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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Comorbidities; Cardiovascular Disease (CVD); Pulmonary Arterial Hypertension (PAH)
• Intervention / Treatment: Drug: Tadalafil; Drug: Ambrisentan; Drug: Placebo (Ambrisentan-matching)

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.

• Study Type: Interventional
• Enrollment (Estimated): 186
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Laurent SAVALE,, MD, PhD; Phone Number: +33 1 45 21 79 08; Email: laurent.savale@aphp.fr

Study Locations

• France
  • Le Kremlin-Bicêtre, France, 94270
    • Recruiting
    • Hôpital Bicêtre -Service de pneumologie et soins intensifs respiratoires
    • Contact: Laurent SAVALE, Md, PhD; Phone Number: +33 (0)1 45 21 79 08; Email: laurent.savale@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tadalafil + Ambrisentan; Tadalafil - 20 mg once daily for 7 days, then 40 mg once daily (2 × 20 mg tablets). Dose may be reduced to 20 mg once daily if not tolerated. Ambrisentan - 5 mg once daily for 4 weeks, then 10 mg once daily (2 × 5 mg tablets). Dose may be maintained at 5 mg once daily in case of intolerance	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.
Active Comparator: Tadalafil + Placebo; Tadalafil - 20 mg once daily for 7 days, then 40 mg once daily (2 × 20 mg tablets). Dose may be reduced to 20 mg once daily if not tolerated. Placebo - Matching placebo for ambrisentan, 2 tablets once daily.	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: Placebo (Ambrisentan-matching); Matching placebo for ambrisentan, 2 tablets once daily, identical in appearance to active drug.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mesurement of the risk profile according to the non-invasive 4-risk strata method	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.	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary vascular resistance	Change from baseline to Week 24 in pulmonary vascular resistance, assessed by right heart catheterization and expressed in Wood units (WU).	week 24
BNP or NT-proBNP	Percent change from baseline to week 24 in BNP or NT-proBNP	Week 24
6-Minute Walk Distance (6-MWD)	Change from baseline to week 24 in 6-MWD	Week 24
WHO/NYHA Functional class	Proportion of participants who improve in WHO/NYHA FC at the end of the DBPC Treatment period	Week 24
TAPSE/systolic pulmonary artery pressure (SPAP) ratio	Change from baseline to week 24 in the TAPSE/systolic pulmonary artery pressure (SPAP) ratio	Week 24
Death or Nonfatal Clinical Worsening	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	Week 24
emPHasis-10 score	Change from baseline to week 24 in the emPHasis-10 score	Week 24
EuroQoL-5 dimensions scale 5 levels (EQ-5D-5L)	Change from baseline to week 24 EuroQoL-5 dimensions scale 5 levels (EQ-5D-5L)	Week 24
Death	All causes of death	Week 24

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2026
• Primary Completion (Estimated): February 14, 2029
• Study Completion (Estimated): February 14, 2029

Study Registration Dates

• First Submitted: September 22, 2025
• First Submitted That Met QC Criteria: November 17, 2025
• First Posted (Actual): November 24, 2025

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Combination Therapy; Pulmonary arterial hypertension; PAH; Endothelin Receptor Antagonist (Ambrisentan); Phosphodiesterase-5 Inhibitor (Tadalafil); Cardiovascular Comorbidities
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Cardiovascular Diseases; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indoles; Indole Alkaloids; Heterocyclic Compounds, 3-Ring; Carbolines; Tadalafil; ambrisentan
• Other Study ID Numbers: APHP230847; 2023-509891-40-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No