Fontan-palliated Adult and Adolescent Subjects

Primary objective To assess the effect of macitentan on exercise capacity (measured by peak VO2) in comparison with placebo in Fontan-palliated subjects. Secondary objectives • To assess the effect of macitentan on daily Physical Activity measured by Accelerometer (PA-Ac). • To evaluate the safety and tolerability of macitentan. Other objectives • To assess the efficacy of macitentan on endpoints related to exercise capacity. • To assess the effect of macitentan on NT-proBNP. • To assess the effect of macitentan on clinical worsening. • To assess the effect of macitentan on Quality of life (QoL). • To assess the effect of macitentan on pharmacoeconomic endpoints. • To assess the plasma concentration of macitentan and its metabolite at trough.

Macitentan

Macitentan

FILM-COATED TABLETS

10 mg

Primary Outcome Measures :
Change in peak VO2 (oxygen uptake) [ Time Frame: 16 weeks, i.e. from Baseline (Randomization/Visit 2) to Week 16 (Visit 4) ]
Change in peak VO2 (oxygen uptake)


Secondary Outcome Measures :
Change in peak VO2 [ Time Frame: 52 weeks, i.e. from Baseline (Visit 2) over 52 weeks ]
Change in peak VO2

Physical activity measured by accelerometer [ Time Frame: 16 weeks, i.e. from Baseline (Visit 2) to Week 16 (Visit 4) ]
Change in mean count per minute of daily physical activity measured by accelerometer

Treatment-emergent AEs and SAEs [ Time Frame: at least 52 weeks, i.e. up to 30 days after study treatment discontinuation ]
Treatment-emergent AEs and SAEs

Trough (pre dose) plasma concentrations [ Time Frame: at Week 8 (Visit 3) and Week 16 (Visit 4): 2 days OR at EOT in the case of premature study drug discontinuation: 1 day ]
Trough (pre dose) plasma concentrations

1. Written informed consent/assent from the subject and/or a legal representative prior
to initiation of any study-mandated procedures.
2. Male or female ≥ 12 years old.
3. Fontan-palliated subjects with either LT-TCPC, or EC-TCPC surgery > 1 year before
Screening. LT-TCPC, or EC-TCPC surgery can be primary or secondary to
atrio-pulmonary connection.
4. NYHA FC II or III (assessed by the investigator using the Specific Activity Scale
[Appendix 4]).
5. Ability to understand and comply with the instructions, and ability to physically
perform the CPET.
6. Women of childbearing potential must:
6.1. Have a negative serum pregnancy test at the Screening visit and a negative urine
pregnancy test at the Randomization visit (Visit 2), and,
6.2. Agree to perform monthly pregnancy tests up to the end of the S-FU period, and,
6.3. Agree to use reliable contraception [Section 4.5.2] from at least 30 days prior to
Visit 2 and up to at least 30 days after study drug discontinuation.

1. Pattern of Fontan circulation severity. Any of the following:
1.1. Known severely reduced single ventricle ejection fraction (< 30%)
1.2. Known Fontan circulation stenosis, affected area > 50% of the diameter
1.3. Known valvular defects (severe atrioventricular [AV] valve regurgitation, outflow
obstruction)
1.4. Known pulmonary-venous pathway obstruction
1.5. Peripheral oxygen saturation (SpO2) of < 88% at rest at Screening
2. Deterioration of the Fontan-palliated condition. Any of the following events within
3 months prior to Screening:
2.1. Candidate on the active list for heart transplantation
2.2. Clinical worsening leading to medical interventions including reoperation of
Fontan circulation (e.g., mechanical circulatory support, Fontan take-down,
Fontan revision/conversion, AV valve repair/replacement).
2.3. Unscheduled hospitalization due to deterioration of the Fontan-palliated
condition2
2.4. Signs and symptoms of HF3
requiring change in diuretic therapy
2.5. Ventricular tachyarrhythmia or supraventricular tachyarrhythmia4
2.6. Peritoneal, pleural, mediastinal, or pericardial effusions
2.7. Thrombotic or hemorrhagic complications (including thromboembolism and
hemoptysis)
2.8. Protein losing enteropathy (PLE) (serum albumin < 30 g/L and total
protein < 50 g/L)
2.9. Plastic bronchitis/chyloptysis
2.10.Signs and symptoms requiring the addition of a new class of cardiovascular
medication (e.g., nitrates, alpha-blockers, or ERAs)
3. Limitations to CPET:
3.1. History of syncope during exercise
3.2. Symptomatic coronary artery disease at Screening
3.3. Respiratory limitation with a breathing reserve of < 10%
3.4. Iron deficiency defined as ferritin < 10 µg/L at Screening
3.5. Iron supplementation, regardless of route of administration, unless already present
at stable dose for more than 3 months prior to Screening
3.6. Body mass index (BMI)-for-age reference (z-scored) equivalent to
BMI > 35 kg/m2 (for adults) at Screening
3.7. Exercise training program for cardiopulmonary rehabilitation in the 3-month
period prior to Screening
3.8. Myocardial infarction < 6 months before Screening
3.9. Pacemaker at Screening
4. Peak VO2 < 15 mL/kg/min at Baseline.
5. Systolic BP < 90 mmHg (< 85 mmHg for subjects < 18 years old and < 150 cm of
height) at rest or during CPET at Screening or at Baseline.
6. Criteria related to macitentan use:
6.1. Hemoglobin < 75% of the lower limit of normal assessed by central laboratory at
Screening
6.2. Known or suspected pulmonary veno-occlusive disease
6.3. Known and documented severe hepatic impairment defined as Child-Pugh
Score C, based on measurement of total bilirubin, serum albumin, international
normalized ratio or prothrombin time (except for patients under non-Vitamin K
antagonists) and based also on presence/absence and severity of ascites and
hepatic encephalopathy
6.4. Serum AST and/or ALT > 3 × upper limit of normal range assessed by central
laboratory at Screening
6.5. Severe renal impairment (estimated creatinine clearance < 30 mL/min/1.73m2
)
assessed by central laboratory at Screening
6.6. Pregnancy, breastfeeding, or intention to become pregnant during the study, or
women of childbearing potential not using a reliable method of contraception
6.7. Hypersensitivity to any active substance or excipient of any of the study drugs
6.8. Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer such as
carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital,
phenytoin, and St. John’s wort, within 1 month prior to Randomization (Visit 2)
6.9. Treatment with a strong CYP3A4 inhibitor such as ketoconazole, itraconazole,
voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and
saquinavir, within 1 month prior to Randomization (Visit 2)
7. General exclusion criteria:
7.1. Any factor or condition likely to affect protocol compliance of the subject, as
judged by the investigator
7.2. Treatment with another investigational therapy in the 3-month period prior to
Screening
7.3. Treatment with nitrates, alpha-blockers, or ERAs in the 3-month period prior to
Screening
7.4. Introduction or change of dose of PH-specific drugs (other than ERAs) in the
3-month period prior to Screening
7.5. Known drug or substance (e.g., alcohol) abuse, unstable psychiatric illness, or any
other condition that, in the opinion of the investigator, may interfere with
participation in the study
7.6. Any planned surgical intervention (e.g., organ transplant) during the study period,
except minor interventions (e.g., tooth extraction)
8. Any known factor or disease that may interfere with treatment compliance or full
participation in the study (e.g., chemotherapy treatment for cancer) or illness with an
anticipated life expectancy of less than 12 months.