Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH) Clinical Trial
— A DUEOfficial title:
Prospective, Multi-center, Double-blind, Randomized, Active-controlled, Triple-dummy, Parallel-group, Group-sequential, Adaptive Phase 3 Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed Dose Combination in Subjects With Pulmonary Arterial Hypertension (PAH), Followed by an Open-label Treatment Period With Macitentan and Tadalafil Fixed Dose Combination Therapy
| Verified date | May 2024 |
| Source | Actelion |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | |
| Study type | Interventional |
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.
| 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 |
| 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 Educaçao 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 | SPSK2 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 |
| Lead Sponsor | Collaborator |
|---|---|
| Actelion |
United States, Australia, Brazil, Bulgaria, Canada, China, Czechia, Germany, Hungary, Italy, Japan, Malaysia, Mexico, Poland, Russian Federation, South Africa, Spain, Taiwan, Turkey,
| 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) |