| 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 an increase in blood pressure in the pulmonary arteries leading to shortness of breath, dizziness, fainting and other symptoms. |
|
| 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 |
1. To evaluate the effect of the macitentan/tadalafil fixed dose combination (M/T FDC) vs macitentan 10 mg alone on PVR at End of Double-blind Treatment (EDBT) in participants with symptomatic World Health Organization (WHO) Group 1 PAH who are PAH-specific treatment-naïve or are currently being treated with an ERA as monotherapy.
2. To evaluate the effect of the M/T FDC vs tadalafil 40 mg alone on PVR at EDBT in participants with symptomatic WHO Group 1 PAH who are PAH-specific treatment-naïve or are currently being treated with a PDE-5i as monotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of the M/T FDC compared to the respective
monotherapies on:
- Exercise capacity.
- PAH symptoms in participants' cardiopulmonary and cardiovascular
function
- WHO FC.
• To evaluate the safety and tolerability of the M/T FDC in the
participant population. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated ICF.
2. Male and female participants ≥ 18 years old and ≤ 75 years old.
3. Confirmed diagnosis of symptomatic PAH in WHO FC II or III.
4. Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary hypertension [Simonneau 2013]:
− Idiopathic.
− Heritable.
− Drug- or toxin-induced.
− Associated with one of the following:
o Connective tissue disease.
o HIV infection.
o Portal hypertension.
o Congenital heart disease with simple systemic-to-pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) with persistent pulmonary hypertension documented by a right heart catheterization (RHC) ≥ 1 year after surgical repair.
5. PAH diagnosis confirmed by hemodynamic evaluation (based on central reading) at rest, evaluated within 5 weeks prior to randomization:
− Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, AND
− Pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg, AND
− Pulmonary vascular resistance (PVR) ≥ 3 WU (i.e., ≥ 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 can be eligible if currently treated with PAH therapy for more than 3 months and PAH diagnosis confirmed by hemodynamic evaluation at least 3 months after introduction of their PAH therapy).
7. Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months prior to baseline RHC, within the following prespecified doses below or no history of PAH-specific treatment:
- Bosentan: 250 mg total daily dose
- Macitentan: 10 mg total daily dose
- Ambrisentan: 10 mg total daily dose
- Sildenafil: 60–120 mg total daily dose
- Tadalafil: 40 mg total daily dose
- Vardenafil: 10 mg total daily dose
8. Participant able to perform the 6MWT with a minimum distance of 100 m and maximum distance of 450 m at Screening.
9. A woman of childbearing potential is eligible only if the following applies:
- Negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization.
- Agreement to undertake monthly urine pregnancy tests during the study and up to at least 30 days after study treatment discontinuation.
- Agreement to follow the contraception scheme from Screening up to at least 30 days after study treatment discontinuation. |
|
| E.4 | Principal exclusion criteria |
PAH treatments:
1. Treatment with a soluble guanylate cyclase stimulator, L-arginine, any form of prostanoids or prostacyclin-receptor agonists (including oral, inhaled, or infused routes) in the 3-month period prior to start of treatment.
2. Treatment with combination therapy of ERA and PDE-5i in the 3-month period prior to start of treatment or history of intolerance to ERA and PDE-5i combination therapy.
3. Hypersensitivity to any of the study treatments or any excipient of their formulations.
Other therapies:
4. Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer (e.g., rifabutin, rifampin, rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) in the 1-month period prior to start of treatment.
5. Treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, elithromycin, nefazodone, ritonavir, or saquinavir) or a moderate dual CYP3A4/CYP2C9 inhibitor (e.g., fluconazole, amiodarone) or coadministration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors in the 1-month period prior to start of treatment.
6. Treatment with doxazosin.
7. Treatment with any form of organic nitrate, either regularly or intermittently
8. Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start of treatment.
9. Treatment with another investigational drug in the 3-month period prior to start of treatment.
Medical history/current medical conditions:
10. Body mass index (BMI) > 40 kg/m2 at Screening.
11. Known presence of three or more of the following risk factors for heart failure with preserved ejection fraction at Screening:
- BMI > 30 kg/m2.
− Diabetes mellitus of any type.
− Essential hypertension (even if well controlled).
− Coronary artery disease, i.e., any of the following:
o History of stable angina, or
o Known more than 50% stenosis in a coronary artery, or
o History of myocardial infarction, or
o History of or planned coronary artery bypass grafting and/or coronary artery stenting.
12. Known presence of moderate or severe obstructive lung disease (forced expiratory volume in 1 second [FEV1] / forced vital capacity [FVC] < 70%; and FEV1 < 65% of predicted after bronchodilator administration) any time prior to Screening.
13. Known presence of moderate or severe restrictive lung disease (total lung capacity or FVC < 60% of normal predicted value) any time prior to Screening.
14. Clinically significant aortic or mitral valve disease; pericardial constriction; restrictive or congestive leftsided cardiomyopathy; life-threatening cardiac arrhythmias; significant left ventricular dysfunction; or left ventricular outflow obstruction.
15. Known permanent atrial fibrillation.
16. Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism).
17. Documented pulmonary veno-occlusive disease.
Criteria linked to macitentan/tadalafil use:
18. Hemoglobin < 100 g/L (<10 g/dL) at Screening.
19. Known severe hepatic impairment defined as Model for End-Stage Liver Disease (MELD) score ≥ 19.
20. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 × upper limit of normal (ULN) at Screening.
21. Severe renal impairment (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation [Levey 2009] calculated creatinine clearance < 30 mL/min) at Screening.
22. Systemic hypotension (systolic blood pressure [SBP] < 90 or diastolic blood pressure [DBP] < 50 mmHg) at Screening or Randomization.
23. Systemic hypertension (SBP > 160 or DBP > 100 mmHg) at Screening.
24. Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26 weeks prior to Screening.
25. Known bleeding disorder.
26. Loss of vision in one or both eyes because of nonarteritic anterior ischemic optic neuropathy, regardless of whether or not this episode was in connection with previous PDE-5i treatment.
27. Hereditary degenerative retinal disorders, including retinitis pigmentosa.
28. History of priapism, conditions that predispose to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie’s disease).
General restrictions:
29. Difficulty swallowing large pills/tablets that would interfere with the ability to comply with study treatment regimen.
30. Any planned surgical intervention (including organ transplant) during the double-blind treatment period, except minor interventions.
31. Exercise training program for cardiopulmonary rehabilitation in the 12-week period prior to Start of treatment, or planned to be started during the double-blind period of the study.
32. Pregnant, planning to become pregnant or lactating. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Change in PVR expressed as the ratio of the geometric means of end of double blind treatment (EDBT) to baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| end of double blind treatment (EDBT) |
|
| E.5.2 | Secondary end point(s) |
• Change from baseline to EDBT in 6-minute walk distance.
• Change from baseline to Week 16 in PAH-SYMPACT™:
- Symptoms and Impact™ (PAH-SYMPACT™) in Cardiopulmonary
symptom domain score
- Change from baseline to Week 16 in PAH-SYMPACT™ in
Cardiovascular symptom domain score
• Proportion of participants with absence of worsening in WHO FC from baseline to EDBT. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| end of double blind treatment (EDBT) |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| 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 |
| Malaysia |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| Japan |
| Mexico |
| Russian Federation |
| South Africa |
| Turkey |
| United States |
| Bulgaria |
| Czechia |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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