REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Ventricular Remodeling
Intervention: Macitentan
Intervention description: All patients take open-label macitentan 10mg o.d.
Intervention MeSH terms: Macitentan
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 89.0
Sex: All
Minimum age: 18 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: Pulmonary Arterial Hypertension

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed informed consent prior to any study-mandated procedure

          2. Symptomatic pulmonary arterial hypertension (PAH)

          3. World Health Organization (WHO) Functional Class (FC) I to III

          4. 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

          5. 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. 6-minute walk distance (6MWD) ≥ 150 m during screening

          7. For patients treated with oral diuretics, treatment dose must have been stable at
             least 1 month prior to RHC during the screening period

          8. 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

          9. For patients treated with beta blockers, treatment dose must have been stable at least
             1 month prior to the RHC during the screening period

         10. Men or women ≥18 and < 65 years

         11. 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:

          1. Body weight < 40 kg

          2. 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.

          3. Pregnancy, breastfeeding or intention to become pregnant during the study

          4. Recently started (< 8 weeks prior to informed consent signature) or planned
             cardio-pulmonary rehabilitation program

          5. Known concomitant life-threatening disease with a life expectancy < 12 months

          6. Any condition likely to affect protocol or treatment compliance

          7. Hospitalization for PAH within 3 months prior to informed consent signature

          8. Left atrial volume indexed for body surface area ≥ 43mL/m2 by echocardiography or
             cardiac MRI

          9. Valvular disease grade 2 or higher

         10. History of pulmonary embolism or deep vein thrombosis

         11. Documented moderate to severe chronic obstructive pulmonary disease

         12. Documented moderate to severe restrictive lung disease

         13. 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

         14. Diabetes mellitus

         15. Moderate to severe renal insufficiency (calculated creatinine clearance < 60
             mL/min/1.73 m2)

         16. Cancer

         17. Systolic blood pressure < 90 mmHg

         18. 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.

         19. Hemoglobin < 100g/L

         20. AST and/or alanine aminotransferase (ALT) > 3× ULN

         21. Need for dialysis

         22. Responders to acute vasoreactivity test based on medical history

         23. Prior use of endothelin receptor antagonists (ERAs), stimulators of soluble guanylate
             cyclase or prostacyclin or prostacyclin analogues

         24. 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)

         25. 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)

         26. Treatment with another investigational drug (planned, or taken within the 3 months
             prior to study treatment initiation).

         27. 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)

         28. Claustrophobia

         29. Permanent cardiac pacemaker, automatic internal cardioverter

         30. Metallic implant (e.g., defibrillator, neurostimulator, hearing aid, permanent use of
             infusion device)

         31. Atrial fibrillation, multiple premature ventricular or atrial contractions, or any
             other condition that would interfere with proper cardiac gating during MRI.

         32. For patients enrolling in the metabolism sub-study only: glucose intolerance

         33. For patients enrolling in the biopsy sub-study only: PAH etiology belonging to Nice
             classification 1.4.4: PAH associated with congenital heart diseases