| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary arterial hypertension |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary Arterial Hypertension is a condition in which the pressure in the blood vessels going to the lungs (the pulmonary arteries) is higher than normal |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064911 |
| E.1.2 | Term | Pulmonary arterial hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
- 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 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- One "PK/PD sub-study" (AC-055-315 Protocol):
To evaluate the pharmacokinetics (PK) of macitentan and its metabolite aprocitentan and the Pharmacodynamic (PD) profile of endothelin-1 (ET-1) levels in response to macitentan treatment in patients with PAH (subset of participants)
- One "cardiac remodeling sub-study" (AC-055-315 Protocol):
To evaluate the effect of macitentan 75 mg on right ventricular properties compared to macitentan 10 mg (subset of participants)
- One "hemodynamic sub-study" (AC-055-315 Protocol):
To evaluate effect of macitentan 75 mg on hemodynamic measures compared to macitentan 10 mg (subset of participants)
- One "Male Reproductive System Safety Sub-study" (AC-055-315 Protocol):
To provide additional safety data of chronic treatment with macitentan 75 mg on testicular function in patients with PAH |
|
| E.3 | Principal 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 (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). |
|
| E.4 | Principal 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 atrial flutter, in the opinion of the investigator.
10. Known or suspected pulmonary veno-occlusive disease (PVOD).
11. 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.
12. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)> 1.5 X upper limit of normal (ULN) at Screening.
13. Hemoglobin < 100 g/L (< 10 g/dL) at Screening.
14. 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
15. Systemic hypotension (systolic blood pressure [SBP] < 90 or diastolic blood pressure [DBP] < 50 mm Hg) at Screening.
16. For selected sites taking part to the cardiac MRI sub-study only: participants must not be considered for this sub-study in case of MRI-incompatible 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). |
|
| E.5 End points |
| E.5.1 | 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 |
|
| E.5.1.1 | 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 |
|
| E.5.2 | 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. |
|
| E.5.2.1 | 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 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| single arm after the Double Blind period |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Canada |
| China |
| Colombia |
| Israel |
| Japan |
| Malaysia |
| Mexico |
| Singapore |
| Thailand |
| United States |
| Viet Nam |
| Belarus |
| Russian Federation |
| Turkey |
| Ukraine |
| Serbia |
| Austria |
| Belgium |
| Bulgaria |
| Czechia |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Slovakia |
| Spain |
| Sweden |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS or last subject last telephone call |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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