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A Study to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension (MACiTEPH)

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ClinicalTrials.gov Identifier: NCT04271475
Recruitment Status : Not yet recruiting
First Posted : February 17, 2020
Last Update Posted : May 13, 2020
Sponsor:
Information provided by (Responsible Party):
Actelion

Brief Summary:
The purpose of the study is to evaluate the effect of macitentan 75 mg versus placebo on exercise capacity at Week 28 in participants with chronic thromboembolic pulmonary hypertension (CTEPH).

Condition or disease Intervention/treatment Phase
Chronic Thromboembolic Pulmonary Hypertension Drug: Macitentan Drug: Placebo Phase 3

Detailed Description:
CTEPH is one of the leading causes of severe pulmonary hypertension (PH), classified within World Health Organization (WHO) group 4 PH. It is a rare, progressive pulmonary vascular disease that if left untreated, leads to progressively increasing pulmonary vascular resistance (PVR) and eventually right ventricle failure and death. Histopathologic findings including endothelial cell dysfunction and distal pulmonary arterial remodeling are shared between PAH and CTEPH, and PH-specific therapies (that is, riociguat) have shown efficacy in inoperable and persistent/recurrent CTEPH. The endothelin receptor antagonist macitentan offers a different mode of action and addresses an important unmet medical need for an alternative treatment option in this indication. This study will assess the effect of macitentan 75 mg on exercise capacity and is expected to confirm the role of macitentan as a first line, as well as add-on treatment for CTEPH. The study comprises of screening period (at least 14- and up to 60 days), a 52-week double-blind (DB) treatment period (which includes an 8-week up-titration phase), an open-label (OL) extension period (which starts at Week 52 and will end 104 weeks after the last participant has completed the DB treatment period) and 30-day safety follow-up period. Participants who discontinue DB study intervention will be followed until Week 52 in a post-treatment-observation period (PTOP). The total duration of the study is approximately 6 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Prospective, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel Group, Adaptive Phase 3 Study With Open-label Extension to Evaluate Efficacy and Safety of Macitentan 75 mg in Inoperable or Persistent/Recurrent Chronic Thromboembolic Pulmonary Hypertension
Estimated Study Start Date : June 15, 2020
Estimated Primary Completion Date : May 14, 2024
Estimated Study Completion Date : April 1, 2026


Arm Intervention/treatment
Active Comparator: Macitentan
Participant will receive macitentan at a dose of 10 mg for 4 weeks, followed by a dose of macitentan 37.5 mg for another 4 weeks prior to reaching the target dose of macitentan 75 mg. Participants who have reached the target dose of macitentan 75 mg and completed the double blind (DB) period as per protocol (up to Week 52; either on treatment or in post treatment observation period [PTOP]) are eligible for transitioning into the open-label (OL) extension period and will receive macitentan 75 mg.
Drug: Macitentan
Participants will receive Macitentan film-coated tablets orally od.
Other Names:
  • ACT-064992,
  • Opsumit

Drug: Placebo
Participant will receive matching placebo tablets orally od.

Experimental: Placebo
Participants will receive placebo tablets matching the macitentan 10 mg, macitentan 37.5mg and macitentan 75 mg tablets, respectively. Participants who completed the DB period as per protocol (up to Week 52; either on treatment or in PTOP) are eligible for transitioning to the OL extension period and will receive macitentan 75 mg after an 8-week double-dummy uptitration (macitentan 10 mg for 4 weeks, followed by 37.5mg for another 4 weeks).
Drug: Macitentan
Participants will receive Macitentan film-coated tablets orally od.
Other Names:
  • ACT-064992,
  • Opsumit

Drug: Placebo
Participant will receive matching placebo tablets orally od.




Primary Outcome Measures :
  1. Change From Baseline to Week 28 in 6- minute Walk Distance [6MWD] [ Time Frame: Baseline up to Week 28 ]
    Change from baseline to week 28 in 6MWD as measured by 6-minute walk test [6MWT]) will be reported. The purpose of the six-minute walk test (6MWT) is 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 6 minutes.


Secondary Outcome Measures :
  1. Time to Clinical Worsening up to Week 52 [ Time Frame: Up to Week 52 ]
    Clinical event committee (CEC) confirmed clinical worsening up to Week 52 will be reported. Clinical worsening is defined as the occurrence of at least one of the following events: All-cause death; Heart and/or lung transplantation; Unplanned pulmonary hypertension (PH)-related hospitalization; Persistent increase in World Health Organization functional class (WHO FC) that cannot be explained by another cause (for example, viral infection); Persistent deterioration by at least 15 percent (%) in exercise capacity; as measured by the 6MWD; New or worsening signs or symptoms of right heart failure; Initiation or dose escalation of PH-specific therapy due to worsening of PH based on additional assessments performed at the discretion of the investigator and confirmed by the CEC; or Rescue pulmonary endarterectomy (PEA) and/or balloon pulmonary angioplasty (BPA) procedure due to worsening of PH.

  2. Number of Participants with Improvement in WHO Functional Class (WHO FC) From Baseline to Week 28 [ Time Frame: Baseline up to Week 28 ]
    Improvement in WHO FC from baseline to Week 28 will be calculated for each participant. WHO FC test is used to assess disease severity. Four functional classes (FC) are defined from FC I (no limitation of physical activity) to FC IV (inability to carry out any physical activity without symptoms). Improvement is considered when a participant changes from a higher class to a lower class.

