REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension

Study Overview
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Brief Summary
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The study evaluates the effect of macitentan on right ventricular and hemodynamic properties in patients with symptomatic pulmonary arterial hypertension. Patients are treated with macitentan for 1 year. Patients undergo right heart catheterization (RHC) at baseline and Week 26. They also undergo cardiac magnetic resonance imaging (MRI) at baseline, Week 26 and Week 52. Safety is monitored throughout the study. The study has three stub-studies. Each patient can participate in no sub-study or in one sub-study. The sub-studies are: (1) metabolism sub-study (with PET-MR scans); (2) biopsy sub-study (biopsies taken during the RHC); (3) Echo sub-study.

Official Title
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A Prospective, Multicenter, Single-arm, Open-label, Phase 4 Study to Evaluate the Effects of Macitentan on Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension Assessed by Cardiac Magnetic Resonance Imaging

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Macitentan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent prior to any study-mandated procedure Symptomatic pulmonary arterial hypertension (PAH) World Health Organization (WHO) Functional Class (FC) I to III PAH etiology belonging to one of the following groups according to Nice classification: Idiopathic PAH Heritable PAH Drug- and toxin-induced PAH PAH associated with congenital heart diseases: only simple (atrial septal defect, ventricular septal defect, patent ductus arteriosus) congenital systemic to pulmonary shunts at least 2 year post surgical repair Hemodynamic diagnosis of PAH confirmed by right heart catheterization (RHC) during screening showing: • mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and PCWP (pulmonary capillary wedge pressure) or left ventricular end diastolic pressure (LVEDP) ≤ 12 mmHg and pulmonary vascular resistance (PVR) ≥ 4 Wood Units (WU) (320 dyn.sec.cm-5) or 12 mmHg ≤ PCWP or LVEDP ≤ 15 mmHg and PVR ≥ 6WU (480 dyn.sec.cm-5) 6-minute walk distance (6MWD) ≥ 150 m during screening For patients treated with oral diuretics, treatment dose must have been stable at least 1 month prior to RHC during the screening period For patients treated with phosphodiesterase type-5 (PDE-5) inhibitors, treatment dose must have been stable at least 3 months prior to RHC during the screening period For patients treated with beta blockers, treatment dose must have been stable at least 1 month prior to the RHC during the screening period Men or women ≥18 and < 65 years Women of childbearing potential (defined in protocol) must: Have a negative serum pregnancy test during screening and a negative urine pregnancy test on Day 1, and Agree to use reliable methods of contraception (defined in protocol) from screening up to 30 days after study treatment discontinuation, and Agree to perform monthly pregnancy tests up to 30 days after study treatment discontinuation Exclusion Criteria: Body weight < 40 kg Body mass index (BMI) > 35kg/m2. For patients with 30kg/m2 < BMI < 35kg/m2, an eligibility form will be submitted to a Steering Committee member who will reserve the right to exclude the patient. Pregnancy, breastfeeding or intention to become pregnant during the study Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program Known concomitant life-threatening disease with a life expectancy < 12 months Any condition likely to affect protocol or treatment compliance Hospitalization for PAH within 3 months prior to informed consent signature Left atrial volume indexed for body surface area ≥ 43mL/m2 by echocardiography or cardiac MRI Valvular disease grade 2 or higher History of pulmonary embolism or deep vein thrombosis Documented moderate to severe chronic obstructive pulmonary disease Documented moderate to severe restrictive lung disease Historical evidence of significant coronary artery disease established by: History of myocardial infarction or More than 50% stenosis in a coronary artery (by percutaneous coronary intervention or angiography) or Elevation of the ST segment on electrocardiogram or History of coronary artery bypass grafting or Stable angina Diabetes mellitus Moderate to severe renal insufficiency (calculated creatinine clearance < 60 mL/min/1.73 m2) Cancer Systolic blood pressure < 90 mmHg Severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × upper limit of the normal range (ULN) accompanied by an aspartate aminotransferase (AST) elevation > ULN at Screening. Hemoglobin < 100g/L AST and/or alanine aminotransferase (ALT) > 3× ULN Need for dialysis Responders to acute vasoreactivity test based on medical history Prior use of endothelin receptor antagonists (ERAs), stimulators of soluble guanylate cyclase or prostacyclin or prostacyclin analogues Treatment with strong inducers of cytochrome P450 isozyme 3A4 (CYP3A4) within 4 weeks prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin, phenytoin and St. John's Wort) Treatment with strong inhibitors of CYP3A4 within 4 weeks prior to study treatment initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) Treatment with another investigational drug (planned, or taken within the 3 months prior to study treatment initiation). Hypersensitivity to any ERA or any excipients of the formulation of macitentan (lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, polyvinyl alcohol, polysorbate, titanium dioxide, talc, xanthan gum, and lecithin soya) Claustrophobia Permanent cardiac pacemaker, automatic internal cardioverter Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of infusion device) Atrial fibrillation, multiple premature ventricular or atrial contractions, or any other condition that would interfere with proper cardiac gating during MRI. For patients enrolling in the metabolism sub-study only: glucose intolerance For patients enrolling in the biopsy sub-study only: PAH etiology belonging to Nice classification 1.4.4: PAH associated with congenital heart diseases

