Clinical Study to Assess the Efficacy and Safety of Macitentan in Patients With Pulmonary Hypertension After Left Ventricular Assist Device Implantation (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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension
• Intervention / Treatment: Drug: Macitentan 10mg; Drug: Placebo sugar pill

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • #125_Mayo Clinic Arizona
    • Tucson, Arizona, United States, 85724
      • #144_University of Arizona
  • California
    • Beverly Hills, California, United States, 90211
      • #106_Cedars-Sinai Medical Center
    • La Jolla, California, United States, 92037
      • #154_University of California San Diego
    • Sacramento, California, United States, 95819
      • #110_Sutter Heart Institute
    • San Francisco, California, United States, 94143
      • #132_University of California San Francisco
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • #123_MedStar Washington Hospital Center
  • Florida
    • Orlando, Florida, United States, 32804
      • #126_Florida Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • #135_University of Chicago Medical Center
    • Oak Lawn, Illinois, United States, 60453
      • #113_Advocate Christ Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • #108_Indiana University Health Physicians Cardiology
    • Indianapolis, Indiana, United States, 46260
      • #112_St. Vincent Medical Group, Inc
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • #120_University of Iowa Hospitals and Clinics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • #117_University of Louisville
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • #105_Ochsner Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • #129_John Hopkins University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • #143_Tufts Medical Center
    • Boston, Massachusetts, United States, 02114
      • #138_Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • #119_Brigham and Women's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • #115_Henry Ford Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • #102_Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • #150_Saint Luke's Hospital
    • Saint Louis, Missouri, United States, 63110
      • #104_Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 68918
      • #131_University of Nebraska Medical Center
  • New York
    • Bronx, New York, United States, 10467
      • #133_Montefiore Medical Center
    • New York, New York, United States, 10021
      • #103_Weill Cornell Medical College
    • New York, New York, United States, 94080
      • #139_Icahn School of Medicine at Mount Sinai
    • Valhalla, New York, United States, 10595
      • #147_Westchester Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • #148_University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • #153_Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • #101_The Ohio State University Wexner Medical Center
    • Toledo, Ohio, United States, 43614
      • #145_The University of Toledo Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • #121_Integris Baptist Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • #142_Penn State Heart and Vascular Institute
    • Philadelphia, Pennsylvania, United States, 19104
      • #140_Hospital of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • #134_Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • #130_University of Pittsburgh Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Columbia, South Carolina, United States, 29203
      • #141_Palmetto Health / Palmetto Heart
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • #151_Stern Cardiovascular Foundation
    • Nashville, Tennessee, United States, 37232
      • #146_Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States, 78705
      • #149_Seton Heart Institute
    • Dallas, Texas, United States, 75226
      • #136_Baylor Health - Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • #107_Houston Methodist Hospital
    • San Antonio, Texas, United States, 78229
      • #122_Advanced Heart Failure Clinic - HCM
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • #127_The University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22905
      • #114_University of Virginia
    • Falls Church, Virginia, United States, 22042
      • #111_Inova Fairfax Hospital
    • Richmond, Virginia, United States, 23298
      • #116_Virginia Commonwealth University (VCU) Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • #155_University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Macitentan 10 mg po; Approximately 78 adult subjects with PH post-LVAD implantation will be randomized (1:1) to receive either macitentan 10 mg, or matching placebo, once daily orally.	Drug: Macitentan 10mg; 2 groups, randomized in a 1:1 ratio by an Interactive Voice/Web Randomization System to macitentan 10 mg or placebo; Other Names: Active drug
Placebo Comparator: Placebo sugar pill; Approximately 78 adult subjects with PH post-LVAD implantation will be randomized (1:1) to receive either macitentan 10 mg, or matching placebo, once daily orally.	Drug: Placebo sugar pill; 2 groups, randomized in a 1:1 ratio by an Interactive Voice/Web Randomization System to macitentan 10 mg or placebo; Other Names: placebo comparator

