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

Resistant Hypertension Clinical Trial

— PRECISION  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03541174
• Other study ID #: ID-080A301
• Secondary ID: 2017-004393-33
• Status: Completed
• Phase: Phase 3
• Start date: June 18, 2018
• Est. completion date: April 25, 2022

Study information

• Verified date: March 2023
• Source: Idorsia Pharmaceuticals Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 730
• Est. completion date: April 25, 2022
• Est. primary completion date: May 14, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Hypertension
• Resistant Hypertension

Intervention

Drug:
• Aprocitentan 12.5 mg
Tablet, oral use
• Aprocitentan 25 mg
Tablet, oral use
• Placebo
Matching placebo tablet

Locations

Country	Name	City	State
Australia	Curtin University, Faculty of Health Sciences, School of Public Health	Bentley	Western Australia
Australia	Renal Research	Gosford	New South Wales
Australia	Baker Heart and Diabetes Institute	Melbourne	Victoria
Australia	Hypertension & Kidney Disease / Huma Neurotransmitter Laboratory	Melbourne	Victoria
Australia	Royal Perth Hospital Unit - The University of Western Australia	Perth	Western Australia
Australia	Westmead Hospital Department of Renal Medicine	Sydney	New South Wales
Belgium	Clinique Universitaires de Saint Luc, Departement cardio-vasculaires intensives	Brussels
Belgium	Hospital Erasme - Cardiology department	Brussels
Belgium	Universitair Ziekenhuis Gent Cardiologie	Gent
Belgium	Centre Hospitalier Universitaire du Sart-Tilman	Liège
Canada	Manna Research Inc (North Burlington)	Hamilton	Ontario
Canada	London Health Sciences Centre - Victoria Hospital	London	Ontario
Canada	Canadian Phase Onward Inc.	Toronto	Ontario
Canada	Stephen S. Chow Medicine Professional Corporation	Toronto	Ontario
Canada	Clinical Research Solutions Inc.	Waterloo	Ontario
China	The First Affiliated Hospital of Baotou Medical College of Inner Mongolia	Baotou
China	The Third Xiangya Hospital of Central South University	Changsha
China	Guangdong General Hospital	Guangzhou
China	Zhejiang Province People's Hospital	Hangzhou
China	Hainan NO.3 Provincial people's Hospital	Sanya
China	Ruijin Hospital Shanghai Jiaotong University School of Medicine	Shanghai
China	The First Affiliated Hospital of Xi'an Jiaotong University	Xi'an
Czechia	FN U Sv.Anny Brno, kardiologická klinika	Brno
Czechia	Interni oddeleni, Nefrologie	Prague
Czechia	Všeobecní fakultní nemocnice Praha	Praha 2
Czechia	Thomayerova nemocnice	Praha 4
Czechia	Kardio Václavík s.r.o	Prerov
Finland	University of Oulu, Medical Research Center	Oulu
Finland	TAYS RDI center (Tampere University Hospital,Specialist Internal Medicine, Rare Diseases)	Tampere
Finland	Turku University Central Hospital - Turun yliopistollinen keskussairaala Sisätautien klinikka	Turku
France	CHU Grenoble - Alpes	Grenoble cedex 9
France	Hôpital de la Croix-Rousse - Rhône	Lyon
France	Hôpital Européen Georges Pompidou- Centre d' Investigation Clinique	Paris
France	Centre Hospitalier Intercommunal Toulon La Seyne sur Mer	Toulon
Germany	Jewish Hospital Berlin	Berlin
Germany	Universitätsklinikum Düsseldorf Klinik für Nephrologie	Düsseldorf
Germany	Universitätsklinikum Erlangen Klinische Forschungsstation (CRC)	Erlangen
Germany	Universitätsklinikum des Saarlandes	Homburg/Saar
Germany	Herzzentrum Leipzig Universitätsklinik für Kardiologie	Leipzig
Germany	Universitätsklinikum Nürnberg Süd	Nürnberg
Greece	Asklepeion General Hospital	Athens
Greece	General Hospital of Athens Georgios Gennimatas	Athens
Greece	General Hospital of Athens, Ippokrateio	Athens
Greece	General Hospital Konstantopouleio-Patision	Nea Ionia
Hungary	DRC Gyógyszervizsgáló Központ Kft.	Balatonfüred
Hungary	Gottsegen György Országos Kardiológiai Intézet	Budapest
Hungary	Debreceni Egyetem - Klinikai Központ	Debrecen
Hungary	Markusovszky Egyetemi Oktatókórház	Szombathely
Israel	Haemek Medical Center	Afula
Israel	Barzilai Medical Center, Cardiovascular Institute	Ashkelon
Israel	Shaare Zedek Medical Center	Jerusalem
Israel	Galilee Medical Center	Nahariya
Israel	Sheba Medical Center	Tel HaShomer
Italy	University Brescia Department Clinical and Experimental Science	Brescia
Italy	Ospedale San Gerardo, Clinica Medica	Monza
Italy	Azienda Ospedaliero Universitaria Pisana - Department Clinical and Experimental Medicine	Pisa
