A Long Term Study to Find Out if Macitentan is an Effective and Safe Treatment for Patients With Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease (SERENADE OL)

A Long-term, Multicenter, Single-arm, Open-label Extension of the SERENADE Study, to Assess the Safety and Efficacy of Macitentan in Subjects With Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease

The aim of this open-label (OL) extension trial is to study the long-term safety and efficacy of macitentan in subjects with heart failure with preserved ejection fraction (HFpEF) and pulmonary vascular disease (PVD) beyond the treatment in the double-blind parent SERENADE study (AC-055G202, NCT03153111). Furthermore, this OL extension study will give eligible subjects of the main study (SERENADE/AC-055G202, NCT03153111) an opportunity to continue or start receiving macitentan.

Study Overview

• Status: Terminated
• Conditions: Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease
• Intervention / Treatment: Drug: macitentan 10 mg

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Mar Del Plata, Buenos Aires, Argentina, B7600FZN
    • Instituto de Investigaciones Clínicas Mar del Plata
• Austria
  • Vienna, Austria, 1090
    • Medizinische Universität Wien
• Brazil
  • Blumenau, Brazil, 89020-430
    • Maestri E Kormann Consultoria Médico- Científica Ltda
  • Marilia, Brazil, 17515-000
    • Instituto do Coracao de Marília
• Bulgaria
  • Sliven, Bulgaria, 8800
    • Diagnostic - Consulting Center I-Sliven
  • Sofia, Bulgaria, 1784
    • Medical Centre Synexus
• Denmark
  • Copenhagen, Denmark, 2400
    • Bispebjerg Og Frederiksberg Hospital
• France
  • Grenoble Cedex 9, France
    • CHU de Grenoble - Hôpital Albert Michallon
  • Le Kremlin Bicetre, France, 94270
    • Hopital de Bicetre
  • Rouen Cedex, France, 76031
    • CHU Rouen - Hôpital Charles Nicolle
• Germany
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus Medizinische Klinik und Poliklinik 1-Pneumologie
  • Giessen, Germany, 35392
    • Universitaetsklinikum Giessen
  • Kiel, Germany, 24105
    • Universitaetsklinikum Schleswig-Holstein Campus Kiel
• Hungary
  • Budapest, Hungary, 1122
    • Semmelweis Egyetem Városmajor Szív- és Érgyógyászati Klinika
• Israel
  • Ashkelon, Israel
    • Barzilai Medical Center
  • Hadera, Israel, 3810101
    • Hillel Yaffe Medical Center
  • Haifa, Israel, 3339419
    • Bnai Zion Medical Center
  • Nahariya, Israel, 2210001
    • Galilee Medical Center
  • Petah Tikva, Israel, 4941492
    • Rabin Medical Center, Beilinson Campus
  • Rehovot, Israel, 7610001
    • Kaplan Medical Center
• Poland
  • Krakow, Poland, 31-202
    • Krakowski Szpital Specjalityczny im. Jana Pawla II, Oddzial Kliniczny Chorob Serca i Naczyn
  • Lublin, Poland, 20-718
    • Wojewodzki Szpital Specjalistyczny im. Stefana Kardynala Wyszynskiego SPZOZ
  • Wroclaw, Poland, 50-513
    • 4 Wojskowy Szpital Kliniczny z Poliklinika SP ZOZ
• Romania
  • Craiova, Romania, 200505
    • Cardiomed
  • Pitesti, Romania, 110437
    • SAL MED Pitesti
  • Targu-Mures, Romania, 540503
    • Cmi Dr Podoleanu Cristian
• Russian Federation
  • Ekaterinburg, Russian Federation, 620039
    • Ekaterinburg City Clinical Hospital #14
  • Kemerovo, Russian Federation, 650002
    • Federal State Budget Scientific Institution
  • Moscow, Russian Federation, 121309
    • Moscow City Clinical Hospital No.51
  • St Petersburg, Russian Federation, 197341
    • Federal State Budgetary Institution
• Sweden
  • Goteborg, Sweden, 413 45
    • Sahlgrenska Universitetsjukhuset
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital
  • Sheffield, United Kingdom, S10 2RX
    • Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital
• United States
  • Colorado
    • Littleton, Colorado, United States, 80120
      • South Denver Cardiology Associates PC
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Iowa
    • Iowa City, Iowa, United States, 52242-1081
      • University Of Iowa - Hospitals & Clinics
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny
  • Texas
    • McKinney, Texas, United States, 75069
      • North Dallas Research Associates
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Heart and Vascular Institute
  • Washington
    • Tacoma, Washington, United States, 98405
      • MultiCare Health System
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora Saint Lukes Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Signed and dated Informed Consent Form (ICF).
• Participant remained in the main study (SERENADE/AC-055G202, NCT03153111) for: a) 52 weeks after randomization if entered this Open-label (OL) extension study prior to protocol Version 4, b) At least 24 weeks after randomization if entering this OL extension study under protocol Version 4
• A woman of childbearing potential is eligible only if: (1) Negative pre-treatment serum pregnancy test; (2) Agreement to undertake monthly pregnancy tests from the enrollment visit up to at least 30 days after study treatment discontinuation; and (2) Agreement to use reliable contraception from at least 30 days prior to the enrollment visit up to at least 30 days after study treatment discontinuation.

