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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

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

Первичные конечные точки

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

Вторичные конечные точки (9)

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

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Франция · 1 центр

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

Идентификаторы

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

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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