SOPRANO

A prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study to assess the efficacy and safety of macitentan in patients with pulmonary hypertension after left ventricular assist device implantation - Jennifer Cook, MD

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 (e.g., HeartMate II or HeartWare) within 45 days prior to Randomization. 

4. Hemodynamic evidence of PH on Baseline right heart catheterization (RHC). Baseline RHC is defined as the last hemodynamic measurements after LVAD implantation and prior to Screening. Baseline RHC can be obtained via either routine RHC or pulmonary artery catheter. PH is defined as: 

a) Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg and 

b) Pulmonary artery wedge pressure (PAWP) ≤ 18 mmHg 

5. PVR > 3 Wood units. 

6. Stabilization of the patient after removal of the pulmonary artery catheter, defined as: 

a) No LVAD pump speed/flow rate changes for 48 h prior to Screening and 

b) Stable dose of diuretics for 48 h prior to Screening and 

c) No intravenous (i.v.) inotropes or vasopressors for 48 h prior to Screening and 

d) Patient able to ambulate 48 h prior to Screening. 

7.  A woman of childbearing potential is eligible if she has: 

a) A negative serum pregnancy test at Screening and a negative serum pregnancy test at Baseline. 

b) Agreed to undertake monthly serum pregnancy tests during the study and up to 30 days after study drug discontinuation. 

c) Agreed to use one of the methods of contraception / follow the contraception scheme described in Section 4.5 from Screening up to at least 30 days after study treatment discontinuation. 

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 Screening. 

6. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 . the upper limit of normal (ULN) at Screening. 

7. Severe hepatic impairment, e.g., Child-Pugh Class C liver disease. 

8. Body weight < 40 kg at Screening. 

9. Doppler mean blood pressure < 65 mmHg at Screening. 

10. GFR < 30 mL/min at Screening. 

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 planned treatment during the study period. 

13 . reatment with inhaled prostanoids (e.g., iloprost, 

epoprostenol) or nitric oxide within 24 h prior to Baseline RHC, or planned treatment during the study period. 

14. Treatment with i.v. inotropes or vasopressors within 24 h prior to Baseline RHC. 

15. 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). 

16. 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). 

17. Treatment with another investigational drug (planned, or taken within the 28 days prior to Baseline RHC). 

18. Known hypersensitivity to ERAs, or to any of the study treatment excipients. 

19. Any condition that prevents compliance with the protocol or adherence to therapy. 

20. Known concomitant life-threatening disease with a life expectancy < 12 months.

For more information, contact coordinators: Tammy Pate-Lamb, tpatelamb@shc.arizona.edu and Fernando Blumendron, blumenkf@email.arizona.edu