A Clinical Study to Find Out if Macitentan is Effective and Safe in Japanese Patients With Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

Study Overview
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Brief Summary
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The endothelin receptor antagonist macitentan showed significant improvement compared with placebo in pulmonary vascular resistance (PVR) and 6-minute walking distance (6MWD) in inoperable CTEPH patients in the phase II MERIT-1 trial (AC-055E201, NCT02021292). However, in the MERIT-1 trial Japanese patients were not included. Therefore, in line with Japan's medical environment, this phase III study is to confirm the efficacy and safety of macitentan in Japanese CTEPH patients.

Official Title
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A Prospective, Multicenter, Open-label, Single Arm, Phase III Study to Assess the Efficacy and Safety of Macitentan (ACT-064992) in Subjects With Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Conditions
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Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Intervention / Treatment
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* Drug: macitentan 10 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent to participate in the study obtained from the subject or legal representative a) prior to initiation of any study mandated procedure Japanese subjects who have been diagnosed as having CTEPH: Subjects who have not undergone balloon pulmonary angioplasty (BPA) and for whom the investigator determines not to implement pulmonary endarterectomy (PEA) at the time of the acquisition of informed consent due to the organized thrombosis localized in the peripheral regions, high risk (complications, old age, etc.) or for any other reasons. Subjects who have postoperative persistent or recurrent pulmonary hypertension (PH) after undergoing pulmonary endarterectomy (PEA) and/or BPA. PH subjects whose WHO FC is I to IV 6MWD measured during the screening period ranges from 150 m to 450 m Subjects who meet the following conditions according to the right heart catheterization (RHC) performed during the screening period or within 8 weeks before the acquisition of the informed consent: Resting mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg (if PAWP cannot be measured or the value of PAWP is not reliable, left ventricular end-diastolic pressure ≤ 13 mmHg) Resting PVR ≥ 400 dyn*sec/cm5 Subjects treated with anti-coagulation agents, unfractionated heparin or low molecular weight heparin at least 90 days prior to RHC at baseline Women with childbearing potential with negative serum pregnancy test results and able to follow the appropriate contraceptive methods from the date of starting the study drug administration up to 30 days after the discontinuation or completion of the study drug administration. Fertile male subjects able to use condom during the same period. Exclusion Criteria: BPA within 90 days prior to undergoing baseline RHC PEA within 180 days prior to undergoing baseline RHC Subjects with unstable pulmonary hemodynamics who have postoperative persistent or recurrent PH after undergoing PEA and/or BPA Recurrent thromboembolism undergoing treatment with oral anti-coagulation agents Symptomatic acute pulmonary embolism within 180 days prior to the start of study drug administration Known moderate-to-severe restrictive lung disease or obstructive lung disease or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema) Acute myocardial infarction during Screening period Severe liver impairment. Systolic blood pressure (SBP) < 90 mmHg at screening. Any known factor or disease that may interfere with treatment compliance or full participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label treatment period<br>oral administration of macitentan 10 mg once daily | Drug: macitentan 10 mg<br>* macitentan 10 mg, film-coated tablet, oral use<br>* Other names: ACT-064992, Opsumit®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the ratio in pulmonary vascular resistance (PVR) at rest from baseline to Week 16 | The resistance in the artery carrying blood to the lungs is called PVR. The PVR is the resistance in the artery carrying blood to the lungs and that has to be overcome by the right ventricle in heart in order to let blood flow to the lungs occur. The ratio in PVR at rest indicates the efficacy of macitentan in patients with CTEPH. The ratio in PVR at rest is calculated as PVR at Week 16 divided by baseline PVR. The ratio in PVR at rest from baseline to Week 16 of administration of macitentan is evaluated in subjects with CTEPH who are not indicated for pulmonary endarterectomy (PEA) and/or subjects who have postoperative persistent or recurrent pulmonary hypertension (PH) after PEA and/or balloon pulmonary angioplasty (BPA). | From Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Week 16 in PVR at rest | The PVR at rest will be calculated to evaluate the change in PVR at rest from pre-dosing (baseline) to post-dosing (Week 16). | From baseline to Week 16 | 
| Change from baseline to Week 16 in pulmonary vascular resistance index (PVRI) at rest | The indexed PVR (PVRI) at rest will be calculated to evaluate the change in PVRI at rest from pre-dosing (baseline) to post-dosing (Week 16). | From baseline to Week 16 | 
| Change from baseline to Week 24 in 6-minute walk distance (6MWD) | The purpose of the 6-minute walk is to test exercise tolerance and capacity. The 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. This endpoint evaluates the change in 6MWD from pre-dosing (baseline) to post-dosing (Week 24). | From baseline to Week 24 | 
| Change from baseline to Week 24 in Borg dyspnea index | The Borg dyspnea index rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 ('Nothing at all') to 10 ('Very, very severe - maximal'). A decrease in the Borg dyspnea index indicates an improvement. This endpoint evaluates the change in the Borg dyspnea index assessed at the end of measuring the 6MWD from pre-dosing (baseline) to post-dosing (Week 24). | From baseline to Week 24 | 
| Change from baseline to Week 24 in WHO functional class (WHO FC) | This endpoint evaluates the change of WHO functional class from pre-dosing (baseline) to post-dosing (Week 24). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure. | From baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CTEPH, chronic thromboembolic pulmonary hypertension, macitentan