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

NCT03714815 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: AC-055G2032018-001603-37
• Study Type: interventional
• Target: 91
• Locations: 15 countries
• Sites: 44

Brief Summary

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.

Conditions

Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease

Keywords

pulmonary vascular disease; macitentan; heart failure with preserved ejection fraction

Outcome Measures

Primary Outcomes (21)

• 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

Study Arms (1)

Open-label treatment period

EXPERIMENTAL

oral administration of 10 mg macitentan once daily

Drug: macitentan 10 mg

Interventions

macitentan 10 mg DRUG

macitentan 10 mg, film-coated tablet, oral use

Open-label treatment period

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Actelion: lead
• Almac Clinical Technologies: collaborator
• Frontier Science & Technology Research Foundation, Inc.: collaborator
• Covance: collaborator
• Chiltern International Ltd.: collaborator
• WorldCare Clinical, LLC: collaborator
• AcitGraph: collaborator
• Medidata Solutions: collaborator

Study Sites (44)

South Denver Cardiology Associates PC

Littleton, Colorado, 80120, United States

Location

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

University Of Iowa - Hospitals & Clinics

Iowa City, Iowa, 52242-1081, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Washington University School Of Medicine

St Louis, Missouri, 63110, United States

Location

Allegheny

Pittsburgh, Pennsylvania, 15212, United States

Location

North Dallas Research Associates

McKinney, Texas, 75069, United States

Location

Inova Heart and Vascular Institute

Falls Church, Virginia, 22042, United States

Location

MultiCare Health System

Tacoma, Washington, 98405, United States

Location

Aurora Saint Lukes Medical Center

Milwaukee, Wisconsin, 53215, United States

Location

Instituto de Investigaciones Clinicas Mar del Plata

Mar del Plata, B7600FZN, Argentina

Location

Medizinische Universitaet Wien

Vienna, 1090, Austria

Location

Maestri E Kormann Consultoria Médico- Científica Ltda

Blumenau, 89020-430, Brazil

Location

Instituto do Coracao de Marília

Marília, 17515-000, Brazil

Location

Diagnostic Consulting Center I Sliven

Sliven, 8800, Bulgaria

Location

Medical Centre Synexus

Sofia, 1784, Bulgaria

Location

Bispebjerg Og Frederiksberg Hospital

Copenhagen, 2400, Denmark

Location

CHU de Grenoble Hopital Albert Michallon

Grenoble, France

Location

Hopital de Bicetre

Le Kremlin-Bicêtre, 94270, France

Location

CHU Rouen Hopital Charles Nicolle

Rouen, 76031, France

Location

Universitätsklinikum Carl Gustav Carus Medizinische Klinik und Poliklinik 1-Pneumologie

Dresden, 01307, Germany

Location

Universitaetsklinikum Giessen

Giessen, 35392, Germany

Location

Universitaetsklinikum Schleswig Holstein Campus Kiel

Kiel, 24105, Germany

Location

Semmelweis Egyetem Varosmajor Sziv es Ergyogyaszati Klinika

Budapest, 1122, Hungary

Location

Barzilai Medical Center

Ashkelon, Israel

Location

Hillel Yaffe Medical Center

Hadera, 3810101, Israel

Location

Bnai Zion Medical Center

Haifa, 3339419, Israel

Location

Galilee Medical Center

Nahariya, 2210001, Israel

Location

Rabin Medical Center Beilinson Campus

Petah Tikva, 4941492, Israel

Location

Kaplan Medical Center

Rehovot, 7610001, Israel

Location

Krakowski Szpital Specjalityczny im Jana Pawla II Oddzial Kliniczny Chorob Serca i Naczyn

Krakow, 31 202, Poland

Location

Wojewodzki Szpital Specjalistyczny im Stefana Kardynala Wyszynskiego SPZOZ

Lublin, 20 718, Poland

Location

4 Wojskowy Szpital Kliniczny Z Poliklinika SP ZOZ

Wroclaw, 50 513, Poland

Location

Cardiomed

Craiova, 200505, Romania

Location

SAL MED Pitesti

Piteşti, 110437, Romania

Location

Cmi Dr Podoleanu Cristian

Târgu Mureş, 540503, Romania

Location

Federal State Budget Scientific Institution

Kemerovo, 650002, Russia

Location

Moscow City Clinical Hospital No.51

Moscow, 121309, Russia

Location

Federal State Budgetary Institution

Saint Petersburg, 197341, Russia

Location

Ekaterinburg City Clinical Hospital #14

Yekaterinburg, 620039, Russia

Location

Sahlgrenska Universitetsjukhuset

Gothenburg, 413 45, Sweden

Location

Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital

Sheffield, S10 2RX, United Kingdom

Location

Related Publications (1)

• Shah SJ, Bonderman D, Borlaug BA, Cleland JGF, Lack G, Lu W, Voors AA, Zannad F, Gladwin MT. Macitentan for Heart Failure With Preserved or Mildly Reduced Ejection Fraction and Pulmonary Vascular Disease: Results of the SERENADE Randomized Clinical Trial and Open-Label Extension Study. Circ Heart Fail. 2025 Mar;18(3):e011381. doi: 10.1161/CIRCHEARTFAILURE.123.011381. Epub 2025 Mar 11.

  PMID: 40066571 DERIVED

MeSH Terms

Interventions

macitentan

Limitations and Caveats

Limited number of efficacy parameters were assessed in an exploratory manner. Study was stopped prematurely as main double-blind study did not meet the primary efficacy outcome measure.

Results Point of Contact

• Title: Clinical Scientific Leader
• Organization: Actelion Pharmaceuticals Ltd

ClinicalTrialDisclosure@its.jnj.com

844-434-4210

Study Officials

• William Byra, MD

  Actelion

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subjects who remained in main study (SERENADE/AC-055G202, NCT03153111) after randomization and who meet the eligibility criteria described will be eligible to enter this single-arm OL extension study. All enrolled subjects will receive macitentan 10 mg. For this OL extension study no primary efficacy endpoint has been defined and all efficacy endpoints are of exploratory nature. The ones listed below are considered safety endpoints.

Study Record Dates

• First Submitted: October 19, 2018
• First Posted: October 22, 2018
• Study Start: December 7, 2018
• Primary Completion: October 12, 2021
• Study Completion: October 12, 2021
• Last Updated: February 4, 2025
• Results First Posted: November 4, 2022

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will share

Locations

US (11); BR (2); AR (1); RU (4); DK (1); DE (3); GB (2); PL (3); FR (3); SE (1); HU (1); RO (3); IL (6); BU (2); AU (1)