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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Actelion Pharmaceuticals Ltd.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

30 Jun 2020 → ongoing

Decision date (initial)

2024-09-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-515669-32-00

EudraCT number

2019-002533-11

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Safety

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.

Conditions and MedDRA coding

Pulmonary arterial hypertension

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

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 systemicto 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/toxininduced 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 legallyacceptable 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 (β-human chorionic gonadotropin [β-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 highly effective method while receiving study intervention and until 30 days after last dose - the end of relevant systemic exposure. Examples of highly effective methods of contraception are located in Appendix 6. (Contraceptive and Barrier Guidance and Collection )
12. Willing and able to adhere to the lifestyle restrictions specified in this protocol.
13. A Belgium-specific inclusion criterion is detailed in Section 10.19 (see Appendix 19: Country/Territory-Specific Requirements).

Exclusion criteria 15

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Permanent atrial fibrillation or atrial flutter, in the opinion of the investigator.
9. Known or suspected pulmonary veno-occlusive disease (PVOD).
10. Known moderate to severe hepatic impairment, defined as Child- Pugh Class B or C (see Appendix 5), based on records that confirm documented medical history.
11. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)> 1.5 X upper limit of normal (ULN) at Screening.
12. Hemoglobin < 100 g/L (< 10 g/dL) at Screening.
13. Severe renal impairment as defined with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 (Chronic Kidney Disease Epidemiology Collaboration [CKD EPI] 2009 equation) at screening
14. Systemic hypotension (systolic blood pressure [SBP] < 90 or diastolic blood pressure [DBP] < 50 mm Hg) at Screening.
15. For selected sites taking part to the cardiac MRI sub-study only: participants must not be considered for this sub-study in case of MRIincompatible permanent cardiac pacemaker, automatic internal cardioverter, metallic implant (eg, defibrillator, neurostimulator, hearing aid, permanent use of infusion device), multiple premature ventricular or atrial contractions, or any other condition that may confound cardiac MRI assessment or for which, in the opinion of the investigator, participation would not be in the best interests of the participant (eg, compromise well-being).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Actelion Pharmaceuticals Ltd.

Sponsor organisation

Actelion Pharmaceuticals Ltd.

Address

Gewerbestrasse 16

City

Allschwil

Postcode

4123

Country

Switzerland

Scientific contact point

Organisation

Actelion Pharmaceuticals Ltd.

Contact name

CTIS Point of Contact

Public contact point

Organisation

Actelion Pharmaceuticals Ltd.

Contact name

CTIS Point of Contact

Third parties 9

Locations

16 EU/EEA countries · 44 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 165 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications