A clinical study to compare the efficacy and safety of macitentan and tadalafil monotherapies with the corresponding fixed dose combination in subjects with pulmonary arterial hypertension (PAH).

• Register: EUCTR
• Last refreshed on: 8 July 2024
• Main ID: EUCTR2014-004786-25-PL
• Date of registration: 28/05/2019
• Prospective Registration: Yes
• Primary sponsor: Actelion Pharmaceuticals Ltd.
• Public title: A clinical study to compare the efficacy and safety of macitentan and tadalafil monotherapies with the corresponding fixed dose combination in subjects with pulmonary arterial hypertension (PAH).
• Scientific title: Prospective, multi-center, double-blind, randomized, active-controlled, triple-dummy, parallel-group, group-sequential, adaptive Phase 3 clinical study to compare the efficacy and safety of macitentan and tadalafil monotherapies with the corresponding fixed dose combination in subjects with pulmonary arterial hypertension (PAH), followed by an open-label treatment period with macitentan and tadalafil fixed dose combination therapy
• Date of first enrolment: 10/08/2019
• Target sample size: 250
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004786-25
• 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: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Brazil, Bulgaria, Canada, China, Czechia, Germany, Hungary, Italy, Japan, Malaysia, Mexico, Poland, Russian Federation, South Africa, Spain, Taiwan, Türkiye, United States

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. 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, PAH.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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 187
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 63

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 a 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

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

Health Condition(s) or Problem(s) studied

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

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

Intervention(s)

Product Code: CJNJ-68150420-ZZZ-G001(ACT-064992D)
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: MACITENTAN
CAS Number: 441798-33-0
Current Sponsor code: JNJ-67896062- AAA
Other descriptive name: ACT-064992
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
INN or Proposed INN: TADALAFIL
CAS Number: 171596-29-5
Current Sponsor code: JNJ-10291697-AAA
Other descriptive name: ACT-178418
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Adcirca®
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: TADALAFIL
CAS Number: 171596-29-5
Current Sponsor code: JNJ-10291697-AAA
Other descriptive name: ACT-178418
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Capsule
Route of administration of the placebo: Oral use

Trade Name: Opsumit®
Product Name: macitentan
Product Code: ACT-064992
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: MACITENTAN
CAS Number: 441798-33-0
Current Sponsor code: JNJ-67896062- AAA
Other descriptive name: ACT-064992
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

Primary Outcome(s)

Primary end point(s): • Change in PVR expressed as the ratio of the geometric means of end of double blind treatment (EDBT) to baseline.

Secondary Objective: • 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.

Timepoint(s) of evaluation of this end point: end of double blind treatment (EDBT)

Main Objective: 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.

Secondary Outcome(s)

Secondary end point(s): • Change from baseline to EDBT in 6-minute walk distance.
• Change from baseline to Week 16 in PAH-SYMPACT™:
- Symptomps 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.

Timepoint(s) of evaluation of this end point: end of double blind treatment (EDBT)

Secondary ID(s)

2014-004786-25-DE

NCT03904693

AC-077A301

Source(s) of Monetary Support

Actelion Pharmaceuticals Ltd.

Ethics review

Status: Approved
Approval date: 10/07/2019
Contact: