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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT03904693
Other study ID # AC-077A301
Secondary ID 2014-004786-25AC
Status Active, not recruiting
Phase Phase 3
First received
Last updated
Start date July 29, 2019
Est. completion date September 24, 2024

Study information

Verified date June 2024
Source Actelion
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

Combination therapy in pulmonary arterial hypertension (PAH) has been the subject of active investigation for more than a decade, with the benefit of targeting different pathways known to be involved in the pathogenesis of the disease. Adherence to prescribed therapy has an impact on clinical outcomes. Reducing the pill/tablet count and frequency has a major impact on patients' adherence to therapies and therefore the observed clinical outcomes. One way to simplify treatment is to use fixed-dose combination (FDC) products that combine multiple treatments targeting different pathways into a single tablet. This study aims to demonstrate that the FDC of macitentan and tadalafil is more effective than therapy with 10 mg of macitentan alone or 40 mg of tadalafil alone. This phase 3 study will evaluate the efficacy and safety at 16 weeks of an FDC (macitentan 10 mg and tadalafil 40 mg) against these two PAH-approved therapies given as monotherapy to further confirm the added value of the FDC.


Description:

PAH is characterized by a progressive increase in pulmonary arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading to right heart failure and death. Current PAH-specific therapeutic options include treatments that target the three pathways (endothelin, nitric oxide, and prostacyclin pathways). While combination treatment is common, FDC pills or tablets that combine two or more PAH-specific therapies are not available, thereby requiring participants to take multiple pills/tablets daily. An FDC is an attractive option for PAH participants because it simplifies the treatment regimen by combining two therapies (which would otherwise involve a total of three tablets: one macitentan 10 mg tablet and two tadalafil 20 mg tablets) into a single tablet. Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B antagonist. Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). This study comprises the following consecutive periods: Screening period (lasts up to 30 days), Double-blind treatment period (consists of the titration phase [the first 2 weeks] and the maintenance phase [Week 3 through Week 16]), Open-label treatment period, End-of-Treatment (EOT), Safety follow-up (S-FU) period, and End of Study (EOS). The total study duration for a participant will be up to 30 months. Study assessments like physical examinations, vital signs, right heart catheterization, 6-minute walk test will be performed. Safety will be assessed throughout the study.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 187
Est. completion date September 24, 2024
Est. primary completion date August 23, 2022
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Signed and dated informed consent form (ICF) - Confirmed diagnosis of symptomatic PAH in WHO FC II or III - Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary hypertension: - Idiopathic - Heritable - Drug- or toxin-induced - Associated with connective tissue disease, HIV infection, portal hypertension or congenital heart disease with simple systemic-to-pulmonary shunt with persistent pulmonary hypertension documented by a right heart catheterization (RHC) = 1 year after surgical repair - PAH diagnosis confirmed by hemodynamic evaluation at rest (through central reading), evaluated within 5 weeks prior to randomization: - Mean pulmonary artery pressure (mPAP) = 25 mmHg, AND - Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) = 15 mmHg, AND - Pulmonary vascular resistance (PVR) = 3 WU (i.e., = 240 dyn·sec·cm-5) - Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH. (Participants for whom no vasoreactivity test was performed at diagnosis can be eligible if currently treated with PAH therapy for more than 3 months and PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after introduction of their PAH therapy). - Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the prespecified doses in the study protocol or no history of PAH-specific treatment - Participant able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at Screening - A woman of childbearing potential must: - have negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization - agree to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation - agree to follow the contraception scheme from Screening up to at least 30 days after study treatment discontinuation Exclusion Criteria: - Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period prior to start of treatment - Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior to start of treatment or history of intolerance to ERA and PDE-5i combination therapy - Hypersensitivity to any of the study treatments or any excipient of their formulations - Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer in the 1-month period prior to start of treatment - Treatment with a strong CYP3A4 inhibitor or a moderate dual CYP3A4/CYP2C9 inhibitor or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period prior to start of treatment - Treatment with doxazosin - Treatment with any form of organic nitrate, either regularly or intermittently - Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of treatment - Treatment with another investigational drug in the 3-month period prior to start of treatment - Body mass index (BMI) > 40 kg/m2 at Screening - Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening: - BMI > 30 kg/m2 - Diabetes mellitus of any type - Essential hypertension (even if well controlled) - Coronary artery disease, i.e. history of stable angina or known more than 50% stenosis in a coronary artery or history of myocardial infarction or history of or planned coronary artery bypass grafting and/or coronary artery stenting - Known presence of moderate or severe obstructive lung disease any time prior to Screening as specified in study protocol - Known presence of moderate or severe restrictive lung disease any time prior to Screening as specified in study protocol - Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction, in the opinion of the investigator - Known permanent atrial fibrillation, in the opinion of the investigator - Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism) - Documented pulmonary veno-occlusive disease - Hemoglobin < 100 g/L (<10 g/dL) at Screening - Known severe hepatic impairment as specified in study protocol - Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 × upper limit of normal (ULN) at Screening - Severe renal impairment at Screening as specified in study protocol - Systemic hypotension at Screening or Randomization and systemic hypertension at Screening as specified in study protocol - Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening - Known bleeding disorder, in the opinion of the investigator - Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic neuropathy - Hereditary degenerative retinal disorders, including retinitis pigmentosa - History of priapism, conditions that predispose to priapism (example, sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (example, angulation, cavernosal fibrosis, or Peyronie's disease) - Difficulty swallowing large pills/tablets that would interfere with the ability to comply with study treatment regimen - Any planned surgical intervention (including organ transplant) during the double-blind treatment period, except minor interventions - Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to start of treatment, or planned to be started during the double-blind period of the study - Pregnant, planning to become pregnant or lactating - Any known factor or disease that might interfere with treatment adherence, full participation in the study or interpretation of the results as judged by the investigator (e.g., drug or alcohol dependence etc.) - Known concomitant life-threatening disease with a life expectancy less than (<) 12 months - Calcium channel blocker treatment initiated, or dose changed within 3 months prior to right heart catheterization (RHC) at screening

