Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH)

• Register: ClinicalTrials.gov
• Last refreshed on: 8 April 2024
• Main ID: NCT03904693
• Date of registration: 04/04/2019
• Prospective Registration: Yes
• Primary sponsor: Actelion
• Public title: Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension (PAH) A DUE
• 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: July 29, 2019
• Target sample size: 187
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03904693
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 3

Countries of recruitment

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

Contacts

• Name: Hany Rofael, MD
• Affiliation: Janssen, LP

Key inclusion & exclusion criteria

Inclusion Criteria:

- Signed and dated informed consent form (ICF)

- Confirmed diagnosis of symptomatic PAH in WHO FC II or III

- Symptomatic PAH belonging to one of the following subgroups of WHO Group 1 pulmonary
hypertension:

- Idiopathic

- Heritable

- Drug- or toxin-induced

- Associated with connective tissue disease, HIV infection, portal hypertension or
congenital heart disease with simple systemic-to-pulmonary shunt with persistent
pulmonary hypertension documented by a right heart catheterization (RHC) = 1 year
after surgical repair

- PAH diagnosis confirmed by hemodynamic evaluation at rest (through central reading),
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)

- Negative vasoreactivity test in idiopathic, heritable, and drug/toxin-induced PAH.
(Participants 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).

- Currently receiving a stable dose of ERA or PDE-5i monotherapy for at least 3 months
prior to baseline RHC, within the prespecified doses in the study protocol or no
history of PAH-specific treatment

- Participant able to perform the 6MWT with a minimum distance of 100 m and maximum
distance of 450 m at Screening

- A woman of childbearing potential must:

- have negative serum pregnancy test at Screening and a negative urine pregnancy
test at Randomization

- agree to undertake monthly urine pregnancy tests during the study and up to at
least 30 days after study treatment discontinuation

- agree to follow the contraception scheme from Screening up to at least 30 days
after study treatment discontinuation

Exclusion Criteria:

- 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

- 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

- Hypersensitivity to any of the study treatments or any excipient of their formulations

- Treatment with a strong cytochrome P450 3A4 (CYP3A4) inducer in the 1-month period
prior to start of treatment

- 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 start of treatment

- Treatment with doxazosin

- Treatment with any form of organic nitrate, either regularly or intermittently

- Diuretic treatment initiated or dose changed within 1 week prior to the RHC or start
of treatment

- Treatment with another investigational drug in the 3-month period prior to start of
treatment

- Body mass index (BMI) > 40 kg/m2 at Screening

- 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. 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

- Known presence of moderate or severe obstructive lung disease any time prior to
Screening as specified in study protocol

- Known presence of moderate or severe restrictive lung disease any time prior to
Screening as specified in study protocol

- Clinically significant aortic or mitral valve disease; pericardial constriction;
restrictive or congestive left-sided cardiomyopathy; life-threatening cardiac
arrhythmias; significant left ventricular dysfunction; or left ventricular outflow
obstruction, in the opinion of the investigator

- Known permanent atrial fibrillation, in the opinion of the investigator

- Known or suspected uncontrolled thyroid disease (hypo- or hyperthyroidism)

- Documented pulmonary veno-occlusive disease

- Hemoglobin < 100 g/L (<10 g/dL) at Screening

- Known severe hepatic impairment as specified in study protocol

- Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 ×
upper limit of normal (ULN) at Screening

- Severe renal impairment at Screening as specified in study protocol

- Systemic hypotension at Screening or Randomization and systemic hypertension at
Screening as specified in study protocol

- Acute myocardial infarction or cerebrovascular event (e.g., stroke) within the last 26
weeks prior to Screening

- Known bleeding disorder, in the opinion of the investigator

- Loss of vision in one or both eyes because of non-arteritic anterior ischemic optic
neuropathy

- Hereditary degenerative retinal disorders, including retinitis pigmentosa

- History of priapism, conditions that predispose to priapism (example, sickle cell
anemia, multiple myeloma, or leukemia) or anatomical deformation of the penis
(example, angulation, cavernosal fibrosis, or Peyronie's disease)

- Difficulty swallowing large pills/tablets that would interfere with the ability to
comply with study treatment regimen

- Any planned surgical intervention (including organ transplant) during the double-blind
treatment period, except minor interventions

- 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

- Pregnant, planning to become pregnant or lactating

- Any known factor or disease that might interfere with treatment adherence, full
participation in the study or interpretation of the results as judged by the



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)

Intervention(s)

Drug: Placebo macitentan

Drug: Placebo FDC

Drug: Macitentan 10 mg

Drug: Tadalafil 40 mg

Drug: Placebo tadalafil

Drug: FDC macitentan/tadalafil

Primary Outcome(s)

Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline [Time Frame: Baseline, EDBT (up to 16 weeks)]

Secondary Outcome(s)

Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT [Time Frame: Baseline, EDBT (up to 16 weeks)]

Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT [Time Frame: Baseline, EDBT (up to 16 weeks)]

Change From Baseline in 6-minutes Walking Distance (6MWD) to EDBT [Time Frame: Baseline, EDBT (up to 16 weeks)]

Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline to EDBT [Time Frame: Baseline, EDBT (up to 16 weeks)]

Secondary ID(s)

2014-004786-25

AC-077A301

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 13/11/2023
• URL: https://clinicaltrials.gov/ct2/show/results/NCT03904693