Exclusion Criteria:

• Premature discontinuation of study treatment in the main study (SERENADE/AC-055G202, NCT03153111) due to an adverse event related to: (1) Edema or fluid retention; (2) Worsening of heart failure; (3) Liver aminotransferase elevation; and (4) Study treatment, based on investigators' discretion
• Liver aminotransferase elevations, at the enrollment visit, fulfilling the following criteria: (1) Alanine amino transferase (ALT) / aspartate aminotransferase (AST) greater than or equal to (>=) 8 * the upper limit of normal (ULN); (2) ALT/AST >= 3 * ULN and associated clinical symptoms of liver injury, for example: nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, myalgia, fever); and (3) ALT/AST >= 3 * ULN and associated increase in total bilirubin to >= 2 * ULN
• Treatment with the following forbidden medications within 1 month prior to the enrollment visit: (1) Treatments that may interfere with the assessment of efficacy (that is, endothelin receptor antagonists, prostanoids, phosphodiesterase-5 inhibitors, guanylate cyclase stimulators); (2) Strong cytochrome P-450 3A4 (CYP3A4) inducers such as rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, or St. John's wort; (3) Strong CYP3A4 inhibitors such as ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir or a moderate dual CYP3A4/CYP2C9 inhibitor (for example, fluconazole or amiodarone) or co-administration of a combination of moderate CYP3A4 (for example, ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitors (for example, miconazole, piperine), in the 1-month period prior to baseline. This will not necessarily apply to participants who are already well-managed on such an ongoing combination; and (4) any other investigational treatment
• Pregnant, planning to be become pregnant or lactating.
• Any known factor or disease that might interfere with treatment compliance, study conduct, or interpretation of the results, such as drug or alcohol dependence or psychiatric disease.
• Known hypersensitivity to macitentan or drugs of the same class, or any of the study drug excipients (for example, soy lecithin, lactose)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Open-label treatment period; oral administration of 10 mg macitentan once daily	Drug: macitentan 10 mg; macitentan 10 mg, film-coated tablet, oral use