Italy	Azienda Ospedaliera S. Andrea di Roma - Division of Cardiology and of Cardiothoracic and Vascular Science Department -	Roma
Italy	SCU Medicina Interna e Centro Ipertensione arteriosa. Dipartimento di Scienze Mediche Università di Torino, Aou Citta' Salute E Scienza Torino	Torino
Lithuania	JSC "InMedica"	Kaunas
Lithuania	Clinic of Cardiology and Rehabilitation	Klaipeda
Netherlands	Academic Medical Center Amsterdam	Amsterdam
Netherlands	Zuyderland Medical Center	Geleen
Netherlands	Maastricht University Medical Center, Dept. of Medicine	Maastricht
Netherlands	Radboud University Medical Center	Nijmegen
Poland	Uniwersyteckie Centrum Kliniczne Centrum Kardiologii	Gdansk
Poland	Samodzielny Publiczny Szpital Kliniczny im. Andrzeja Mieleckiego Slaskiego Uniwersytetu Medycznego w Katowicach	Katowice
Poland	Diamond Clinic	Kraków
Poland	SPZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego w Lodzi	Lodz
Poland	ETG Lublin	Lublin
Poland	KO-MED. CentraKliniczne Sp. Z o.o. Osrodek Badan Klinicznych w Lublinie II	Lublin
Poland	Etyka Osrodek Badan Klinicznych	Olsztyn
Poland	KO-MED. Centra Kliniczne Sp. Z o.o. Osrodek Badan Klinicznych w Pulawach	Pulawy
Poland	ETG Skierniewice	Skierniewice
Poland	ETG Warszawa	Warszawa
Poland	Klinika Wad Wrodzonych Serca Instytut Kardiologii im. Kardynala Wyszynskiego	Warszawa
Poland	Medycyna Kliniczna	Warszawa
Poland	Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie	Warszawa
Poland	Samodzielny Publiczny Szpital Wojewódzki im. Papieza Jana Pawla II w Zamosciu	Zamosc
Poland	ETG Zgierz	Zgierz
Russian Federation	State Budgetary Healthcare Institution of Arkhangelsk Region "First City Clinical Hospital n.a. E.E. Volosevich"	Arkhangelsk
Russian Federation	Federal State Autonomous Institution of Higher Education "Kazan (Volga Region) Federal University"	Kazan
Russian Federation	Federal State Budget Scientific Institution "Scientific Research Institute for Complex Issues of Cardiovascular Diseases"	Kemerovo
Russian Federation	Scientific Research Institute - Regional Clinical Hospital ?1	Krasnodar
Russian Federation	National Medical Research Center for Preventive Medicine	Moscow
Russian Federation	Federal State Budget Scientific Institution "Federal Research Center Institute of Cytology and Genetics of Siberian Department of Russian Academy of Sciences"	Novosibirsk
Russian Federation	State budget healthcare institution of Novosibirsk region "City clinical hospital #34"	Novosibirsk
Russian Federation	Federal State Budget Institution National Medical Research Center n.a. V.A. Almazov of the Ministry of Healthcare of the Russia	Saint Petersburg
Russian Federation	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	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	Saratov
Russian Federation	State Healthcare Institution "Regional Clinical Cardiology Dispensary"	Saratov
Russian Federation	State Budgetary Educational Institution of Higher Professional Education Smolensk State Medical Academy	Smolensk
Russian Federation	Federal State Budget Institution "National Medical Research Center n.a. V.A. Almazov" of the Ministry of healthcare of the Russian Federation	St. Petersburg
Russian Federation	Federal State Budget Scientific Institution "Tomsk National Research Medical Center of the Russian Academy of Sciences"	Tomsk
Russian Federation	Tyumen Cardiology Research Center, Tomsk National Research Medical Center, Russian Academy of Science	Tyumen
Spain	Fundació Puigvert	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitari de Bellvitge	Barcelona
Spain	Hospital Vall d'Hebron de Barcelona	Barcelona
Spain	Hospital Virgen de las Nieves - Internal Medicine Department	Granada
Spain	Hospital Clinico San Carlos - Istituto de Investigacion Sanitaria San Carlos (IdISSC)	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Virgen del Rocio Departamento de Medicina Interna	Sevilla
Spain	Hospital Clínic Universitari de València	Valencia
Spain	Hypertension Clinic, Internal Medicine, Hospital Clinico, University of Valencia, Valencia	Valencia
Ukraine	Municipal non-profit enterprise "Clinical Hospital # 8"of Kharkiv City Council	Kharkiv
Ukraine	State Institution "L.T. Malaya Therapy National Institute of the NAMS of Ukraine"	Kharkiv
Ukraine	Kyiv City Clinical Hospital # 1	Kyiv
Ukraine	Kyiv Municipal Clinical Emergency Hospital	Kyiv
Ukraine	State Institution "D.F. Chebotarev Institute of Gerontology, National Academy of Medical Science of Ukraine"	Kyiv
