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
Overview
- Phase
- Phase 3
- Intervention
- FDC macitentan/tadalafil
- Conditions
- Pulmonary Arterial Hypertension (PAH) (WHO Group 1 PH)
- Sponsor
- Actelion
- Enrollment
- 187
- Locations
- 147
- Primary Endpoint
- Change in Pulmonary Vascular Resistance (PVR) Expressed as the Ratio of Geometric Means of End of Double-blind Treatment (EDBT) to Baseline
- Status
- Completed
- Last Updated
- 4 months ago
Overview
Brief Summary
Combination therapy in pulmonary arterial hypertension (PAH) has been the subject of active investigation for more than a decade, with the benefit of targeting different pathways known to be involved in the pathogenesis of the disease. Adherence to prescribed therapy has an impact on clinical outcomes. Reducing the pill/tablet count and frequency has a major impact on patients' adherence to therapies and therefore the observed clinical outcomes. One way to simplify treatment is to use fixed-dose combination (FDC) products that combine multiple treatments targeting different pathways into a single tablet.
This study aims to demonstrate that the FDC of macitentan and tadalafil is more effective than therapy with 10 mg of macitentan alone or 40 mg of tadalafil alone. This phase 3 study will evaluate the efficacy and safety at 16 weeks of an FDC (macitentan 10 mg and tadalafil 40 mg) against these two PAH-approved therapies given as monotherapy to further confirm the added value of the FDC.
Detailed Description
PAH is characterized by a progressive increase in pulmonary arterial pressure (PAP) and in pulmonary vascular resistance (PVR) potentially leading to right heart failure and death. Current PAH-specific therapeutic options include treatments that target the three pathways (endothelin, nitric oxide, and prostacyclin pathways). While combination treatment is common, FDC pills or tablets that combine two or more PAH-specific therapies are not available, thereby requiring participants to take multiple pills/tablets daily. An FDC is an attractive option for PAH participants because it simplifies the treatment regimen by combining two therapies (which would otherwise involve a total of three tablets: one macitentan 10 mg tablet and two tadalafil 20 mg tablets) into a single tablet. Macitentan is an orally active, non-peptide, potent dual endothelin receptor A and B antagonist. Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE-5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). This study comprises the following consecutive periods: Screening period (lasts up to 30 days), Double-blind treatment period (consists of the titration phase \[the first 2 weeks\] and the maintenance phase \[Week 3 through Week 16\]), Open-label treatment period, End-of-Treatment (EOT), Safety follow-up (S-FU) period, and End of Study (EOS). The total study duration for a participant will be up to 30 months. Study assessments like physical examinations, vital signs, right heart catheterization, 6-minute walk test will be performed. Safety will be assessed throughout the study.
Investigators
Eligibility 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
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
Arms & Interventions
FDC therapy + Placebo macitentan + Placebo tadalafil
Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments.
Intervention: FDC macitentan/tadalafil
FDC therapy + Placebo macitentan + Placebo tadalafil
Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments.
Intervention: Placebo macitentan
FDC therapy + Placebo macitentan + Placebo tadalafil
Subjects to receive FDC macitentan/tadalafil (macitentan 10 mg and tadalafil 40 mg) plus matching placebos for the two other study treatments.
Intervention: Placebo tadalafil
Macitentan mono-therapy + Placebo tadalafil + Placebo FDC
Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments.
Intervention: Macitentan 10 mg
Macitentan mono-therapy + Placebo tadalafil + Placebo FDC
Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments.
Intervention: Placebo FDC
Macitentan mono-therapy + Placebo tadalafil + Placebo FDC
Subjects to receive macitentan 10 mg plus matching placebos for the two other study treatments.
Intervention: Placebo tadalafil
Tadalafil mono-therapy + Placebo macitentan + Placebo FDC
Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.
Intervention: Tadalafil 40 mg
Tadalafil mono-therapy + Placebo macitentan + Placebo FDC
Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.
Intervention: Placebo FDC
Tadalafil mono-therapy + Placebo macitentan + Placebo FDC
Subjects to receive tadalafil 40 mg (2 x 20 mg) plus matching placebos for the two other study treatments.
Intervention: Placebo macitentan
Outcomes
Primary Outcomes
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)
Change in PVR expressed as the ratio of geometric means of EDBT to baseline were reported.
Secondary Outcomes
- Change From Baseline to EDBT in 6-minutes Walking Distance (6MWD)(Baseline, EDBT (Week 16))
- Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiopulmonary Symptom Domain Scores to EDBT(Baseline, EDBT (Week 16))
- Change From Baseline in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT) in Cardiovascular Symptom Domain Scores to EDBT(Baseline, EDBT (Week 16))
- Percentage of Participants With Absence of Worsening in World Health Organization (WHO) Functional Class (FC) From Baseline at EDBT(At Week 16 (EDBT))