A Phase 3, Prospective, Multicenter, Double-blind, Double-dummy, Randomized, Active-controlled, Parallel-group, Group-sequential, Adaptive, Event-driven Study to Compare Efficacy, Safety, and Tolerability of Macitentan 75 mg Versus Macitentan 10 mg in Patients with Pulmonary Arterial Hypertension, Followed by an Open-label Treatment Period With Macitentan 75 mg (UNISUS)
Outcome Study Assessing a 75 milligrams (mg) Dose of Macitentan in Patients with Pulmonary Arterial Hypertension (UNISUS)
Nakano Masayoshi
Janssen Pharmaceutical K.K.
3-5-2 Nishikanda Chiyoda-ku, Tokyo
+81-120-183-275
DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com
Medical Information Center
Janssen Pharmaceutical K.K.
3-5-2 Nishikanda Chiyoda-ku, Tokyo
+81-120-183-275
DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com
Not Recruiting
April. 30, 2021
June. 23, 2021
900
Interventional
randomized controlled trial
double blind
placebo control
parallel assignment
treatment purpose
- Target population: greater than or equal to (>=) 18 (or the legal age of consent in the jurisdiction in which the study is taking place) years of age
- Target population: Symptomatic Pulmonary Arterial Hypertension (PAH) in World Health Organization Functional Class (WHO FC) II, III, or IV
- Target population: PAH subtype falling in one of the below classifications:
Idiopathic; Heritable; Drug- or toxin-induced; Related to: Connective tissue disease, HIV infection, Portal hypertension, and Congenital heart disease with small/coincidental cardiac defect with systemic-to-pulmonary shunt ( for example atrial septal defect, ventricular septal defect, patent ductus arteriosus, atrioventricular septal defect) which does not account for the elevated pulmonary vascular resistance (PVR) or persistent PH documented by an Right heart catheterization (RHC) >= 1 year after simple systemic-to pulmonary shuntrepair
- PAH diagnosis confirmed by hemodynamic evaluation at rest at any time
prior to screening: Mean pulmonary artery pressure (mPAP) > 20 millimeters of mercury (mmHg), and; Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) less than or equal to (<=) 15 mmHg, and PVR >= 3 Wood Units (that is, >= 240 dyn*sec/cm^5)
- Able to perform the 6-minute walking test (6MWT) with a minimum
distance of 50 meters and maximum distance of 440 meters at screening. Participants able to walk more than 440m at screening are eligible if they are in WHO FC III or IV and n-terminal prohormone of brain natriuretic peptide or n-terminal pro B-type natriuretic peptide (NT-proBNP) level is >=300 nanograms per liter (ng/L) at screening, based on central laboratory results
- Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at screening, based on records that confirm documented medical history: Body mass index (BMI) > 30 kilograms per meter square (kg/m^2), Diabetes mellitus of any type, Essential hypertension (even if well controlled); Coronary artery disease,that is, any of the following: history of stable angina, or known more than 50 percent (%) stenosis in a coronary artery, or history of myocardial infarction, or history of or planned coronary artery bypass grafting and/or coronary artery stenting
- Presence of moderate or severe obstructive lung disease (forced expiratory volume in 1 second [FEV1] / forced vital capacity [FVC] < 70%; and FEV1 < 60% of predicted after bronchodilator administration)in participants with a known or suspected history of significant lung disease as documented by a spirometry test performed within 1 year prior to screening
- Known moderate to severe hepatic impairment, defined as Child-Pugh Class B or C, based on records that confirm documented medical history
- Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5*upper limit of normal (ULN) at screening
- Hemoglobin < 100 gram per liter (g/L) (< 10 gram per deciliter [g/dL]) at screening
18age old over
No limit
Both
Pulmonary Arterial Hypertension
Macitentan 10 mg:Participants will receive macitentan 10 mg film-coated tablets orally
Macitentan 37.5 mg:Participants will receive macitentan 37.5 mg film-coated tablets orally.
Macitentan 75 mg:Participants will receive macitentan 75 mg film-coated tablets orally
Placebo:Participants will receive matching placebo film-coated tablets orally.
Macitentan 10 milligrams (mg) +Placebo:Run-in period:Participants who are either endothelin receptor antagonist (ERA)-naive or who are receiving daily dose of macitentan or ambrisentan less (<) 10 milligrams (mg), or daily dose of bosentan <250 mg, will enter 4-week open-label run-in period with macitentan 10 mg prior to randomization. ERA-pre-treated participants will bypass run-in period and will be randomized to either macitentan 75 mg or macitentan 10 mg directly.Double-blind Treatment (DBT) Period:Participants will receive macitentan 10 mg orally up to End of DBT.To maintain blind, participants will receive macitentan 37.5 mg-matching placebo for 4 weeks and macitentan 75 mg-matching placebo thereafter up to DBT.Treatment Extension Period:After EDBT, participants will receive macitentan 37.5 mg once a day (qd) orally for 4 weeks, prior to receiving open-label macitentan 75 mg qd orally for 2 years. To maintain blind, participants will receive macitentan 75 mg-matching placebo during 4-week uptitration.