Ukraine	State Institution "Institute of Gerontology named after D.F. Chebotarev of National Academy of Medical Sciences of Ukraine"	Kyiv
Ukraine	State Institution "National Scientific Center "M.D. Strazhesko Institute of Cardiology" of the National Academy of Medical Sciences of Ukraine"	Kyiv
Ukraine	Volyn Regional Center for Cardiovascular Pathology, Rehabilitation Department	Lutsk
Ukraine	Danylo Halytsky Lviv National Medical University	Lviv
Ukraine	Communal Non-profit Enterprise "Vinnytsya regional Clinical Hospital named after. N.I. Pirogov Vinnytsia Regional Council"/ National Pirogov Memorial Medical University, Vinnytsya	Vinnytsya
Ukraine	O.F. Herbachevsky Zhytomyr Regional Clinical Hospital, Cardiology department	Zhytomyr
United Kingdom	Aberdeen Royal Infirmary, Clinical Pharmacology Unit	Aberdeen
United Kingdom	Clinical Research Centre The University of Edinburgh Centre for Cardiovascular Science	Edinburgh
United Kingdom	Queen Mary University of London	London
United States	Albany Medical College	Albany	New York
United States	Renal Medicine Associates	Albuquerque	New Mexico
United States	Advanced Cardiovascular, LLC	Alexander City	Alabama
United States	Amarillo Heart Clinical Research Institute, Inc.	Amarillo	Texas
United States	Grace Research, LLC	Bossier City	Louisiana
United States	Bay Area Cardiology Associates, P.A.	Brandon	Florida
United States	Burke Internal Medicine & Research	Burke	Virginia
United States	Metrolina Internal Medicine/Internal Medicine Research	Charlotte	North Carolina
United States	University Hospitals Cleveland Medical Center - Neurological Institute	Cleveland	Ohio
United States	TLM Medical Services LLC	Columbia	South Carolina
United States	Century Clinical Research, Inc	Daytona Beach	Florida
United States	Hypertension and Nephrology Association PA	Eatontown	New Jersey
United States	Willamette Valley Clinical Studies	Eugene	Oregon
United States	Stern Cardiovascular Foundation, Inc	Germantown	Tennessee
United States	East Carolina University	Greenville	North Carolina
United States	Physician's East Endocrinology	Greenville	North Carolina
United States	DeGarmo Institute of Medical Research	Greer	South Carolina
United States	MedStar Health Research Institute	Hyattsville	Maryland
United States	Midwest Institute for Clinical Research	Indianapolis	Indiana
United States	Chrishard Medical Group	Inglewood	California
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	Clinical Research Consultants, LLC	Kansas City	Missouri
United States	Canvas Clinical Research, LLC	Lake Worth	Florida
United States	Scott Research Inc	Laurelton	New York
United States	Clinical Trials Research	Lincoln	California
United States	Academic Medical Research Institute Inc	Los Angeles	California
United States	Manassas Clinical Research Center	Manassas	Virginia
United States	LifeDOC Research PLLC	Memphis	Tennessee
United States	Carteret Medical Group	Morehead City	North Carolina
United States	Cardiovascular Research of Northwest Indiana, L.L.C.	Munster	Indiana
United States	Amicis Research Center	Northridge	California
United States	LinQ Research, LLC	Pearland	Texas
United States	Reid Physician Associates	Richmond	Indiana
United States	East Coast Institute for Research	Saint Augustine	Florida
United States	St. George Kidney Care LLC dba Southern Utah Kidney and Hypertension Center	Saint George	Utah
United States	California Kidney Specialists	San Dimas	California
United States	SIU School of Medicine Center for Clinical Research	Springfield	Illinois
United States	Premier Medical Associates	The Villages	Florida
United States	Milwaukee Nephrologists, SC	Wauwatosa	Wisconsin
United States	Mercury Clinical Research	Webster	Texas
United States	Great Lakes Medical Research LLC	Westfield	New York

Sponsors (2)

Lead Sponsor	Collaborator
Idorsia Pharmaceuticals Ltd.	Janssen Biotech, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  China,  Czechia,  Finland,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Lithuania,  Netherlands,  Poland,  Russian Federation,  Spain,  Ukraine,  United Kingdom, 

References & Publications (3)

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 — View Citation

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. — View Citation

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. — View Citation

Outcome

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