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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease

Intervention / Treatment
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* Drug: macitentan 10 mg


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary vascular disease, macitentan, heart failure with preserved ejection fraction