Ensayos clínicos

Inclusion Criteria

• Written informed consent prior to initiation of any study-mandated procedure
• Males or females ≥ 18 years of age
• Surgical implantation of LVAD (e.g., HeartMate II or HeartWare) within 45 days prior to randomization
• Hemodynamic evidence of PH on Baseline right heart catheterization.
  • Baseline RHC is defined as the last hemodynamic measurements after LVAD implantation and prior to screening. Baseline RHC can be obtained via routine RHC
  • PH is defined as: Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and Pulmonary artery wedge pressure (PAWP) ≤ 18 mmHg
• PVR > 3 Wood units
• Stabilization of the patient defined as
  • No LVAD pump speed/flow rate changes for 48 h prior to baseline RHC
  • Stable dose of oral diuretics for 48 h prior to baseline RHC
  • No intravenous (i.v.) inotropes or vasopressors for 48 hours (h) prior to baseline RHC
  • Patient able to ambulate 48 h prior to baseline RHC
• A woman of childbearing potential is eligible if she has
  • A negative serum pregnancy test at screening and a negative serum pregnancy test at baseline
  • Agreed to undertake monthly serum pregnancy tests during the study and up to 30 days after study drug discontinuation
  • Agreed to use one of the methods of contraception / follow the contraception scheme described in the protocol from screening up to at least 30 days after study treatment discontinuation
• Randomization (visit 2) must be within 14 days of baseline RHC

Exclusion Criteria

• Documented severe obstructive lung disease defined as
  • Forced expiratory volume (FEV) in 1 second / forced vital capacity (FEV1/FVC) < 0.7 associated with FEV1 < 50% of predicted value after bronchodilator administration
• Documented moderate to severe restrictive lung disease defined as
  • total lung capacity < 60% of predicted value
• Documented pulmonary veno-occlusive disease
• Patients undergoing dialysis
• Hemoglobin < 8.5 g/dL at randomization
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × the upper limit of normal (ULN) at randomization
• Severe hepatic impairment, e.g., Child-Pugh Class C liver disease
• Body weight < 40 kg at randomization
• Doppler mean blood pressure < 65 mmHg at randomization
• GFR < 30 mL/min at randomization
• Pregnant, planning to become pregnant during the study period, or breastfeeding
• Treatment with endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE5) inhibitors, intravenous (i.v)., subcutaneous (s.c.), or oral prostanoids, or guanylate cyclase stimulators within 7 days prior to baseline RHC, or planned treatment during the study period
• Treatment with inhaled prostanoids (e.g., iloprost, epoprostenol) or nitric oxide within 24 h prior to baseline RHC, or planned treatment during the study period
• 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)
• 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)
• Treatment with another investigational drug within 28 days prior to study treatment initiation
• Known hypersensitivity to ERAs, or to any of the study treatment excipients
• Any condition that prevents compliance with the protocol or adherence to therapy
• Known concomitant life-threatening disease with a life expectancy < 12 months