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Macitentan<br>All patients take open-label macitentan 10mg o.d. | Drug: Macitentan<br>* All patients take open-label macitentan 10mg o.d.<br>* Other names: ACT-064992;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Right Ventricular Stroke Volume (RVSV) to Week 26 | Change from baseline in RVSV assessed by cardiac magnetic resonance imaging (MRI) from pulmonary artery flow was reported at Week 26. Primary analysis were based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is. | Baseline and Week 26 | 
| Ratio of Week 26 to Baseline Pulmonary Vascular Resistance (PVR) | Ratio of Week 26 to baseline PVR as assessed by RHC was reported. PVR represents the resistance against which the right ventricle needs to pump. PVR is determined by right heart catheterization (RHC). PVR was calculated as 80*(Mean pulmonary arterial pressure [mPAP] -[Pulmonary capillary wedge pressure {PCWP} or Left ventricular end diastolic pressure {LVEDP} if PCWP not available/cardiac output [CO]). Primary analysis were based on interim results as pre-planned and the primary outcome measures data table reported is finalized as is. | Baseline and Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Right Ventricular End Diastolic Volume (RVEDV) to Week 26 | Change from baseline to Week 26 in RVEDV assessed by cardiac MRI was reported. | Baseline to Week 26 | 
| Change From Baseline in Right Ventricular End Systolic Volume (RVESV) to Week 26 | Change from baseline to Week 26 in RVESV assessed by cardiac MRI was reported. | Baseline to Week 26 | 
| Change From Baseline in Right Ventricular Ejection Fraction (RVEF) to Week 26 (% Blood Volume) | Change from baseline to Week 26 in RVEF based on pulmonary artery flow assessed by cardiac MRI was reported. | Baseline to Week 26 | 
| Change From Baseline in Right Ventricle (RV) Mass to Week 26 | Change from baseline to Week 26 in RV mass assessed by cardiac MRI was reported. | Baseline to Week 26 | 
| Change From Baseline in Six-minutes Walk Distance (6MWD) to Week 26 | 6MWD is a non-encouraged test performed in a 30 meter (m) long flat corridor, where the participant is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. This test is used to assess exercise capacity. The test was performed about 30 minutes after study drug administration. Any increase in the walk distance was considered improvement from baseline. | Baseline to Week 26 | 
| Change From Baseline in World Health Organization Functional Class (WHO FC) to Week 26 | WHO FC is a classification which reflects disease severity based on symptoms. WHO Functional Classification of pulmonary hypertension comprises of Class I (participants with pulmonary hypertension but without resulting limitation of physical activity), II (participants with pulmonary hypertension resulting in slight limitation of physical activity), III (participants with pulmonary hypertension resulting in marked limitation of physical activity) and IV (participants with pulmonary hypertension with inability to carry out any physical activity without symptoms). Changes from baseline to Week 26 included: improvement (change from a higher to a lower FC), worsening (change from a lower to a higher FC) or unchanged/stable (same FC at baseline and at the post-baseline time point). | Baseline to Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Arterial Hypertension