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
FDC macitentan/tadalafil
Film-coated tablet with 10 mg macitentan and 40 mg tadalafil, to be administered orally once daily.
Macitentan 10 mg
Film-coated tablet with 10 mg macitentan, to be administered orally once daily.
Tadalafil 40 mg
Film-coated tablet with 40 mg tadalafil (2 x 20 mg tablets), to be administered orally once daily.
Placebo FDC
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Placebo macitentan
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.
Placebo tadalafil
Matching placebo not containing any active substance but otherwise identical in appearance to the respective active drug tablet, to be administered orally once daily.

Locations

Country Name City State
Australia Royal Adelaide Hospital Adelaide
Australia Pulmonary Arterial Hypertension Clinic Hobart
Australia Core Research Group Milton
Brazil Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa Belo Horizonte
Brazil Universidade Federal De Minas Gerais - Hospital das Clínicas Belo Horizonte
Brazil Fundacao para o Desenvolvimento Medico Hospitalar (UNESP Botucatu) Botucatu
Brazil Secretaria da Saude do Estado do Ceara - Hospital Doutor Carlos Alberto Studart Gomes Fortaleza
Brazil Universidade Federal de Goias - Hospital das Clinicas da UFG Goiania
Brazil Hospital das Clinicas de Porto Alegre Porto Alegre
Brazil Irmandade Santa Casa de Misericordia de Porto Alegre Porto Alegre
Brazil Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da PUCRS Porto Alegre
Brazil Hospital Das Clinicas Da Faculdade De Medicina Da USP Sao Paulo
Brazil SPDM - Associacao Paulista para o Desenvolvimento da Medicina - Hospital Sao Paulo São Paulo
Bulgaria National Heart Hospital Sofia
Bulgaria University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD Sofia
Canada Alberta Health Services Calgary Alberta
Canada University of Alberta Edmonton Alberta
Canada London Health Sciences Centre London Ontario
Canada Vancouver General Hospital Vancouver British Columbia
China Beijing Anzhen Hospital Beijing
China The Second Xiangya Hospital of Central South Hospital Changsha
China The First Affiliated Hospital of Guangzhou Medical University Guangzhou
China Jiangsu Province Hospital Nanjing
China Shanghai Pulmonary Hospital Shanghai
China The General Hospital of Northern Theater Command Shenyang
China Tianjin Medical University General Hospital Tian Jin
China The First Affiliated Hospital of Xian Jiaotong University Xi'An
Czechia General University Hospital II.department of Internal Medicine-cardiology and angiology Praha 2
Germany Universitatsklinikum Bonn Bonn
Germany Universitatsklinikum Carl Gustav Carus Dresden Dresden
Germany Universitaetsklinikum Giessen Giessen
Germany Universitat Greifswald Greifswald
Germany Universitaetsklinikum Hamburg Eppendorf Hamburg
Germany Thoraxklinik am Universitatsklinikum Heidelberg Heidelberg
Germany Kardiologische Praxis Papenburg Papenburg
Germany Universitaetsklinikum Regensburg Regensburg
Germany Klinikum Würzburg Mitte gGmbH Standort Missioklinik Würzburg
Hungary Gottsegen György Országos Kardiológiai Intézet, Felnott kardiológiai osztály Budapest
Hungary Semmelweis Egyetem,Pulmonológiai Klinika Budapest
Hungary Pecsi Tudomanyegyetem Klinikai Kozpont Pecs
Hungary Szegedi Tudomanyegyetem Szeged
Italy Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari Bari
Italy Cardiologia c/o Spedali Civili Brescia
Italy Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico Milano
Italy Azienda Ospedaliera San Gerardo Monza
