Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects

Study Overview
=================
Brief Summary
-----------------
The primary objective is to assess the effect of macitentan 10 mg as compared to placebo on exercise capacity through cardiopulmonary exercise testing.

Official Title
-----------------
Prospective, Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Adult and Adolescent Subjects

Conditions
-----------------
Congenital Heart Disease

Intervention / Treatment
-----------------
* Drug: Macitentan 10 mg
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent/assent from the subject and/or a legal representative prior to initiation of any study-mandated procedures Fontan-palliated subjects with either intra-atrial lateral tunnel total cavopulmonary connection (LT-TCPC), or extra cardiac tunnel TCPC (EC-TCPC) surgery > 1 year before Screening. Either LT- or EC-TCPC can be primary or secondary to atrio-pulmonary connection New York Heart Association (NYHA) functional class (FC) II or III (assessed by the investigator using the Specific Activity Scale Women of childbearing potential must have a negative serum pregnancy test use reliable contraception Exclusion Criteria: Pattern of Fontan circulation severity Deterioration of the Fontan-palliated condition. Limitations to Cardiopulmonary exercise testing (CPET) Peak VO2 < 15 mL/kg/min. Any known factor or disease that may interfere with treatment compliance or full participation in the study

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Macitentan<br>Macitentan 10 mg per day; film-coated tablet; oral use | Drug: Macitentan 10 mg<br>* film-coated tablet; oral use<br>|
| Placebo Comparator: Placebo<br>film-coated tablet; oral use | Drug: Placebo<br>* film-coated tablet; oral use<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Peak Oxygen Uptake/Consumption (VO2) Up to Week 16 | Change from baseline in peak VO2 up to Week 16 was reported. | Baseline up to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Peak VO2 Up to Week 52 | Change from baseline in peak VO2 up to Week 52 was reported. | Baseline up to Week 52 | 
| Change From Baseline in Mean Count Per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac) Up to Week 16 | Change from baseline in mean count per minute of daily PA-Ac up to Week 16 was reported. The daily physical activity (counts per min) of the participant was assessed via accelerometer during daytime. The accelerometer was given to the participant at Visit 1, and data was collected for 9 consecutive daily daytime periods after Visit 1 (baseline) to Visit 4 (Week 16). | Baseline up to Week 16 | 
| Number of Participants With Treatment-emergent Serious Adverse Events (SAEs) | 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. | Up to 56 weeks | 
| Number of Participants With Treatment-emergent Adverse Events (AEs) | 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. | Up to 56 weeks | 
| Number of Participants With AEs Leading to Premature Discontinuation of Study Treatment | Number of participants with AEs leading to premature discontinuation of study treatment was reported. AEs leading to premature discontinuation of study treatment were those with action taken with study drug reported as 'permanently discontinued' by the investigator. | Up to 56 weeks | 
| Change From Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) | Change from baseline in systolic and diastolic arterial BP at Week 8, Week 16, Week 32 and Week 52 was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Pulse Rate | Change from baseline in pulse rate at Week 8, Week 16, Week 32 and Week 52 was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Oxygen Saturation (SpO2) | Change from baseline in SpO2 was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Body Weight | Change from baseline in body weight was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values | Number of participants with treatment-emergent markedly laboratory abnormal laboratory values were reported. Abnormal values for platelets (LL < 75); Lymphocytes (HH > 4.0); Neutrophils (LL < 1.5); Prothrombin International Normalized Ratio: HH (greater than and equal to [>=] 1.5 upper limit of normal [ULN]), Ratio: HH >= 2.5 ULN); Bilirubin (HH >= 2 ULN); Alkaline Phosphatase (HH > 2.5 ULN); Glomerular Filtration Rate (LL < 60); Glucose (HH > 8.9); Triglycerides (HH > 3.42). Here HH refers to values above the normal range, where H stands for high and LL refers to values below the normal range where L stands for low. | Up to 56 weeks | 
| Change From Baseline in Hemoglobin | Change from baseline in hemoglobin was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Hematocrit | Change from baseline in hematocrit was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Erythrocytes and Reticulocytes | Change from baseline in erythrocytes and reticulocytes at Week 8, Week 16, Week 32 and Week 52 was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Leucocytes, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils and Platelets | Change from baseline in leucocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets at Week 8, Week 16, Week 32 and Week 52 was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Prothrombin Time | Change from baseline in prothrombin time was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Prothrombin International Normalized Ratio | Change from baseline in prothrombin international normalized ratio was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Alkaline Phosphatase (AP) | Change from baseline in ALT, AST and AP were reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Bilirubin and Direct Bilirubin | Change from baseline in bilirubin and direct bilirubin was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Gamma Glutamyl Transferase | Change from baseline in gamma glutamyl transferase was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Creatinine | Change from baseline in creatinine was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Urea Nitrogen | Change from baseline in urea nitrogen was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Urate | Change from baseline in urate was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Glucose, Cholesterol, Triglycerides, Sodium, Potassium, Chloride and Calcium | Change from baseline in glucose, cholesterol, triglycerides, sodium, potassium, chloride and calcium was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Albumin and Protein | Change from baseline in albumin and protein was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Alpha Fetoprotein | Change from baseline in alpha fetoprotein was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 | 
| Change From Baseline in Cystatin C | Change from baseline in cystatin C was reported. | Baseline, Week 8, Week 16, Week 32 and Week 52 |