  3. Change From Baseline to Week 28 in Pulmonary Arterial Hypertension - Symptoms Based on (PAH-SYMPACT) - Cardiopulmonary Symptom Domain Score [ Time Frame: Baseline up to Week 28 ]
    The Cardiopulmonary Symptoms domain consists of 6 items (shortness of breath, fatigue, lack of energy, swelling in ankles or legs, swelling in stomach area and cough) 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-SYMPACT will be administered daily over 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. It will be administered two times (daily for 7 days each time) prior to administration of Macitentan. Questionnaires to be completed at site at screening for training purpose. PAH-SYMPACT to be performed at home, during the 7-day period prior to the scheduled visit.

  4. Change from Baseline to Week 28 in PAH-SYMPACT - Cardiovascular Symptom Domain Score [ Time Frame: Baseline up to Week 28 ]
    The Cardiovascular Symptoms domain consists of 5 items (heart palpitations [fluttering], rapid heartbeat, chest pain, chest tightness, and lightheadedness) 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 will be administered daily over 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. It will be administered two times (daily for 7 days each time) prior to administration of Macitentan Questionnaires to be completed at site at screening for training purpose. PAH-SYMPACT to be performed at home, during the 7-day period prior to the scheduled visit.

  5. Change from baseline to Week 28 in Euro Quality of life-5-Dimension-5-Level (EQ-5D-5L) Utility Score [ Time Frame: Baseline up to Week 28 ]
    The EQ-5D-5L is a generic measure of health status. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).

  6. Change From Baseline to Week 28 in Accelerometer-assessed Proportion of Time Spent in Moderate to Vigorous Physical Activity [ Time Frame: Baseline up to Week 28 ]
    Change from baseline to week 28 in accelerometer-assessed proportion of time spent in moderate to vigorous physical activity will be assessed.



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 to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 6-minute walk distance (6MWD) greater than or equal to (>=) 100 meter (m) and less than or equal to (<=) 450 meters (m), documented by an eligibility and a baseline 6-minute walk test (6MWT). The baseline 6MWD must not differ by more than 15 percent (%) from the eligibility test
  • World Health Organization functional class (WHO FC) >= II
  • A women must not have child bearing potential or have a negative highly sensitive serum pregnancy test (beta-human chorionic gonadotropin) at Screening and a negative urine pregnancy test at Randomization or practice a highly effective method of contraception (failure rate of less than (<) 1 percent (%) per year when used consistently and correctly) from Screening up to at least 30 days after last dose of study intervention

Exclusion Criteria:

  • Acute pulmonary embolism within 6 months prior to or during Screening
  • Planned (during the double-blind period of the study) balloon pulmonary angioplasty (BPA)
  • Significant obstructive and restrictive lung disease
  • Acute or chronic conditions (other than dyspnea) that limit the ability to comply with study requirements, in particular with 6MWT (for example, intermittent claudication).
  • Symptomatic coronary artery disease requiring an intervention within 3 months prior to or during Screening or anticipated during the DB period of the study
  • Decompensated cardiac failure if not under close supervision
  • Known and documented life-threatening cardiac arrhythmias
  • Acute myocardial infarction within 6 months prior to, or during Screening
  • Cerebrovascular events (including transient ischemic attack) within 3 months prior to, or during Screening
  • Known or suspicion of pulmonary veno-occlusive disease (PVOD)
  • Administration of ERAs, intravenous, inhaled or subcutaneous prostacyclins / prostacyclin analogs, or investigational treatment within 90 days prior to Randomization
  • Administration of riociguat within 90 days prior to Randomization (if its use as background medication becomes permissible based on pharmacokinetic Drug-drug interaction [DDI] data during the conduct of the study, this exclusion criterion will no longer apply)
  • Change in dose or initiation of Phosphodiesterase type-5 (PDE-5) inhibitors, oral prostacyclins / prostacyclin analogues, prostacyclin receptor agonists (or riociguat, if its use becomes permissible during the study) within 90 days prior to Randomization or anticipated during the 52-week double-blind [DB] period
  • Hypotension, that is, systolic blood pressure (SBP) less than (<) 90 millimeters of mercury (mmHg) or diastolic blood pressure (DBP) <50 mmHg at Screening.
  • Severe renal dysfunction with an estimated Glomerular Filtration Rate <30 milliliters per minute per 1.73 meter square (mL/min/1.73 m^2) using the Chronic Kidney Disease Epidemiology Collaboration formula at 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) greater than or equal to (>=) 1.5*upper limit of normal (ULN) at Screening
  • Hemoglobin <100 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): NCT04271475


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 Trial Actelion

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Responsible Party: Actelion
ClinicalTrials.gov Identifier: NCT04271475    
Other Study ID Numbers: CR108742
2019-004131-24 ( EudraCT Number )
67896062CTP3001 ( Other Identifier: Actelion )
First Posted: February 17, 2020    Key Record Dates
Last Update Posted: May 13, 2020
Last Verified: May 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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Hypertension, Pulmonary
Hypertension
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Macitentan
Endothelin A Receptor Antagonists
Endothelin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Endothelin B Receptor Antagonists