Italy Ospedale San Francesco Nuoro
Italy IRCCS Policlinico San Matteo, Università degli studi di Pavi Pavia
Italy Policlinico Umberto I Roma
Japan The University of Tokyo Hospital Bunkyo
Japan Chiba University Hospital Chiba
Japan Kyushu University Hospital Fukuoka
Japan Fukushima Medical University Hospital Fukushima
Japan Gunma University Hospital Gunma
Japan Kure Kyosai Hospital Hiroshima
Japan Tokai University Hospital Isehara
Japan Kagoshima University Hospital Kagoshima City
Japan Kanazawa University Hospital Kanazawa
Japan Kobe University Hospital Kobe
Japan Kumamoto University Hospital Kumamoto-City
Japan Kurume University Hospital Kurume
Japan Kyoto University Hospital Kyoto
Japan University Hospital Kyoto Perfectural University of Medicine Kyoto
Japan Shinshu University Hospital Matsumoto
Japan Kyorin University Hospital Mitaka
Japan Nagasaki University Hospital Nagasaki-shi
Japan National Hospital Organization Okayama Medical Center Okayama
Japan Okayama University Hospital Okayama
Japan Sapporo Medical University Hospital Sapporo
Japan Hokkaido University Hospital Sapporo-shi
Japan Tohoku University Hospital Sendai
Japan National Cerebral and Cardiovascular Center Suita-Shi
Japan Juntendo University Hospital Tokyo
Japan Mie University Hospital Tsu
Japan University of Tsukuba Hospital Tsukuba City
Malaysia Institut Jantung Negara (National Heart Institute) Kuala Lumpur
Malaysia Sarawak Heart Center Kuching
Mexico Instituto Nacional de Cardiologia Dr. Ignacio Chavez Mexico
Mexico Unidad de Investigacion Clinica en Medicina S.C. (UDICEM) Monterrey
Poland Klinika Kardiologii z Oddzialem Intensywnego Nadzoru Kardiologicznego, UM w Bialymstoku Bialystok
Poland Szpital Uniwersytecki nr 2 im dr Jana Biziela w Bydgoszczy, Klinika Kardiologii Bydgoszcz
Poland Uniwersyteckie Centrum Kliniczne Gdansk
Poland GCM SUM, I Oddzial Kardiologii Katowice
Poland Oddzial Kardiologii Wojewodzki Szpital Specjalistyczny im. W.Bieganskiego Lodz
Poland Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego SPZOZ, Oddzial Kardiologii Lublin
Poland ECZ Otwock Klinika Kardiologii, Klinika Krazenia Plucnego Chorób Zakrzepowo-Zatorowych i Kardiologii Otwock
Poland Uniwersytecki Szpital Kliniczny nr 2 PUM Klinika Kardiologii Szczecin
Poland Wojewodzki Szpital Specjalistyczny, Oddzial Kardiologiczny Wroclaw
Russian Federation Altay Regional Cardiological Dispensary Barnaul
Russian Federation Scientific and Research Institution of Cardiovascular Diseases Complex Problems Kemerovo
Russian Federation National Medical Research Center of Cardiology of MoH of Russian Federation Moscow
Russian Federation GU Moscow Regional Research Clinical Institute n.a. M.F.Vla Moscva
Russian Federation National medical Research Center n.a. V.A.Almazov of MoH of Russian Federation Saint-Petersburg
Russian Federation Samara Regional Clinical Cardiological Dispensary Samara
South Africa Abdullah, IA Durban
South Africa Dr Kalla Lenasia
Spain Hosp Clinic de Barcelona Barcelona
Spain Hosp. Univ. Vall D Hebron Barcelona
Spain Hosp Univ Fund Jimenez Diaz Madrid
Spain Hosp. Univ. La Paz Madrid
Spain Hosp. Univ. Ramon Y Cajal Madrid
Spain Hosp Clinico Univ de Salamanca Salamanca
Spain Hosp. Univ. Marques de Valdecilla Santander
Spain Hosp. Virgen de La Salud Toledo
Spain Hosp. Gral. Univ. Valencia Valencia
Taiwan Kaohsiung Veterans General Hospital Kaohsiung
Taiwan National Cheng Kung University Hospital Tainan
Taiwan Mackay Memorial Hospital Taipei
Taiwan National Taiwan University Hospital Taipei
