A Phase 3 study to compare long-term efficacy and safety of macitentan 75 mg versus 10 mg in Pulmonary Arterial Hypertension.

• Register: EUCTR
• Last refreshed on: 3 February 2025
• Main ID: EUCTR2019-002533-11-NL
• Date of registration: 29/04/2020
• Prospective Registration: Yes
• Primary sponsor: ACTELION Pharmacteuticals Ltd.
• Public title: A Phase 3 study to compare long-term efficacy and safety of macitentan 75 mg versus 10 mg in Pulmonary Arterial Hypertension.
• Scientific title: A Phase 3, Prospective, Multicenter, Double-blind, Double-dummy, Randomized, Active-controlled, Parallel-group, Group-sequential, Adaptive, Event-driven Study to Compare Efficacy, Safety, and Tolerability of Macitentan 75 mg Versus Macitentan 10 mg in Patients with Pulmonary Arterial Hypertension, Followed by an Open-label Treatment Period With Macitentan 75 mg. - UNISUS
• Date of first enrolment: 29/09/2020
• Target sample size: 900
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-002533-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: single arm after the Double Blind period If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belarus, Belgium, Bulgaria, Canada, China, Colombia, Czech Republic, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Russian Federation, Serbia, Singapore, Slovakia, Spain, Sweden, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States, Viet Nam

Contacts

• Name: Clinical Registry group
• Affiliation: Janssen-Cilag International NV

• Name: Clinical Registry group
• Affiliation: Janssen-Cilag International NV

Key inclusion & exclusion criteria

Inclusion criteria:
1. Target population: = 18 (or the legal age of consent in the jurisdiction in which the study is taking place) years of age.
2. Target population: Symptomatic PAH in WHO FC II, III, or IV.
3. Must sign an ICF (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
4. Target population: PAH subtype falling in one of the below classifications:
- Idiopathic
- Heritable
- Drug- or toxin-induced
- Related to:
*Connective tissue disease,
*HIV infection,
*Portal hypertension
*Congenital heart disease with
o small/coincidental cardiac defect with systemic-to-pulmonary shunt (eg, atrial septal defect, ventricular septal defect, patent ductus arteriosus, atrioventricular septal defect) which does not account for the elevated PVR or
o persistent PAH documented by an RHC = 1 year after simple systemic-to pulmonary shunt repair.
5. PAH diagnosis confirmed by hemodynamic evaluation at rest at any time prior to Screening:
- Mean pulmonary artery pressure (mPAP) > 20 mm Hg, AND
- Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) = 15 mm Hg, AND
- PVR = 3 Wood Units (ie, = 240 dyn·sec·cm-5).
6. Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH.
Patients for whom no vasoreactivity test was performed at diagnosis and currently treated with PAH therapy for more than 3 months, must have a confirmatory PAH diagnosis documented by hemodynamic evaluation at least 3 months after introduction of their PAH therapy.
7. Able to perform the 6MWT with a minimum distance of 50 m and maximum distance of 440 m at Screening. Patients able to walk more
than 440 m at screening are eligible if they are in WHO FC III or IV and
NT-proBNP level is = 300 ng/L at screening, based on central laboratory
results.
8. Patients already receiving PAH therapies (mono or combination therapies) must be on a stable regimen b for at least 3 months prior to screening visit and planned to be:
- If on ERA therapy: discontinued at randomization or start of run-in (ie, last dose of ERA taken the day before initiating study intervention),
- If on PAH therapy other than ERA: maintained on top of the study intervention.
9. Must sign a separate informed consent form (or their legally-acceptable representative must sign) if he or she agrees to provide optional samples for biomarker research (where local regulations permit). Refusal to give consent for the optional biomarker research samples does not exclude a participant from participation in the study.
10. A female participant of childbearing potential must have a negative highly sensitive serum (ß-human chorionic gonadotropin [ß-hCG]) test at Screening and a negative urine pregnancy test prior to receiving their first dose of study intervention (i.e. either at beginning of the run-in period or prior to randomization [see Section 4.1]).
11. A female participant must be (as defined in Appendix 6
(Contraceptive and Barrier Guidance and Collection )
a) Not of childbearing potential,
b) Of childbearing potential and
- Practicing a highly effective, preferably user-independent method of contraception (failure rate of < 1% per year when used consistently and correctly) and agrees to remain on a high
Exclusion criteria:
1. Does meet any of the following run-in failure criteria (applies only to participants who are required to have a run-in period):
- Study intervention compliance < 80%,
- Laboratory results showing a decrease in hemoglobin by > 50 g/L from Screening or hemoglobin < 100 g/L or need for transfusion not explained by other confounding factors (if central laboratory results are not available at time of randomization local laboratory results will be used to confirm participants eligibility),
- Significant fluid retention as evidenced by one of the following:
*Administration of iv diuretics due to fluid retention,
*Addition of high potency thiazide diuretic (metolazone, indapamide), = 100% increase in loop diuretic to a total oral dose = 120 mg of furosemide equivalents/day,
*Increase in body weight by = 5% or = 5 kg from the value at the start of the run-in period.
- The investigator considers that for safety reasons or tolerability reasons (eg, AE) it is in the best interests of the participant to discontinue the study.
Subjects who are run-in failures per the criteria described above will be considered screen failures (see Section 5.4).
2. Treatment with a strong CYP3A4 inducer (eg, rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) within 1 month prior to randomization or start of run-in, if applicable.
3. Treatment with a strong CYP3A4 inhibitor or a moderate dual CYP3A4/CYP2C9 inhibitor, or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period prior to randomization, or start of run-in, if applicable. External use (cream, shampoo, etc) per approved label is permitted.
4. For participants involved in the cardiac remodeling and/or hemodynamic substudies only: Diuretic treatment initiated or dose changed within 1 week prior to the MRI or RHC assessment.
5. Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening, based on records that confirm documented medical history:
- Body mass index (BMI) > 30 kg/m2,
- Diabetes mellitus of any type,
- Essential hypertension (even if well controlled),
- Coronary artery disease, ie, any of the following:
*History of stable angina, or
*Known more than 50% stenosis in a coronary artery, or
*History of myocardial infarction, or
*History of or planned coronary artery bypass grafting and/or coronary artery stenting.
6. Presence of moderate or severe obstructive lung disease (forced expiratory volume in 1 second [FEV1] / forced vital capacity [FVC] < 70%; and FEV1 < 60% of predicted after bronchodilator administration) in participants with a known or suspected history of significant lung disease, as documented by a spirometry test performed within 1 year prior to Screening.
7. Presence of moderate or severe restrictive lung disease (eg, total lung capacity [TLC] or FVC < 60% of normal predicted value) in participants with a known or suspected history of significant lung disease, as documented by a spirometry test performed within 1 year prior to Screening.
8. Significant unrepaired structural left heart valvular disease (ie, moderate or severe aortic or mitral stenosis or regurgitation); pericardial constriction; restrictive or congestive left-sided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction.
9. Permanent atrial fibrillation or a

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Pulmonary arterial hypertension
MedDRA version: 21.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Intervention(s)

Trade Name: Opsumit®
Product Name: macitentan tablets
Product Code: JNJ-67896062 / ACT-064992
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: MACITENTAN
CAS Number: 441798-33-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: macitentan tablets
Product Code: JNJ-67896062 / ACT-064992
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: MACITENTAN
CAS Number: 441798-33-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 75-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: macitentan tablets
Product Code: JNJ-67896062 / ACT-064992
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: MACITENTAN
CAS Number: 441798-33-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 37.5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: To demonstrate superiority of macitentan 75 mg in prolonging the time to the first CEC-adjudicated morbidity or mortality (M/M) event in participants with symptomatic pulmonary arterial hypertension (PAH) compared to macitentan 10 mg.

Timepoint(s) of evaluation of this end point: At each study visits, monthly and at any time in case of event occurrence, until 217 M/M events are reached

Primary end point(s): Time to first CEC-adjudicated M/M event on-treatment (ie, up to 7 days after the last dose of double-blind (DB) study intervention), defined as time from randomization to the first of the following events:
- All-cause death, including deaths caused by an on-treatment AE, that occur within 4 weeks of study DB treatment discontinuation
- Non-planned PAH-related hospitalization (including for worsening of PAH, atrial septostomy, lung transplantation with or without heart transplantation, or initiation of parenteral prostacyclins)
- PAH-related disease progression, defined as (both criteria must be satisfied):
o Deterioration by at least 15% in exercise capacity, as measured by the 6-minute walk distance (6MWD), from baseline, confirmed by a second 6MWD test performed on a different day within 2 weeks of the initial test
o Initiation of additional PAH therapy or Worsening of WHO FC

Secondary Objective: - To demonstrate that macitentan 75 mg improves exercise capacity compared to macitentan 10 mg
- To demonstrate that macitentan 75 mg prolongs the time to death or hospitalization due to PAH (adjudicated by an independent CEC) compared to macitentan 10 mg
- To assess the effect of macitentan 75 mg compared to macitentan 10 mg on PAH symptoms on participants' life
- To assess the effect on prolongation of the CEC-adjudicated time to death of macitentan 75 mg compared to macitentan 10 mg

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Screening, Day 1, Month 3, and all scheduled visits thereafter until EDBT or anytime in case of event, with the exception of PAH-SYMPACT

Secondary end point(s): - Change from baseline to Week 24 in 6MWD
- Time to first occurrence of either death due to PAH or hospitalization for PAH, CEC adjudicated event on-treatment (ie, up to 7 days after the last dose of DB study intervention), as defined hereafter:
- Death due to PAH, including deaths caused by on-treatment AE that occur within 4 weeks of study DB treatment discontinuation OR
- Non-planned PAH-related hospitalization
- Change from baseline to Week 24 in PAH-SYMPACT:
- Cardiopulmonary symptom domain score
- Cardiovascular symptom domain score
- Time to death occurring between randomization and end of double-blind treatment (EDBT) period as defined hereafter:
- All-cause death, including all deaths occurring during the DB period regardless of potential discontinuation of study intervention or initiation or change in PAH medication.

Secondary ID(s)

2019-002533-11-DE

AC-055-315

Source(s) of Monetary Support

Actelion Pharmaceuticals Ltd

Ethics review

Status: Approved
Approval date: 29/09/2020
Contact: