Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation
Condition: Pulmonary Hypertension
MeSH terms: Hypertension, Pulmonary; Hypertension
Intervention: Macitentan 10mg; Placebo sugar pill
Intervention description: 2 groups, randomized in a 1:1 ratio by an Interactive Voice/Web Randomization System to macitentan 10 mg or placebo; 2 groups, randomized in a 1:1 ratio by an Interactive Voice/Web Randomization System to macitentan 10 mg or placebo
Intervention MeSH terms: Macitentan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 57.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: LVAD

Summary:

      STUDY OBJECTIVES Primary objective To evaluate the effect of macitentan 10 mg on pulmonary
      vascular resistance (PVR) as compared to placebo in subjects with pulmonary hypertension (PH)
      after left ventricular assist device (LVAD) implantation.

      Secondary objectives To evaluate the effect of macitentan 10 mg as compared to placebo on
      cardio-pulmonary hemodynamics and disease severity in subjects with PH after LVAD
      implantation.

      To evaluate the safety and tolerability of macitentan 10 mg in subjects with PH after LVAD
      implantation.

      Exploratory objectives To explore the potential effect of macitentan 10 mg as compared to
      placebo on right ventricular function in subjects with PH after LVAD implantation.

      To explore the potential effect of macitentan 10 mg as compared to placebo on selected
      clinical events in subjects with PH after LVAD implantation.

      To explore the potential effect of macitentan 10 mg as compared to placebo on renal function
      as measured by glomerular filtration rate (GFR) in subjects with PH after LVAD implantation.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Written Informed Consent prior to initiation of any study-mandated procedure.

          2. Males or females ≥ 18 years of age.

          3. Surgical implantation of LVAD within 90 days prior to Randomization.

          4. Hemodynamic evidence of PH on Baseline right heart catheterization (RHC) by the
             thermodilution method. Baseline RHC is defined as the last hemodynamic measurements
             after LVAD implantation and prior to the first dose of study treatment. PH is defined
             as:

               1. Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and

               2. Pulmonary artery wedge pressure (PAWP) ≤ 18 mmHg and

               3. PVR > 3 Wood units.

          5. Stabilization of the patient for 48 h prior to the Baseline RHC, defined as:

               1. No LVAD pump speed/flow rate changes and

               2. Stable dose of oral diuretics and

               3. No intravenous (i.v.) inotropes or vasopressors and

               4. Patient able to ambulate.

          6. A woman of childbearing potential is eligible only if she has:

               1. A negative serum pregnancy test result during the Screening period (Visit 1) and
                  Randomization (Visit 2) and

               2. Agreement to undertake monthly serum pregnancy tests during the study and up to
                  30 days after study treatment discontinuation and

               3. Agreement to use one of the methods of contraception / follow the contraception
                  scheme described in Section 4.5 from Screening and up to at least 30 days after
                  study treatment discontinuation.

          7. Patient must be randomized within 14 days of Baseline RHC.

        Exclusion Criteria:

          1. Documented severe obstructive lung disease defined as: forced expiratory volume in 1
             second / forced vital capacity (FEV1/FVC) < 0.7 associated with FEV1 < 50% of
             predicted value after bronchodilator administration.

          2. Documented moderate to severe restrictive lung disease defined as: total lung capacity
             < 60% of predicted value.

          3. Documented pulmonary veno-occlusive disease.

          4. Patients undergoing dialysis.

          5. Hemoglobin < 8.5 g/dL at Randomization.

          6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × the upper
             limit of normal (ULN) at Randomization.

          7. Severe hepatic impairment, e.g., Child-Pugh Class C liver disease.

          8. Body weight < 40 kg at Randomization.

          9. Doppler mean blood pressure < 65 mmHg at Randomization.

         10. GFR < 30 mL/min at Randomization.

         11. Pregnant, planning to become pregnant during the study period, or breastfeeding.

         12. Treatment with endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE5)
             inhibitors, i.v., subcutaneous (s.c.), or oral prostanoids, or guanylate cyclase
             stimulators within 7 days prior to Baseline RHC or study treatment initiation.

         13. Treatment with inhaled prostanoids (e.g., iloprost, epoprostenol) or nitric oxide
             within 24 h prior to Baseline RHC or study treatment initiation.

         14. Treatment with strong inducers of cytochrome P450 isozyme 3A4 (CYP3A4) within 28 days
             prior to study treatment initiation (e.g., carbamazepine, rifampicin, rifabutin,
             phenytoin and St. John's Wort).

         15. Treatment with strong inhibitors of CYP3A4 within 28 days prior to study treatment
             initiation (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin,
             telithromycin, nefazodone, ritonavir, saquinavir, boceprevir, telaprevir, iopinavir,
             fosamprenavir, darunavir, tipranavir, atazanavir, nelfinavir, amprenavir, and
             idinavir).

         16. Treatment with another investigational drug (planned, or taken) within 28 days prior
             to study treatment initiation.

         17. Known hypersensitivity to ERAs, or to any of the study treatment excipients.

         18. Any condition that prevents compliance with the protocol or adherence to therapy.

         19. Known concomitant life-threatening disease with a life expectancy < 12 months.