Macitentan 75 mg + Placebo:Run-in period:Participants who are either ERA-naive or who are receiving a daily dose of macitentan or ambrisentan <10 mg, or a daily dose of bosentan <250 mg, will enter 4-week open-label run-in period with macitentan 10 mg prior to randomization. ERA-pre-treated patients will bypass the run-in period and will be randomized to either macitentan 75 mg or macitentan 10 mg directly.DBT Period: participants will receive macitentan 37.5 mg orally for 4 weeks and macitentan 75 mg thereafter up to End of DBT. To maintain the blind, participants will receive macitentan 10 mg-matching placebo up to End of DBT.Treatment Extension Period: After EDBT, participants will continue to receive macitentan 75 mg orally for 2 years. To maintain the blind, participants will receive macitentan 37.5 mg-matching placebo during the 4-week up-titration period.
Double-blind Treatment Period: Time to First Clinical Events Committee (CEC)-adjudicated Morbidity or Mortality (M/M) Events : Up to 4 years :
Time to first CEC-adjudicated M/M event on-treatment (ie.,up to 7 days after last dose of DB study intervention) is defined as time from randomization to first of following events: All-cause death, including death caused by on-treatment adverse event that occur within 4 weeks of study DB treatment discontinuation;non-planned Pulmonary Arterial Hypertension(PAH)-related hospitalization(including for worsening of PAH, atrial septostomy, lung transplantation with or without heart transplantation, or initiation of parenteral prostacyclins);PAH-related disease progression, defined as worsening of World Health Organization(WHO) Functional Class(FC) from baseline or deterioration by at least 15% in exercise capacity, as measured by 6-minute walk distance(6MWD), from baseline and confirmed by second 6MWD test performed on different day within 2 week of initial test or appearance or worsening of signs or symptoms of right-sided heart failure that require initiation of intravenous diuretics.
-Double-blind Treatment Period: Change From Baseline to Week 24in 6MWD:Baseline up to Week 24:The 6MWT is a non-encouraged test performed to quantify exercise tolerance and capacity. This standardized test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.
-Double-blind Treatment Period: Number of Participants with CEC-adjudicated Death due to PAH and/or Hospitalizations for PAH (First and Recurrent) Events on-treatment:Up to 4 years:Number of Participants with CEC-adjudicated death or hospitalization due to PAH will be reported.
-Double-blind Treatment Period: Change From Baseline to Week 24 in PAH Symptoms Based on PAHSYMPACT Questionnaire- Cardiopulmonary Symptom Domain Score:Baseline up to Week 24:The Cardiopulmonary Symptoms domain consists of 6 items reported on a 5-point Likert scale (from 0 to 4). The value 0 means ""no symptom"" and value 4 corresponds to ""very severe symptoms"". The symptoms part of the PAH symptoms and impact questionnaire (PAH-SYMPACT) is completed daily for a 7-day period. The recall period of symptom items is the last 24 hours. An average Cardiopulmonary Symptoms domain score is determined based on the daily scores of the 6 items.
-Double-blind Treatment Period: Change From Baseline to Week 24 in PAH Symptoms Based on PAH SYMPACT Questionnaire- Cardiovascular Symptom Domain Score:Baseline up to Week 24:The Cardiovascular Symptoms domain consists of 5 items reported on a 5-point Likert scale (from 0 to 4). The value 0 corresponds to ""no symptoms"" and value 4 corresponds to ""very severe symptoms"". The symptoms part of the PAH-SYMPACT is completed daily for a 7 day period. The recall period of symptom items is the last 24 hours. An average cardiovascular symptoms domain score is determined based on the daily scores of the 5 items.
-Double-blind Treatment Period: Time to Death Occurring Between Randomization and End of Double-blind Treatment (EDBT):Up to 4 years:Time to death occurring between randomization and EDBT will be reported.
-Treatment Extension Period: Time to Death Occurring Between Randomization and End of Study (EOS):Up to 6 years:Time to death occurring between randomization and EOS will be reported.
Janssen Pharmaceutical K.K.
Kure Kyosai Hospital IRB
2-3-28, Nishichuo, Kure-shi, Hiroshima
+81-823-22-2111
Approval
Feb. 09, 2021
Yes
The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinicaltrials/ transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu
