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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 : September 30, 2020
Sponsor:
Information provided by (Responsible Party):
Actelion

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

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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 : August 21, 2026


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 and matching placebo of macitentan 37.5 for 4 weeks (Uptitration) and 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 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.




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 (that is up to 7 days after the last dose of double-blind study treatment) is defined as time from baseline to the first of the following events: All-cause death, including deaths caused by an on-treatment adverse event (AE) 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); and PAH-related disease progression, defined as deterioration by at least 15 percent (%) in exercise capacity, as measured by the 6-Minute Walk Distance (6MWD), from baseline, confirmed by two 6MWD tests performed on separate days within 2 weeks of each other and Initiation of additional PAH therapy or Worsening of World Health Organization Functional Class (WHO FC).


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 Baseline and End of Double-blind Treatment (EDBT) [ Time Frame: Up to 4 years ]
    Time to death occurring between baseline and EDBT will be reported.

  6. Double-blind Treatment Period: Number of Deaths [ Time Frame: Up to 4 years ]
    Number of deaths will be reported.

  7. Double-blind Treatment Period: Number of Participants with Intervention-emergent AEs [ Time Frame: Up to 4 years ]
    Number of participants with intervention-emergent AEs will be reported.

  8. Double-blind Treatment Period: Number of Participants with AEs Leading to Premature Discontinuation of Study Drug [ Time Frame: Up to 4 years ]
    Number of participants with AEs Leading to premature discontinuation of study drug will be reported. An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.

  9. Double-blind Treatment Period: Number of Participants With Intervention-emergent AEs of Special Interest [ Time Frame: Up to 4 years ]
    Number of participants with intervention-emergent AEs of Special Interest (that is, liver events, hemoglobin decrease/anemia, hypotension, edema/fluid retention) will be reported.

  10. Double-blind Treatment Period: Number of Participants With Serious Adverse Events (SAEs) [ Time Frame: Up to 4 years ]
    Number of participants with SAEs will be reported.

  11. Double-blind Treatment Period: Number of Participants with Intervention-emergent Electrocardiogram (ECG) Abnormalities [ Time Frame: Up to 4 years ]
    Number of participants with intervention-emergent ECG abnormalities will be reported.

  12. Double-blind Treatment Period: Number of Participants with Intervention-emergent Laboratory Abnormalities [ Time Frame: Up to 4 years ]
    Number of participants with intervention-emergent laboratory abnormalities will be reported.

  13. Double-blind Treatment Period: Change from Baseline in Blood Pressure [ Time Frame: Baseline up to 4 years ]
    Change from baseline in blood pressure will be reported.

  14. Double-blind Treatment Period: Change from Baseline in Heart Rate [ Time Frame: Baseline up to 4 years ]
    Change from baseline in heart rate will be reported.

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

  16. Treatment Extension Period: Number of Deaths [ Time Frame: Up to 6 years ]
    Number of deaths will be reported.

  17. Treatment Extension Period: Number of Participants With Intervention-emergent AEs [ Time Frame: Up to 6 years ]
    Number of participants with intervention-emergent AEs will be reported.

  18. Treatment Extension Period: Number of Participants With AEs Leading to Premature Discontinuation of study Drug [ Time Frame: Up to 6 years ]
    Number of participants with AEs leading to premature discontinuation of study drug will be reported.

  19. Treatment Extension Period: Number of Participants with Intervention-emergent AEs of Special Interest [ Time Frame: Up to 6 years ]
    Number of participants with intervention-emergent AEs of Special Interest (liver events, hemoglobin decrease/anemia, hypotension, edema/fluid retention) will be reported.

  20. Treatment Extension Period: Number of Participants With SAEs [ Time Frame: Up to 6 years ]
    Number of participants with SAEs will be reported.

  21. Treatment Extension Period: Number of Participants With Intervention-emergent Laboratory Abnormalities [ Time Frame: Up to 6 years ]
    Number of participants With intervention-emergent laboratory abnormalities will be reported.

  22. Treatment Extension Period: Change from Baseline in Blood Pressure [ Time Frame: Baseline up to 6 years ]
    Change from baseline in blood pressure will be reported.

  23. Treatment Extension Period: Change from Baseline in Heart Rate [ Time Frame: Baseline up to 6 years ]
    Change from baseline in heart rate will be reported.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 simple systemic-to-pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) with persistent PH documented by an Right heart catheterization (RHC) >= 1 year after surgical repair
  • 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

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
  • Known 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) 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

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 JNJ.CT@sylogent.com

Locations
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Sponsors and Collaborators
Actelion
Investigators
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Study Director: Actelion Clinical Trials Actelion
Additional 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: September 30, 2020
Last Verified: September 2020
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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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