Clinical trial NCT02554903: Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Hypertension
Keywords: LVAD
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2015-09-18
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Primary outcomes:
measure: Pulmonary Vascular Resistance (PVR) Ratio of Week 12 to Baseline
timeFrame: Baseline to Week 12
Secondary outcomes:
measure: Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)
timeFrame: Baseline to Week 12
measure: Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP)
timeFrame: Baseline to Week 12
measure: Change From Baseline to Week 12 in Pulmonary Arterial Wedge Pressure (PAWP)
timeFrame: Baseline to Week 12
measure: Change From Baseline to Week 12 in Cardiac Index (CI)
timeFrame: Baseline to Week 12
measure: Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR)
timeFrame: Baseline to Week 12
measure: Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SvO2)
timeFrame: Baseline to Week 12
measure: Change From Baseline to Week 12 in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels
timeFrame: Baseline to Week 12
measure: Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC)
timeFrame: Baseline to Week 12
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: #125_Mayo Clinic Arizona
state: Arizona
city: Tucson
country: United States
facility: #144_University of Arizona
state: Arizona
city: Beverly Hills
country: United States
facility: #106_Cedars-Sinai Medical Center
state: California
city: La Jolla
country: United States
facility: #154_University of California San Diego
state: California
city: Sacramento
country: United States
facility: #110_Sutter Heart Institute
state: California
city: San Francisco
country: United States
facility: #132_University of California San Francisco
state: California
city: Washington
country: United States
facility: #123_MedStar Washington Hospital Center
state: District of Columbia
city: Orlando
country: United States
facility: #126_Florida Hospital
state: Florida
city: Chicago
country: United States
facility: #135_University of Chicago Medical Center
state: Illinois
city: Oak Lawn
country: United States
facility: #113_Advocate Christ Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: #108_Indiana University Health Physicians Cardiology
state: Indiana
city: Indianapolis
country: United States
facility: #112_St. Vincent Medical Group, Inc
state: Indiana
city: Iowa City
country: United States
facility: #120_University of Iowa Hospitals and Clinics
state: Iowa
city: Louisville
country: United States
facility: #117_University of Louisville
state: Kentucky
city: New Orleans
country: United States
facility: #105_Ochsner Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: #129_John Hopkins University Medical Center
state: Maryland
city: Boston
country: United States
facility: #143_Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: #138_Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: #119_Brigham and Women's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: #115_Henry Ford Hospital
state: Michigan
city: Rochester
country: United States
facility: #102_Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: #150_Saint Luke's Hospital
state: Missouri
city: Saint Louis
country: United States
facility: #104_Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: #131_University of Nebraska Medical Center
state: Nebraska
city: Bronx
country: United States
facility: #133_Montefiore Medical Center
state: New York
city: New York
country: United States
facility: #103_Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: #139_Icahn School of Medicine at Mount Sinai
state: New York
city: Valhalla
country: United States
facility: #147_Westchester Medical Center
state: New York
city: Cincinnati
country: United States
facility: #148_University of Cincinnati Medical Center
state: Ohio
city: Cleveland
country: United States
facility: #153_Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: #101_The Ohio State University Wexner Medical Center
state: Ohio
city: Toledo
country: United States
facility: #145_The University of Toledo Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: #121_Integris Baptist Medical Center
state: Oklahoma
city: Hershey
country: United States
facility: #142_Penn State Heart and Vascular Institute
state: Pennsylvania
city: Philadelphia
country: United States
facility: #140_Hospital of the University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: #134_Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: #130_University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Columbia
country: United States
facility: #141_Palmetto Health / Palmetto Heart
state: South Carolina
city: Memphis
country: United States
facility: #151_Stern Cardiovascular Foundation
state: Tennessee
city: Nashville
country: United States
facility: #146_Vanderbilt University Medical Center
state: Tennessee
city: Austin
country: United States
facility: #149_Seton Heart Institute
state: Texas
city: Dallas
country: United States
facility: #136_Baylor Health - Baylor University Medical Center
state: Texas
city: Houston
country: United States
facility: #107_Houston Methodist Hospital
state: Texas
city: San Antonio
country: United States
facility: #122_Advanced Heart Failure Clinic - HCM
state: Texas
city: Salt Lake City
country: United States
facility: #127_The University of Utah
state: Utah
city: Charlottesville
country: United States
facility: #114_University of Virginia
state: Virginia
city: Falls Church
country: United States
facility: #111_Inova Fairfax Hospital
state: Virginia
city: Richmond
country: United States
facility: #116_Virginia Commonwealth University (VCU) Medical Center
state: Virginia
city: Madison
country: United States
facility: #155_University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: Actelion
name: Mark Rocco
role: STUDY_DIRECTOR
References: