Cardiovascular Disease (CVD), Comorbidities, Pulmonary Arterial Hypertension (PAH)
Conditions
Keywords
PAH, Endothelin Receptor Antagonist (Ambrisentan), Phosphodiesterase-5 Inhibitor (Tadalafil), Cardiovascular Comorbidities, Combination Therapy, Randomized Controlled Trial, Pulmonary arterial hypertension
Brief summary
Pulmonary arterial hypertension (PAH) is a rare, progressive disease associated with poor prognosis, especially in patients with cardiovascular comorbidities. Current guidelines recommend initial combination therapy, but evidence is lacking for patients with significant comorbidities who are often excluded from clinical trials. The COMMODITIES trial is a multicenter, randomized, controlled study designed to compare the efficacy and safety of initial dual oral combination therapy (tadalafil and ambrisentan) versus oral monotherapy in newly diagnosed PAH patients with at least two cardiovascular comorbidities. The study aims to provide robust evidence to guide treatment strategies in this high-risk population.
Detailed description
Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance leading to right heart failure and premature death. Although initial combination therapy with phosphodiesterase-5 inhibitors and endothelin receptor antagonists has demonstrated improved outcomes in patients without major comorbidities, little is known about its benefit-risk balance in patients with cardiovascular comorbidities. The COMMODITIES study is an investigator-initiated, prospective, randomized, controlled, open-label, phase IV trial conducted under European Regulation (EU) 536/2014. The trial will enroll newly diagnosed PAH patients (confirmed by right heart catheterization) who present with at least two cardiovascular comorbidities (including systemic hypertension, diabetes mellitus, coronary artery disease, obesity, or atrial fibrillation). Eligible patients will be randomized 1:1 to receive either: Experimental arm : tadalafil + ambrisentan, Control arm : : tadalafil +placebo. The primary endpoint will be the proportion of patients with PAH and cardiovascular comorbidities who achieve after 6 months a low- or an intermediate-low risk profile according to the noninvasive 4-risk strata method as proposed by the 2022 European pulmonary hypertension guidelines. The total planned sample size is 186, with a study duration of 37 months . Results will provide crucial evidence to inform guideline recommendations and optimize therapeutic strategies in PAH patients with comorbidities.
Interventions
DRUGTadalafil
Oral phosphodiesterase-5 inhibitor. Initiated at 20 mg once daily for 7 days, then increased to 40 mg once daily (2 × 20 mg tablets). Dose may be reduced to 20 mg once daily if not tolerated.
DRUGAmbrisentan
Oral endothelin receptor antagonist. Initiated at 5 mg once daily for 4 weeks, then increased to 10 mg once daily (2 × 5 mg tablets). Dose may be maintained at 5 mg once daily in case of intolerance.
DRUGPlacebo (Ambrisentan-matching)
Matching placebo for ambrisentan, 2 tablets once daily, identical in appearance to active drug.
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-blind design: participants and investigators are blinded to treatment allocation. A matching placebo is used in place of ambrisentan to ensure blinding, while tadalafil is given in both arms.
Intervention model description
Participants will be randomized in a 1:1 ratio to receive either tadalafil plus ambrisentan or tadalafil plus placebo, in a parallel assignment design with two treatment arms under double-blind masking.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Initial PAH diagnosis \< 6 months preceding randomisation * Negative vasoreactivity test * Treatment-naïve PAH (group 1): idiopathic, heritable, associated with drugs and toxin, associated with connective tissue disease, HIV infection or systemic-to-pulmonary congenital shunt corrected for more than one year * Meet all of the following hemodynamic criteria by means of a RHC prior to screening: * mPAP≥25 mmHg and * PAWP\<15 mmHg and * with PVR≥3 WU • Presence of at least two of the following criteria, as listed in the European pulmonary hypertension guidelines: * History of essential hypertension * Diabetes mellitus (any type) * Obesity (defined by a BMI ≥30 kg/m2) * Coronary heart disease (established by any of the following: history of myocardial infarction, history of percutaneous coronary intervention, angiographic evidence of coronary artery disease (\>50% stenosis in ≥1 vessel), positive ST, previous coronary artery bypass graft, stable angina) * Participant able to understand the study procedures * For women of childbearing potential (WOCBP), effective form of contraception\* from screening up to 1 month following discontinuation of the last study treatment * Affiliation to the french social security regime * Signed written informed consent
Exclusion criteria
* Porto-pulmonary hypertension * Uncorrected systemic-to-pulmonary congenital shunt * Evidence of thromboembolic disease assessed by ventilation perfusion (V/Q) lung scan or CT pulmonary angiography * Patients listed for lung or heart-lung transplantation at time of screening * Patients on any PAH-specific drug therapy at any time preceding randomisation * Known moderate-to-severe restrictive lung disease (i.e., total lung capacity \< 60% of predicted value) or obstructive lung disease (i.e., forced expiratory volume in one second \[FEV1\] \< 60% of predicted, with FEV1 / forced vital capacity \< 65%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema). * Known or suspected pulmonary veno-occlusive disease (PVOD) * Severe renal insufficiency (creatinine clearance \< 30 mL/min) * Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin \> 3 x ULN or serum AST and/or ALT \> 3xULN (assessed by local laboratory at screening) and/or Child-Pugh Class C. * Haemoglobin \< 10 g/dL * Patient under guardianship curatorship, deprived of liberty * Pregnant women, or breast-feeding women * Treatment with other PDE-5i for erectile dysfunction * Ongoing or planned treatment with nitrates and/or doxazosin. * Ongoing or planned treatment with riociguat * Treatment with strong inducers of CYP3A4 (e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and St. John's wort) ≤28 days preceding randomisation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mesurement of the risk profile according to the non-invasive 4-risk strata method | Week 24 | Proportion of patients with PAH and with at least two cardiovascular comorbidities who achieve after 24 week a low- or an intermediate-low risk profile according to the non-invasive 4-risk strata method as proposed by the 2022 european pulmonary hypertension guidelines. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EuroQoL-5 dimensions scale 5 levels (EQ-5D-5L) | Week 24 | Change from baseline to week 24 EuroQoL-5 dimensions scale 5 levels (EQ-5D-5L) |
| Death | Week 24 | All causes of death |
| Pulmonary vascular resistance | week 24 | Change from baseline to Week 24 in pulmonary vascular resistance, assessed by right heart catheterization and expressed in Wood units (WU). |
| BNP or NT-proBNP | Week 24 | Percent change from baseline to week 24 in BNP or NT-proBNP |
| 6-Minute Walk Distance (6-MWD) | Week 24 | Change from baseline to week 24 in 6-MWD |
| WHO/NYHA Functional class | Week 24 | Proportion of participants who improve in WHO/NYHA FC at the end of the DBPC Treatment period |
| TAPSE/systolic pulmonary artery pressure (SPAP) ratio | Week 24 | Change from baseline to week 24 in the TAPSE/systolic pulmonary artery pressure (SPAP) ratio |
| emPHasis-10 score | Week 24 | Change from baseline to week 24 in the emPHasis-10 score |
| Death or Nonfatal Clinical Worsening | Week 24 | Rate of Death or Nonfatal Clinical Worsening defined by hospitalisation for PAH worsening or disease progression defined by worsening of functional class and decrease in 6-min walk distance of more than 15% from baseline, or need for additional specific therapy or lung transplantation |
Countries
France
Contacts
CONTACTLaurent SAVALE,, MD, PhD
Outcome results
None listed