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Outcome Study Assessing a 75 Milligrams (mg) Dose of Macitentan in Patients With Pulmonary Arterial Hypertension (UNISUS)

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ClinicalTrials.gov Identifier: NCT04273945
Recruitment Status : Recruiting
First Posted : February 18, 2020
Last Update Posted : May 6, 2023
Sponsor:
Information provided by (Responsible Party):
Actelion

Study Description
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Brief Summary:
The purpose of this study is to demonstrate superiority of macitentan 75 milligrams (mg) in prolonging the time to the first clinical events committee (CEC)-adjudicated morbidity or mortality (M/M) event in participants with symptomatic pulmonary arterial hypertension (PAH) compared to macitentan 10 mg.

Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: Macitentan 10 mg Drug: Macitentan 37.5 mg Drug: Macitentan 75 mg Drug: Placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 900 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 30, 2020
Estimated Primary Completion Date : October 31, 2023
Estimated Study Completion Date : September 21, 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Macitentan

Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Macitentan 10 milligrams (mg) + Placebo
Participants will receive macitentan 10 mg once daily (qd) orally for 4 weeks in open-label Run-in phase prior to randomization (only for participants who are Endothelin Receptor Antagonist [ERA] treatment-naive. Other participants will bypass the Run-in period and go directly to randomization). Double-blind Treatment Period: participants will receive macitentan 10 mg qd for 8 weeks and matching placebo of macitentan 37.5 mg for 4 weeks (Uptitration) and matching placebo of macitentan 75 mg thereafter orally up to End of Double-Blind Treatment period (EDBT). Treatment Extension Period: After EDBT, participants will receive macitentan 37.5 mg qd and macitentan 75 mg matching placebo orally for 4 weeks (Uptitration), followed by open-label macitentan 75 mg qd orally for 2 years.
 Drug: Macitentan 10 mg
Participants will receive macitentan 10 mg film-coated tablets orally.
Other Name: JNJ-67896062

Drug: Macitentan 37.5 mg
Participants will receive macitentan 37.5 mg film-coated tablets orally.
Other Name: JNJ-67896062

Drug: Macitentan 75 mg
Participants will receive macitentan 75 mg film-coated tablets orally.
Other Name: JNJ-67896062

Drug: Placebo
Participants will receive matching placebo film-coated tablets orally.
Experimental: Macitentan 75 mg + Placebo
Participants will receive macitentan 10 mg qd orally for 4 weeks in open-label Run-in phase prior to randomization (only for ERA treatment-naive. Other participants will bypass the Run-in period and go directly to randomization). Double-blind Treatment Period: participants will receive macitentan 37.5 mg for 4 weeks (Uptitration) and 75 mg qd along with matching placebo for macitentan 10 mg orally up to EDBT. Treatment Extension Period: After EDBT, participants will receive macitentan 75 mg qd and macitentan 37.5 mg matching placebo orally for 4 weeks (Uptitration), followed by open-label macitentan 75 mg qd orally for 2 years.
 Drug: Macitentan 10 mg
Participants will receive macitentan 10 mg film-coated tablets orally.
Other Name: JNJ-67896062

Drug: Macitentan 37.5 mg
Participants will receive macitentan 37.5 mg film-coated tablets orally.
Other Name: JNJ-67896062

Drug: Macitentan 75 mg
Participants will receive macitentan 75 mg film-coated tablets orally.
Other Name: JNJ-67896062

Drug: Placebo
Participants will receive matching placebo film-coated tablets orally.


Outcome Measures
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Primary Outcome Measures :
  1. Double-blind Treatment Period: Time to First Clinical Events Committee (CEC)-adjudicated Morbidity or Mortality (M/M) Events [ Time Frame: 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.


Secondary Outcome Measures :
  1. Double-blind Treatment Period: Change From Baseline to Week 24 in 6MWD [ Time Frame: 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.

  2. Double-blind Treatment Period: Time to First occurrence of either CEC-adjudicated Death or Hospitalization due to PAH [ Time Frame: Up to 4 years ]
    Time to first occurrence of either CEC-adjudicated death or hospitalization due to PAH will be reported.

  3. Double-blind Treatment Period: Change From Baseline to Week 24 in PAH Symptoms Based on PAH-SYMPACT Questionnaire- Cardiopulmonary Symptom Domain Score [ Time Frame: 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.

  4. Double-blind Treatment Period: Change From Baseline to Week 24 in PAH Symptoms Based on PAH-SYMPACT Questionnaire- Cardiovascular Symptom Domain Score [ Time Frame: 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.

  5. Double-blind Treatment Period: Time to Death Occurring Between Randomization and End of Double-blind Treatment (EDBT) [ Time Frame: Up to 4 years ]
    Time to death occurring between randomization and EDBT will be reported.

  6. Treatment Extension Period: Time to Death Occurring Between Randomization and End of Study (EOS) [ Time Frame: Up to 6 years ]
    Time to death occurring between randomization and EOS will be reported.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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 PAH documented by an Right heart catheterization (RHC) >= 1 year after simple systemic-to pulmonary shunt repair
  • PAH diagnosis confirmed by hemodynamic evaluation at rest at any time prior to screening: Mean pulmonary artery pressure (mPAP) greater than (>) 20 millimeters of mercury (mm Hg), and; Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) less than or equal to (<=) 15 mm Hg, 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 (m) and maximum distance of 440m 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

Exclusion Criteria:

  • 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04273945


Contacts
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Contact: Study Contact 844-434-4210 Participate-In-This-Study@its.jnj.com

Locations
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Sponsors and Collaborators
Actelion
Investigators
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Study Director: Actelion Clinical Trials Actelion
More Information
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Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT04273945    
Other Study ID Numbers: CR108740
2019-002533-11 ( EudraCT Number )
AC-055-315 ( Other Identifier: Actelion )
First Posted: February 18, 2020    Key Record Dates
Last Update Posted: May 6, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/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.
URL: https://www.janssen.com/clinical-trials/transparency

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Pulmonary Arterial Hypertension
Familial Primary Pulmonary Hypertension
Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
 Respiratory Tract Diseases
Macitentan
Endothelin A Receptor Antagonists
Endothelin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Endothelin B Receptor Antagonists