Effects of Combination Medical Therapy Followed by BPA on Right Ventricular-PA Coupling and Hemodynamics in CTEPH

Study Overview
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Brief Summary
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The main goal of this study is to determine the effects of combination medical therapy (Riociguat and Macitentan) and balloon pulmonary angioplasty (BPA) on hemodynamics and right ventricular (RV) function (including advanced assessments of RV-pulmonary artery (PA) coupling from invasive hemodynamics) in participants with inoperable or post-PTE residual CTEPH.

Detailed Description
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Recent presented but unpublished results from trials of BPA vs riociguat for inoperable CTEPH (NCT02634203) have demonstrated that BPA provides a more significant hemodynamic benefit than medical therapy. The investigators hypothesize that participants who are treated with upfront combination medical therapy followed by BPA will have significant improvements in their hemodynamics and RV-PA coupling that can be monitored over time.

Official Title
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Effects of Combination Medical Therapy Followed by Balloon Pulmonary Angioplasty on Right Ventricular-PA Coupling and Hemodynamics in Chronic Thromboembolic Pulmonary Hypertension

Conditions
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CTEPH

Intervention / Treatment
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* Drug: Macitentan Tablets
* Drug: Riociguat
* Device: balloon pulmonary angioplasty


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the trial: Age ≥ 18 years' old Diagnosis of CTEPH Not a candidate for PTE Candidate for BPA based on suitable anatomy and disease burden Treatment-naïve (no CTEPH or pulmonary arterial hypertension (PAH)-specific medical therapies) with plans for initiation of CTEPH/PAH-specific medical therapy and treatment with BPA. Willing and able to give informed consent and adhere to visit/protocol schedules (Consent must be given before any study procedures are performed). Exclusion Criteria: Subjects presenting with any of the following will not be included in the trials: Moderate to severe heart disease (LVEF < 45% or severe LV Hypertrophy) Sarcoidosis Active cancer Sickle cell anemia Liver disease (Childs-Pugh class C) Prisoners Pregnant, planning pregnancy or lactating Conditions that will prohibit MRI scanning (metal in eye, claustrophobia, inability to lie supine) Contraindication to riociguat or macitentan Medical or psychological conditions which, in the opinion of the investigator, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: participants with inoperable CTEPH<br>subject with inoperable Chronic thromboembolic Pulmonary Hypertension | Drug: Macitentan Tablets<br>* 10 mg oral once daily<br>* Other names: OPSUMIT;Drug: Riociguat<br>* 1 mg to 2.5mg oral three times daily<br>* Other names: Adempas;Device: balloon pulmonary angioplasty<br>* on hemodynamics and RV function (including advanced assessments of RV-PA coupling<br>|
| Active Comparator: post PTE residual CTEPH<br>Subject with post pulmonary endarterectomy (PTE) residual Chronic Thromboembolic Pulmonary Hypertension | Drug: Macitentan Tablets<br>* 10 mg oral once daily<br>* Other names: OPSUMIT;Drug: Riociguat<br>* 1 mg to 2.5mg oral three times daily<br>* Other names: Adempas;Device: balloon pulmonary angioplasty<br>* on hemodynamics and RV function (including advanced assessments of RV-PA coupling<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in end-systolic elastance (Ees) divided by arterial elastance (Ea) (Ees/Ea) at three time points: Baseline, Timepoint 1 and Timepoint 2. | Ees is a measure of right ventricular (RV) - pulmonary arterial (PA) coupling, with a normal value of Ees/Ea > 0.8 (dimensionless - no units). For subjects with Ees/Ea > 0.8 at the start of the study, we will evaluate the absolute change in Ees/Ea between timepoints. For those with an Ees/Ea < 0.8, we will also determine whether participants have an improvement to > 0.8. | Baseline (before starting all treatments); Timepoint 1 (after starting medical therapy; up to 6 months after baseline); Timepoint 2 (after balloon pulmonary angioplasty (BPA); up to 12 months after baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in six-minute walk distance (6MWD) in meters. | 6MWD will be determined at baseline, timepoint 1 and timepoint 2. Absolute change between these timepoints will be determined. | Baseline (before starting all treatments); Timepoint 1 (after starting medical therapy; up to 6 months after baseline); Timepoint 2 (after balloon pulmonary angioplasty (BPA); up to 12 months after baseline) | 
| Change in N-terminal pro-brain natriuretic peptide (NT-proBNP) in picogram/milliliters. | NT-proBNP will be determined at baseline, timepoint 1 and timepoint 2. Absolute change between these timepoints will be determined. | Baseline (before starting all treatments); Timepoint 1 (after starting medical therapy; up to 6 months after baseline); Timepoint 2 (after balloon pulmonary angioplasty (BPA); up to 12 months after baseline) | 
| Change in Cardiac index as measured by liters per minute per meters squared at right heart catheterization. | Right heart catheterization will be performed at baseline, timepoint 1 and timepoint 2 and parameters determined. Absolute change between these timepoints will be determined. | Baseline (before starting all treatments); Timepoint 1 (after starting medical therapy; up to 6 months after baseline); Timepoint 2 (after balloon pulmonary angioplasty (BPA); up to 12 months after baseline) | 
| Change in pulmonary vascular resistance as measured by Wood units at right heart catheterization. | Right heart catheterization will be performed at baseline, timepoint 1 and timepoint 2 and parameters determined. Absolute change between these timepoints will be determined. | Baseline (before starting all treatments); Timepoint 1 (after starting medical therapy; up to 6 months after baseline); Timepoint 2 (after balloon pulmonary angioplasty (BPA); up to 12 months after baseline) | 
| Change in right atrial pressure as measured by millimeters of mercury at right heart catheterization. | Right heart catheterization will be performed at baseline, timepoint 1 and timepoint 2 and parameters determined. Absolute change between these timepoints will be determined. | Baseline (before starting all treatments); Timepoint 1 (after starting medical therapy; up to 6 months after baseline); Timepoint 2 (after balloon pulmonary angioplasty (BPA); up to 12 months after baseline) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inoperable, Post-PTE