COMMODITIES Trial: Initial Dual Oral Therapy vs Monotherapy in PAH With Cardiovascular Comorbidities

Official title

Comparison of Initial Dual Oral COMbination Therapy to MOnotherapy in Pulmonary Arterial Hypertension With Cardiovascular comorbiDITIES

Overview

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

• Drug Tadalafil
  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.
• Drug Ambrisentan
  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.
• Drug Placebo (Ambrisentan-matching)
  Matching placebo for ambrisentan, 2 tablets once daily, identical in appearance to active drug.

Primary outcome measures

• Mesurement of the risk profile according to the non-invasive 4-risk strata method [Time frame: Week 24]

Secondary outcome measures (9)

• Pulmonary vascular resistance [Time frame: week 24]
• BNP or NT-proBNP [Time frame: Week 24]
• 6-Minute Walk Distance (6-MWD) [Time frame: Week 24]
• WHO/NYHA Functional class [Time frame: Week 24]
• TAPSE/systolic pulmonary artery pressure (SPAP) ratio [Time frame: Week 24]
• Death or Nonfatal Clinical Worsening [Time frame: Week 24]
• emPHasis-10 score [Time frame: Week 24]
• EuroQoL-5 dimensions scale 5 levels (EQ-5D-5L) [Time frame: Week 24]
• Death [Time frame: Week 24]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

France · 1 center

• Hôpital Bicêtre -Service de pneumologie et soins intensifs respiratoires — Le Kremlin-Bicêtre

Identifiers

NCT: NCT07245680 · APHP230847 · 2023-509891-40-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