Taiwan Taipei Veterans General Hospital Taipei
Taiwan Chang-Gung Memorial Hospital, LinKou Branch Taoyuan
Turkey Cukurova University Medical Faculty Adana
Turkey Ankara University Medical Faculty Ankara
Turkey Hacettepe University Medical Faculty Ankara
Turkey Bursa Yuksek Ihtisas Training and Research Hospital Bursa
Turkey Istanbul University - Cerrahpasa Cardiology Institution Istanbul
Turkey Istanbul University Cerrahpasa Medical Faculty Istanbul
Turkey Marmara University Medical Faculty Istanbul
Turkey Dokuz Eylul University Hospital Izmir
Turkey Ege University School of Medicine Izmir
Turkey Kartal Kosuyolu Yuksek Ihtisas Egitim Ve Arastirma Hastanesi Kartal Istanbul
Turkey Konya Selcuk University Medical Faculty Konya
Turkey Mersin University Medical Faculty Mersin
United States Piedmont Healthcare Atlanta Georgia
United States The University of North Carolina at Chapel Hill Chapel Hill North Carolina
United States University of Cincinnati Cincinnati Ohio
United States University of Texas Southwestern Medical Center Dallas Texas
United States Sanford Health Fargo North Dakota
United States Providence Medical Foundation Fullerton California
United States Pitt County Memorial Hospital d/b/a Vidant Medical Center Greenville North Carolina
United States University of Iowa Hospitals & Clinics Iowa City Iowa
United States Sparrow Clinical Research Institute Lansing Michigan
United States University of Southern California Los Angeles California
United States Norton Healthcare Louisville Kentucky
United States University of Wisconsin At Madison Madison Wisconsin
United States WellStar Health System Marietta Georgia
United States Medical College of Wisconsin Froedtert Hospital Milwaukee Wisconsin
United States Minneapolis Heart Institute Foundation Minneapolis Minnesota
United States WVU Health Sciences Center Morgantown West Virginia
United States OSF HealthCare Cardiovascular Institute Peoria Illinois
United States Thomas Jefferson University Hospital Philadelphia Pennsylvania
United States University of Pittsburgh Medical Center Pittsburgh Pennsylvania
United States Baylor Scott White - Plano Plano Texas
United States Legacy Hospital Portland Oregon
United States Oregon Health and Science University Portland Oregon
United States VA Sierra Nevada Health Care System Reno Nevada
United States Washington University School Of Medicine Saint Louis Missouri
United States Sanford Health Sioux Falls South Dakota
United States St. Elizabeth Hospital Mercy Bon Secors Youngstown Ohio

Sponsors (1)

Lead Sponsor Collaborator
Actelion

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Bulgaria,  Canada,  China,  Czechia,  Germany,  Hungary,  Italy,  Japan,  Malaysia,  Mexico,  Poland,  Russian Federation,  South Africa,  Spain,  Taiwan,  Turkey, 

Outcome

Type Measure Description Time frame Safety issue
Primary Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline Change in PVR expressed as the ratio of geometric means of EDBT to baseline were reported. Baseline, EDBT (up to 16 weeks)
Secondary Change From Baseline in 6-minutes Walking Distance (6MWD) to EDBT Baseline, EDBT (up to 16 weeks)
Secondary Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT Baseline, EDBT (up to 16 weeks)
Secondary Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT Baseline, EDBT (up to 16 weeks)
Secondary Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline to EDBT Baseline, EDBT (up to 16 weeks)

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