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With All-cause Deaths up to 30 Days After Study Treatment Discontinuation	Number of participants with all-cause deaths up to 30 days after study treatment discontinuation were reported. All-cause deaths are defined as all anticipated and unanticipated deaths due to any cause.	Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
Number of Participants With All-cause Hospital Admissions up to 30 Days After Study Treatment Discontinuation	Number of participants with all-cause hospital admissions up to 30 days after study treatment discontinuation were reported.	Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) up to 30 Days After Study Treatment Discontinuation	An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is a suspected transmission of any infectious agent via a medicinal product, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above. Any AE and SAE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) within the analysis set was considered to be treatment-emergent.	Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
Number of Participants With TEAEs Leading to Premature Discontinuation of Study Treatment	An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Any AE occurring at or after the study treatment start up to 30 days after EOT within the analysis set was considered to be treatment-emergent.	Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 24	Change from baseline in systolic and diastolic arterial BP at Week 24 was reported.	Baseline and Week 24
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 52	Change from baseline in systolic and diastolic arterial BP at Week 52 was reported.	Baseline and Week 52
Change From Baseline in Pulse Rate at Week 24	Change from baseline in pulse rate at Week 24 was reported.	Baseline and Week 24
Change From Baseline in Pulse Rate at Week 52	Change from baseline in pulse rate at Week 52 was reported.	Baseline and Week 52
Change From Baseline in Body Weight at Week 24	Change from baseline in body weight at Week 24 was reported.	Baseline and Week 24
Change From Baseline in Body Weight at Week 52	Change from baseline in body weight at Week 52 was reported.	Baseline and Week 52
Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation	Number of participants with treatment-emergent MLAs (Hemoglobin [grams/Liter{L}], Hematocrit [L/L], Leukocytes [10^9cells/L], Lymphocytes [10^9cells/L], Alanine Aminotransferase [Units/L {U/L}], Aspartate Aminotransferase [U/L], Bilirubin [micromoles/L {mcmol/L}], Alkaline Phosphatase [U/L], Creatinine [mcmol/L], Urea Nitrogen [mmol/L], Urate [mcmol/L], Potassium [mmol/L], Sodium [mmol/L], Magnesium [mmol/L], Calcium [mmol/L] were reported. Abnormalities that occurred after study treatment start and up to 30 days after study treatment discontinuation, that were not present at baseline, were treatment-emergent. Here, > signifies greater than; < signifies less than; ULN signifies upper limit of normal; and L=Low, H=High, LL=low/low, HH=high/high, LLL=lower/worse than LL, HHH=higher/worse than HH.	Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
Change From Baseline in Hemoglobin at Week 24	Change from baseline in hemoglobin at Week 24 was reported.	Baseline and Week 24
Change From Baseline in Hemoglobin at Week 52	Change from baseline in hemoglobin at Week 52 was reported.	Baseline and Week 52
Change From Baseline in Leukocytes and Platelets at Week 24	Change from baseline in leukocytes and platelets at Week 24 was reported.	Baseline and Week 24
Change From Baseline in Leukocytes and Platelets at Week 52	Change from baseline in leukocytes and platelets at Week 52 was reported.	Baseline and Week 52
Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 24	Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 24 was reported.	Baseline and Week 24
Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 52	Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 52 was reported.	Baseline and Week 52
Change From Baseline in Bilirubin at Week 24	Change from baseline in bilirubin at Week 24 was reported.	Baseline and Week 24
Change From Baseline in Bilirubin at Week 52	Change from baseline in bilirubin at Week 52 was reported.	Baseline and Week 52
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24	Change from baseline in eGFR rate at Week 24 was reported.	Baseline and Week 24
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52	Change from baseline in eGFR rate at Week 52 was reported.	Baseline and Week 52

Collaborators and Investigators

• Sponsor: Actelion
• Collaborators: Chiltern International Ltd.; Medidata Solutions; Frontier Science & Technology Research Foundation, Inc.; Almac Clinical Technologies, LLC; Covance Central Laboratory Services, LP; WorldCare Clinical, LLC; AcitGraph
• Investigators: Study Director: William Byra, MD, Actelion

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2018
• Primary Completion (Actual): October 12, 2021
• Study Completion (Actual): October 12, 2021

Study Registration Dates

• First Submitted: October 19, 2018
• First Submitted That Met QC Criteria: October 19, 2018
• First Posted (Actual): October 22, 2018

Study Record Updates

• Last Update Posted (Actual): September 22, 2023
• Last Update Submitted That Met QC Criteria: September 13, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: heart failure with preserved ejection fraction; macitentan; pulmonary vascular disease
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Vascular Diseases; Molecular Mechanisms of Pharmacological Action; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Macitentan
• Other Study ID Numbers: AC-055G203; 2018-001603-37 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials\transparency. As noted on this site, requests for access to the study data can be submitted through Yale open Access (YODA) Project site at yoda.yale.edu

Drug and device information, study documents

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