An Upcoming Clinical Study to Measure the Safety and Impact of a Drug Called Macitentan in Teenage and Adult Fontan Patients.

Study Overview
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Brief Summary
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The aim of this open-label (OL) trial is to study the long-term use of macitentan for up to 2 years in Fontan-palliated adult and adolescent patients beyond the 52 weeks of treatment in the parent RUBATO double-blind (DB) study (AC-055H301, NCT03153137). This OL trial studies the long-term effect of macitentan in Fontan-palliated patients as it is not known if the effect of macitentan is sustained beyond 52 weeks (end of the parent RUBATO DB study). In addition, the trial also studies the long-term safety of macitentan as this is also unknown. Furthermore, the opportunity will be given to patients who were on placebo in the parent RUBATO DB study to receive macitentan 10 mg and benefit from a potentially active treatment.

Official Title
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Prospective, Multi-center, Single-arm, Open-label Long-term Study Assessing the Safety, Tolerability, and Effectiveness of Macitentan in Fontan-palliated Adult and Adolescent Subjects

Conditions
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Congenital Heart Disease With Fontan Circulation

Intervention / Treatment
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* Drug: macitentan 10 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent/assent from the subject and/or a legal representative prior to initiation of any study-mandated procedures. Subjects who have completed Week 52 of the parent AC-055H301/RUBATO DB study (NCT03153137) Women of childbearing potential must: have a negative serum pregnancy test prior to first intake of OL study drug, and, agree to perform monthly pregnancy tests up to the end of the safety follow up (S-FU) period, and, use reliable methods of contraception from enrollment up to at least 30 days after study treatment discontinuation. Exclusion Criteria: Clinical worsening leading to medical interventions including reoperation of Fontan circulation (Fontan take-down) during the enrollment period Systolic blood pressure < 90 mmHg (< 85 mmHg for subjects < 18 years old and < 150 cm of height) at rest Criteria related to macitentan use Any known factor or disease that may interfere with treatment compliance or full participation in the study

Ages Eligible for Study
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Minimum Age: 12 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: The study is designed as an open-label (OL), single-arm, multicenter long-term trial in which all adolescent (≥ 12 years) and adult male and female subjects who had previously completed in the parent RUBATO DB study (AC-055H301, NCT03153137) will enroll. The primary objective of the study is to assess the long-term safety and tolerability of macitentan. All efficacy endpoints including the ones listed below are considered as exploratory in nature.
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 Treatment-emergent Adverse Events (TEAEs) | 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 end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent. | Up to 133 weeks | 
| Number of Participants With Treatment-emergent Serious AEs (TESAEs) | 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 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 SAE occurring at or after the study treatment start up to 30 days after EOT (limits included) within the analysis set was considered to be TESAEs. | Up to 133 weeks | 
| Number of Participants With TEAEs Leading to Death | 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 (limits included) within the analysis set was considered to be treatment-emergent. | Up to 133 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 (limits included) within the analysis set was considered to be treatment-emergent. | Up to 133 weeks | 
| Number of Participants With Treatment-emergent Marked Laboratory Abnormalities up to 30 Days After Study Treatment Discontinuation | Number of participants with treatment-emergent marked laboratory abnormalities (Hemoglobin [gram/Liter {g/L}], Platelets [giga/L {10^9 cells/L}], Leukocytes [10^9 cells/L], Lymphocytes [10^9 cells/L], Neutrophils [10^9 cells/L], Prothrombin International Normalized Ratio [PINR;Ratio], Aspartate Aminotransferase [Units/L {U/L}], Bilirubin [micromoles/L {mcmol/L}], Alkaline Phosphatase [U/L], Glomerular Filtration Rate [milliliter/minute/1.73 meter square], Glucose [millimoles/L {mmol/L}], Potassium [mmol/L], Sodium [mmol/L], Triglycerides [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. Marked laboratory abnormalities reported for at least 1 participant were reported in this outcome measure. >=:greater than or equal to; >:greater than; <:less than; ULN: upper limit of normal; L:Low, H:High, LLL:lower/worse than LL, HHH:higher/worse than HH. | Up to 133 weeks | 
| Change From Baseline in Hemoglobin Over Time | Change from baseline in hemoglobin over time was reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Hematocrit Over Time | Change from baseline in hematocrit over time was reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Leukocytes, Neutrophils, Lymphocytes, and Platelets Over Time | Change from baseline in leukocytes, neutrophils, lymphocytes, and platelets over time were reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) Over Time | Change from baseline in systolic and diastolic arterial BP over time was reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Pulse Rate Over Time | Change from baseline in pulse rate over time was reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Peripheral Oxygen Saturation (SpO2) Over Time | Change from baseline in SpO2 over time was reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Body Weight Over Time | Change from baseline in body weight over time was reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP), and Gamma Glutamyl Transferase (GGT) Over Time | Change from baseline in ALT, AST, AP, and GGT over time were reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Bilirubin, Direct Bilirubin, and Creatinine Over Time | Change from baseline in bilirubin, direct bilirubin, and creatinine over time were reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Glomerular Filtration Rate (GFR) Over Time | Change from baseline in GFR over time was reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Prothrombin Time Over Time | Change from baseline in prothrombin time over time was reported in this outcome measure. | Baseline up to Week 130 | 
| Change From Baseline in Prothrombin International Normalized Ratio Over Time | Change from baseline in prothrombin international normalized ratio over time was reported in this outcome measure. | Baseline up to Week 130 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) | Change from baseline in peak VO2 was reported in this outcome measure. | Baseline, Week 52, and Week 104 | 
| Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) | Change from baseline in mean count per minute of daily PA-Ac was reported in this outcome measure. | Baseline, Week 26, Week 52, Week 78, and Week 104 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congenital Heart Failure, macitentan, Univentricular Heart, Cavopulmonary Anastomosis, Fontan circulation