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

Phase 2

Terminated

Conditions: Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease

Interventions: Drug: macitentan 10 mg

Registration Number: NCT03714815

Lead Sponsor: Actelion

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 91

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open-label treatment period	macitentan 10 mg	oral administration of 10 mg macitentan once daily

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) up to 30 Days After Study Treatment Discontinuation	Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)	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.
Number of Participants With TEAEs Leading to Premature Discontinuation of Study Treatment	Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)	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.
Number of Participants With All-cause Deaths up to 30 Days After Study Treatment Discontinuation	Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)	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.
Number of Participants With All-cause Hospital Admissions up to 30 Days After Study Treatment Discontinuation	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 were reported.
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 24	Baseline and Week 24	Change from baseline in systolic and diastolic arterial BP at Week 24 was reported.
Change From Baseline in Pulse Rate at Week 24	Baseline and Week 24	Change from baseline in pulse rate at Week 24 was reported.
Change From Baseline in Pulse Rate at Week 52	Baseline and Week 52	Change from baseline in pulse rate at Week 52 was reported.
Change From Baseline in Body Weight at Week 24	Baseline and Week 24	Change from baseline in body weight at Week 24 was reported.
Change From Baseline in Body Weight at Week 52	Baseline and Week 52	Change from baseline in body weight at Week 52 was reported.
Number of Participants With Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation	Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)	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.
Change From Baseline in Hemoglobin at Week 24	Baseline and Week 24	Change from baseline in hemoglobin at Week 24 was reported.
Change From Baseline in Hemoglobin at Week 52	Baseline and Week 52	Change from baseline in hemoglobin at Week 52 was reported.
Change From Baseline in Leukocytes and Platelets at Week 24	Baseline and Week 24	Change from baseline in leukocytes and platelets at Week 24 was reported.
Change From Baseline in Leukocytes and Platelets at Week 52	Baseline and Week 52	Change from baseline in leukocytes and platelets at Week 52 was reported.
Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 24	Baseline and Week 24	Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 24 was reported.
Change From Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 52	Baseline and Week 52	Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 52 was reported.
Change From Baseline in Bilirubin at Week 24	Baseline and Week 24	Change from baseline in bilirubin at Week 24 was reported.
Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 52	Baseline and Week 52	Change from baseline in systolic and diastolic arterial BP at Week 52 was reported.
Change From Baseline in Bilirubin at Week 52	Baseline and Week 52	Change from baseline in bilirubin at Week 52 was reported.
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24	Baseline and Week 24	Change from baseline in eGFR rate at Week 24 was reported.
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52	Baseline and Week 52	Change from baseline in eGFR rate at Week 52 was reported.

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (44): Federal State Budgetary Institution
🇷🇺
St Petersburg, Russian Federation
Sahlgrenska Universitetsjukhuset
🇸🇪
Goteborg, Sweden
Royal Free Hospital
🇬🇧
London, United Kingdom
Kaplan Medical Center
🇮🇱
Rehovot, Israel
Krakowski Szpital Specjalityczny im Jana Pawla II Oddzial Kliniczny Chorob Serca i Naczyn
🇵🇱
Krakow, Poland
Wojewodzki Szpital Specjalistyczny im Stefana Kardynala Wyszynskiego SPZOZ
🇵🇱
Lublin, Poland
4 Wojskowy Szpital Kliniczny Z Poliklinika SP ZOZ
🇵🇱
Wroclaw, Poland
Cardiomed
🇷🇴
Craiova, Romania
SAL MED Pitesti
🇷🇴
Pitesti, Romania
Cmi Dr Podoleanu Cristian
🇷🇴
Targu-Mures, Romania
Ekaterinburg City Clinical Hospital #14
🇷🇺
Ekaterinburg, Russian Federation
Federal State Budget Scientific Institution
🇷🇺
Kemerovo, Russian Federation
Moscow City Clinical Hospital No.51
🇷🇺
Moscow, Russian Federation
Galilee Medical Center
🇮🇱
Nahariya, Israel
Rabin Medical Center Beilinson Campus
🇮🇱
Petah Tikva, Israel
Sheffield Teaching Hospitals NHS Foundation Trust Royal Hallamshire Hospital
🇬🇧
Sheffield, United Kingdom
South Denver Cardiology Associates PC
🇺🇸
Littleton, Colorado, United States
Northwestern University Feinberg School of Medicine
🇺🇸
Chicago, Illinois, United States
University Of Iowa - Hospitals & Clinics
🇺🇸
Iowa City, Iowa, United States
University of Maryland
🇺🇸
Baltimore, Maryland, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Washington University School Of Medicine
🇺🇸
Saint Louis, Missouri, United States
Allegheny
🇺🇸
Pittsburgh, Pennsylvania, United States
North Dallas Research Associates
🇺🇸
McKinney, Texas, United States
Inova Heart and Vascular Institute
🇺🇸
Falls Church, Virginia, United States
MultiCare Health System
🇺🇸
Tacoma, Washington, United States
Aurora Saint Lukes Medical Center
🇺🇸
Milwaukee, Wisconsin, United States
Instituto de Investigaciones Clinicas Mar del Plata
🇦🇷
Mar del Plata, Argentina
Medizinische Universitaet Wien
🇦🇹
Vienna, Austria
Maestri E Kormann Consultoria Médico- Científica Ltda
🇧🇷
Blumenau, Brazil
Instituto do Coracao de Marília
🇧🇷
Marilia, Brazil
Diagnostic Consulting Center I Sliven
🇧🇬
Sliven, Bulgaria
Medical Centre Synexus
🇧🇬
Sofia, Bulgaria
Bispebjerg Og Frederiksberg Hospital
🇩🇰
Copenhagen, Denmark
CHU de Grenoble Hopital Albert Michallon
🇫🇷
Grenoble Cedex 9, France
Hopital de Bicetre
🇫🇷
Le Kremlin Bicetre, France
CHU Rouen Hopital Charles Nicolle
🇫🇷
Rouen Cedex, France
Universitätsklinikum Carl Gustav Carus Medizinische Klinik und Poliklinik 1-Pneumologie
🇩🇪
Dresden, Germany
Universitaetsklinikum Giessen
🇩🇪
Giessen, Germany
Universitaetsklinikum Schleswig Holstein Campus Kiel
🇩🇪
Kiel, Germany
Semmelweis Egyetem Varosmajor Sziv es Ergyogyaszati Klinika
🇭🇺
Budapest, Hungary
Barzilai Medical Center
🇮🇱
Ashkelon, Israel
Hillel Yaffe Medical Center
🇮🇱
Hadera, Israel
Bnai Zion Medical Center
🇮🇱
Haifa, Israel