| 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 ACT-132577 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) |
|
| E.3 | Principal inclusion criteria |
1. Restricted population: ≥18 (or the legal age of consent in the jurisdiction in which the study is taking place) and ≤ 75 years of age.
Target population: ≥ 18 (or the legal age of consent in the jurisdiction in which the study is taking place) years of age.
2. Restricted population: Symptomatic PAH in WHO FC II or III
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. Restricted population: PAH subtype falling in one of the below classifications:
- Idiopathic
- Heritable
- Drug- or toxin-induced
- Related to:
*Connective tissue disease,
* HIV infection,
* Congenital heart disease with simple systemic-to-pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) with persistent PH documented by an RHC ≥ 1 year after surgical repair.
Target populationa: 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 simple systemic-to-pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) with persistent PH documented by an RHC ≥ 1 year after surgical repair.
5. PAH diagnosis confirmed by hemodynamic evaluation at rest at any time prior to Screening:
- Mean pulmonary artery pressure (mPAP) > 20 mmHg, AND
- Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg, 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.
8. Patients already receiving PAH therapies (mono or combination therapies) should be on a stable regimen 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 woman 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 woman must be (as defined in Appendix 6)
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.
12. Willing and able to adhere to the lifestyle restrictions specified in this protocol. |
|
| E.4 | Principal exclusion criteria |
1. Restricted population only: Subjects not yet exposed to any PAH treatment at Screening.
2. Restricted population only: Treatment with prostanoids (including oral, inhaled, or infused routes) at Screening. Prostacyclin receptor agonists are allowed, if on stable dose for at least 3 months.
3. 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%,
- Central laboratory results showing a decrease in hemoglobin by > 20 g/L from Screening or hemoglobin < 100 g/L or need for transfusion not explained by other confounding factors,
- 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).
4. Treatment with a strong CYP3A4 inducer (eg, rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) within 1 month prior to Baseline.
5. 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 baseline.
6. Treatment with a soluble guanylate cyclase stimulator within 1 month prior to Baseline, unless results of Drug-Drug Interaction (DDI) study allow its concomitant use with macitentan 75 mg during the course of the study, as communicated by the sponsor.
7. 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.
8. 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.
9. Known 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) as documented by a spirometry test performed within 1 year prior to Screening.
10. Known presence of moderate or severe restrictive lung disease (total lung capacity [TLC] or FVC < 60% of normal predicted value) as
documented by a spirometry test performed within 1 year prior to Screening.
11. Significant unrepaired structural valvular heart 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.
12. Permanent atrial fibrillation or atrial flutter, in the opinion of the investigator.
13. Documented pulmonary veno-occlusive disease (PVOD).
14. 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.
15. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)> 1.5 X upper limit of normal (ULN) at Screening.
16. Hemoglobin < 100 g/L (< 10 g/dL) at Screening.
17. 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
18. Systemic hypotension (systolic blood pressure [SBP] < 90 or diastolic blood pressure [DBP] < 50 mmHg) at Screening.
19. For selected sites taking part to the cardiac MRI sub-study only: participants should 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 treatment), defined as time from baseline 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 two 6MWD tests performed on separate days within 2 weeks of each other
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 treatment), 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 baseline and end of double-blind treatment (EDBT) period as defined hereafter:
- All-cause death, including deaths caused by AE during the DB treatment period that occur within 4 weeks of study DB treatment discontinuation |
|
| 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 | 4 |
| 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 |
| Austria |
| Belarus |
| Belgium |
| Brazil |
| Canada |
| China |
| Colombia |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Singapore |
| Slovakia |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
| Vietnam |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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