submitted: May 17, 2018
• First Submitted That Met QC Criteria: May 29, 2018
• First Posted (Actual): May 30, 2018

Study Record Updates

• Last Update Posted (Actual): March 21, 2023
• Last Update Submitted That Met QC Criteria: March 16, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension
• Other Study ID Numbers: ID-080A301; 2017-004393-33 (EudraCT Number)

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