Comparison of Initial Dual Oral COMbination Therapy to MOnotherapy in Pulmonary Arterial Hypertension With Cardiovascular comorbiDITIES
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 186
- 试验地点
- 1
- 主要终点
- Mesurement of the risk profile according to the non-invasive 4-risk strata method
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Placebo (Ambrisentan-matching) (Drug)
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
干预措施: Ambrisentan (Drug)
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
干预措施: Tadalafil (Drug)
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.
干预措施: Tadalafil (Drug)
结局指标
主要结局
Mesurement of the risk profile according to the non-invasive 4-risk strata method
时间窗: 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.
次要结局
- emPHasis-10 score(Week 24)
- TAPSE/systolic pulmonary artery pressure (SPAP) ratio(Week 24)
- Death(Week 24)
- Pulmonary vascular resistance(week 24)
- BNP or NT-proBNP(Week 24)
- 6-Minute Walk Distance (6-MWD)(Week 24)
- WHO/NYHA Functional class(Week 24)
- Death or Nonfatal Clinical Worsening(Week 24)
- EuroQoL-5 dimensions scale 5 levels (EQ-5D-5L)(Week 24)