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

Pulmonary Hypertension Clinical Trial

— SOPRANO  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02554903
• Other study ID #: AC-055-205
• Status: Completed
• Phase: Phase 2
• Start date: March 28, 2016
• Est. completion date: March 13, 2020

Study information

• Verified date: March 2021
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: March 13, 2020
• Est. primary completion date: March 13, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Drug:
• Macitentan 10mg
2 groups, randomized in a 1:1 ratio by an Interactive Voice/Web Randomization System to macitentan 10 mg or placebo
• Placebo sugar pill
2 groups, randomized in a 1:1 ratio by an Interactive Voice/Web Randomization System to macitentan 10 mg or placebo

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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