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary Vascular Resistance (PVR) Ratio of Week 12 to Baseline	PVR ratio equals to Week 12 PVR / Baseline PVR. PVR represents the resistance against which the right ventricle needs to pump. PVR was calculated using the following formula: mean pulmonary arterial pressure (mPAP) - pulmonary artery wedge pressure (PAWP)/cardiac output (CO); where mPAP and PAWP were measured at end-expiration and CO was measured in triplicate using the thermodilution method.	Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 12 in Mean Right Atrial Pressure (mRAP)	mRAP was collected in the eCRF (electronic case record form). Right atrial pressure (RAP) is the blood pressure in the right atrium of the heart. Change from baseline to Week 12 in mRAP was measured at rest and no correction for multiple testing was applied.	Baseline to Week 12
Change From Baseline to Week 12 in Mean Pulmonary Arterial Pressure (mPAP)	mPAP was collected in the eCRF. The pulmonary artery pressure is a measure of the blood pressure found in the main pulmonary artery. Change from baseline to Week 12 in mPAP was measured at rest and no correction for multiple testing was applied.	Baseline to Week 12
Change From Baseline to Week 12 in Pulmonary Arterial Wedge Pressure (PAWP)	PAWP was collected in the eCRF. PAWP is pressure within the pulmonary arterial system when the catheter tip is 'wedged' in the tapering branch of one of the pulmonary arteries. Change from baseline to Week 12 in PAWP was measured at rest and no correction for multiple testing was applied.	Baseline to Week 12
Change From Baseline to Week 12 in Cardiac Index (CI)	CI was calculated as Cardiac Output (CO)/body surface area (BSA), where CO is Thermodilution Cardiac Output (Liters per minute [L/min]) and BSA (m^2) equals to 0.007184*weight^0.425 (kilograms)*height^0.725 (centimeter). CI was represented in liters per minute per square meter (L/min/m^2). Change from baseline to Week 12 in CI was measured at rest and no correction for multiple testing was applied.	Baseline to Week 12
Change From Baseline to Week 12 in Total Pulmonary Resistance (TPR)	TPR was calculated as mPAP/CO where mPAP is mean pulmonary arterial pressure and CO is cardiac output. Change from baseline to Week 12 in TPR was calculated at rest and no correction for multiple testing was applied.	Baseline to Week 12
Change From Baseline to Week 12 in Mixed Venous Oxygen Saturation (SvO2)	Mixed venous oxygen saturation measures the end result of oxygen consumption and delivery. Change from baseline to Week 12 in SvO2 was reported and measured at rest and no correction for multiple testing was applied.	Baseline to Week 12
Change From Baseline to Week 12 in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) Levels	NT-proBNP levels in the blood are used for diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure.	Baseline to Week 12
Change From Baseline to Week 12 in Participants World Health Organization (WHO) Functional Class (FC)	WHO FC is a classification which reflects disease severity based on symptoms. WHO Functional Classification of pulmonary hypertension comprises of Class I (participants with pulmonary hypertension but without resulting limitation of physical activity), II (participants with pulmonary hypertension resulting in slight limitation of physical activity), III (participants with pulmonary hypertension resulting in marked limitation of physical activity) and IV (participants with pulmonary hypertension with inability to carry out any physical activity without symptoms). Change from baseline in WHO FC was reported. WHO FC was categorized as worsening (change greater than [>] 0); improvement (change less than [<] 0); or no change (change equals to [=] 0).	Baseline to Week 12

Collaborators and Investigators

• Sponsor: Actelion
• Investigators: Study Director: Mark Rocco, Actelion

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2016
• Primary Completion (Actual): March 13, 2020
• Study Completion (Actual): March 13, 2020

Study Registration Dates

• First Submitted: September 8, 2015
• First Submitted That Met QC Criteria: September 17, 2015
• First Posted (Estimate): September 18, 2015

Study Record Updates

• Last Update Posted (Actual): April 1, 2021
• Last Update Submitted That Met QC Criteria: March 8, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: LVAD
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Macitentan
• Other Study ID Numbers: AC-055-205

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No