Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)
- Conditions
- Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
- Interventions
- Drug: Tadalafil 40 mgDrug: FDC macitentan/tadalafilDrug: Macitentan 10 mgDrug: Placebo macitentanDrug: Placebo FDCDrug: Placebo tadalafil
- Registration Number
- NCT03904693
- Lead Sponsor
- Actelion
- Brief 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.
- Detailed 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 & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 187
-
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
-
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
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Tadalafil mono-therapy + Placebo macitentan + Placebo FDC Tadalafil 40 mg Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments. FDC therapy + Placebo macitentan + Placebo tadalafil FDC macitentan/tadalafil Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments. FDC therapy + Placebo macitentan + Placebo tadalafil Placebo macitentan Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments. FDC therapy + Placebo macitentan + Placebo tadalafil Placebo tadalafil Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments. Macitentan mono-therapy + Placebo tadalafil + Placebo FDC Macitentan 10 mg Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments. Macitentan mono-therapy + Placebo tadalafil + Placebo FDC Placebo FDC Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments. Macitentan mono-therapy + Placebo tadalafil + Placebo FDC Placebo tadalafil Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments. Tadalafil mono-therapy + Placebo macitentan + Placebo FDC Placebo FDC Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments. Tadalafil mono-therapy + Placebo macitentan + Placebo FDC Placebo macitentan Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.
- Primary Outcome Measures
Name Time Method Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline Baseline, EDBT (up to 16 weeks) Change in PVR expressed as the ratio of geometric means of EDBT to baseline were reported.
- Secondary Outcome Measures
Name Time Method 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) 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) 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) Change From Baseline in 6-minutes Walking Distance (6MWD) to EDBT Baseline, EDBT (up to 16 weeks)
Trial Locations
- Locations (147)
Piedmont Healthcare
🇺🇸Atlanta, Georgia, United States
WellStar Health System
🇺🇸Marietta, Georgia, United States
OSF HealthCare Cardiovascular Institute
🇺🇸Peoria, Illinois, United States
Norton Healthcare
🇺🇸Louisville, Kentucky, United States
Sparrow Clinical Research Institute
🇺🇸Lansing, Michigan, United States
Minneapolis Heart Institute Foundation
🇺🇸Minneapolis, Minnesota, United States
Washington University School Of Medicine
🇺🇸Saint Louis, Missouri, United States
VA Sierra Nevada Health Care System
🇺🇸Reno, Nevada, United States
The University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Pitt County Memorial Hospital d/b/a Vidant Medical Center
🇺🇸Greenville, North Carolina, United States
Sanford Health
🇺🇸Sioux Falls, South Dakota, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
St. Elizabeth Hospital Mercy Bon Secors
🇺🇸Youngstown, Ohio, United States
Legacy Hospital
🇺🇸Portland, Oregon, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Providence Medical Foundation
🇺🇸Fullerton, California, United States
University of Southern California
🇺🇸Los Angeles, California, United States
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, China
General University Hospital II.department of Internal Medicine-cardiology and angiology
🇨🇿Praha 2, Czechia
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, Germany
Semmelweis Egyetem,Pulmonológiai Klinika
🇭🇺Budapest, Hungary
Gottsegen György Országos Kardiológiai Intézet, Felnőtt kardiológiai osztály
🇭🇺Budapest, Hungary
Pecsi Tudomanyegyetem Klinikai Kozpont
🇭🇺Pecs, Hungary
Szegedi Tudomanyegyetem
🇭🇺Szeged, Hungary
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, Italy
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
University Hospital Kyoto Prefectural University of Medicine
🇯🇵Kyoto, Japan
Kyoto University Hospital
🇯🇵Kyoto, Japan
Shinshu University Hospital
🇯🇵Matsumoto, Japan
Kyorin University Hospital
🇯🇵Mitaka, Japan
Nagasaki University Hospital
🇯🇵Nagasaki-shi, Japan
Okayama University Hospital
🇯🇵Okayama, Japan
National Hospital Organization Okayama Medical Center
🇯🇵Okayama, Japan
Hokkaido University Hospital
🇯🇵Sapporo-shi, Japan
Sapporo Medical University Hospital
🇯🇵Sapporo, Japan
Tohoku University Hospital
🇯🇵Sendai, Japan
National Cerebral and Cardiovascular Center
🇯🇵Suita-Shi, Japan
Juntendo University Hospital
🇯🇵Tokyo, Japan
University of Tsukuba Hospital
🇯🇵Tsukuba City, Japan
Mie University Hospital
🇯🇵Tsu, Japan
Institut Jantung Negara (National Heart Institute)
🇲🇾Kuala Lumpur, Malaysia
Sarawak Heart Center
🇲🇾Kuching, Malaysia
Instituto Nacional de Cardiologia Dr. Ignacio Chavez
🇲🇽Mexico, Mexico
Unidad de Investigacion Clinica en Medicina S.C. (UDICEM)
🇲🇽Monterrey, Mexico
Klinika Kardiologii z Oddzialem Intensywnego Nadzoru Kardiologicznego, UM w Białymstoku
🇵🇱Białystok, 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
Abdullah, IA
🇿🇦Durban, South Africa
Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego SPZOZ, Oddzial Kardiologii
🇵🇱Lublin, Poland
ECZ Otwock Klinika Kardiologii, Klinika Krążenia Płucnego Chorób Zakrzepowo-Zatorowych i Kardiologii
🇵🇱Otwock, Poland
Uniwersytecki Szpital Kliniczny nr 2 PUM Klinika Kardiologii
🇵🇱Szczecin, Poland
Wojewodzki Szpital Specjalistyczny, Oddzial Kardiologiczny
🇵🇱Wrocław, Poland
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, Russian Federation
Dr Kalla
🇿🇦Lenasia, South Africa
Hosp Clinic de Barcelona
🇪🇸Barcelona, Spain
Hosp Univ Vall D Hebron
🇪🇸Barcelona, Spain
Hosp. Univ. Ramon Y Cajal
🇪🇸Madrid, Spain
Hosp Univ Fund Jimenez Diaz
🇪🇸Madrid, Spain
Hosp. Univ. La Paz
🇪🇸Madrid, Spain
Hosp Clinico Univ de Salamanca
🇪🇸Salamanca, Spain
Hosp. Univ. Marques de Valdecilla
🇪🇸Santander, Spain
Hosp. Virgen de La Salud
🇪🇸Toledo, Spain
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Baylor Scott White - Plano
🇺🇸Plano, Texas, United States
WVU Health Sciences Center
🇺🇸Morgantown, West Virginia, United States
University of Wisconsin At Madison
🇺🇸Madison, Wisconsin, United States
Medical College of Wisconsin Froedtert Hospital
🇺🇸Milwaukee, Wisconsin, United States
Royal Adelaide Hospital
🇦🇺Adelaide, Australia
Pulmonary Arterial Hypertension Clinic
🇦🇺Hobart, Australia
Core Research Group
🇦🇺Milton, Australia
Universidade Federal De Minas Gerais - Hospital das Clínicas
🇧🇷Belo Horizonte, Brazil
Instituto das Pequenas Missionárias de Maria Imaculada - Hospital Madre Teresa
🇧🇷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, Brazil
National Heart Hospital
🇧🇬Sofia, Bulgaria
University Multiprofile Hospital for Active Treatment- UMHAT Sveta Anna AD
🇧🇬Sofia, Bulgaria
Alberta Health Services
🇨🇦Calgary, Alberta, Canada
University of Alberta
🇨🇦Edmonton, Alberta, Canada
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
London Health Sciences Centre
🇨🇦London, Ontario, Canada
Beijing Anzhen Hospital
🇨🇳Beijing, China
Hosp. Gral. Univ. Valencia
🇪🇸Valencia, Spain
Kaohsiung Veterans General Hospital
🇨🇳Kaohsiung, Taiwan
National Cheng Kung University Hospital
🇨🇳Tainan, Taiwan
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Mackay Memorial Hospital
🇨🇳Taipei, Taiwan
Taipei Veterans General Hospital
🇨🇳Taipei, Taiwan
Chang-Gung Memorial Hospital, LinKou Branch
🇨🇳Taoyuan, Taiwan
Cukurova University Medical Faculty
🇹🇷Adana, Turkey
Hacettepe University Medical Faculty
🇹🇷Ankara, Turkey
Ankara 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
Ege University School of Medicine
🇹🇷Izmir, Turkey
Dokuz Eylul University Hospital
🇹🇷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, Turkey
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