Randomized Trial Comparing Efficacy and Safety of Initial Triple Therapy Including Parenteral Treprostinil to Initial Double Oral Therapy in Pulmonary Arterial Hypertension (PAH) Group I Patients (TripleTRE)
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 110
- 试验地点
- 19
- 主要终点
- Patients achieving (non-)response status to the assigned treatment in terms of achievement of low-risk status
研究概览
简要总结
TripleTRE investigates the effect of initial triple combination therapy (oral endothelin receptor antagonist (ERA) + oral phosphodiesterase tyüe-5 inhibitor (PDE-5i) + parenteral treprostinil) compared to double oral therapy (oral ERA + oral PDE-5i) in pulmonary arterial hypertension (PAH) patients (group I) with intermediate-high risk or patients with intermediate-low risk with severe hemodynamic impairment at baseline in a prospective, randomized, unblinded setting with scope of increasing evidence for optimization of therapy concepts in PAH.
The effect of initial triple combination therapy vs initial double oral therapy (standard of care (SoC)) will be measured by primary endpoint: (non)response to the assigned treatment.
详细描述
TripleTRE is prospective, randomized, two-arm, open-label, low-interventional, phase IV, multi-centre clinical trial comparing efficacy and safety of initial triple therapy including parenteral treprostinil to initial double oral therapy (standard of care (SoC)) by proportion of patients achieving low risk status according to the simplified four-strata risk-assessment tool from week 24 up to 48 weeks in 110 (55/group) treatment-naïve adult intermediate-high risk or intermediate-low risk participants with severe hemodynamic impairment with pulmonary arterial hypertension (PAH) (group I). Severe hemodynamic impairment is defined in current European Society of Cardiology (ESC)/European Respiratory Society (ERS) Guidelines as at least one of following conditions: mean right atrial pressure (RAP) ≥ 20 mmHg, cardiac index (CI) < 2.0 L/min, stroke volume index (SVI) < 31 mL/m2 and/or pulmonary vascular resistance (PVR) ≥ 12 WU. Risk status will be assessed with the simplified four-strata risk-assessment tool as per ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension (2022).
TripleTRE will be performed in adult participants with a confirmed diagnosis of idiopathic PAH (IPAH), hereditary PAH (HPAH), drug and toxin-induced PAH (DPAH), PAH associated with Connective Tissue Disease (PAH-CTD) and PAH with corrected congenital heart disease (PAH-CHD).
Participants will be randomized to one of the two treatment arms in 1:1 ratio. All patients will start with double oral background medication (endothelin receptor antagonist (ERA) and phosphodiesterase type-5 inhibitor (PDE-5i)). Choice of double oral drug combination underline the discretion of the investigator and applicable treatment guidelines. In both treatment arms all drugs (i.e., background medication in double oral group, background medication and parenteral treprostinil in initial triple group) will be initiated within 3 weeks after randomization. Patients randomized to treprostinil arm will receive training on infusion pump and medication after that investigational medicinal product will be handed out. All patients will be handed out diaries for documentation of treprostinil dose and used vials.
Primary objective of TripleTRE is to investigate the effect of initial triple combination therapy compared to initial double oral therapy on risk status. The effect of initial triple combination therapy vs initial double oral therapy (SoC) will be measured by primary endpoint: (non)response to the assigned treatment, whereas therapy responders/non-responders are defined as:
- Therapy-responder: achievement of low-risk status between week 24 and week 48
- Therapy-non-responder:
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
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent prior to any trial-mandated procedure
- •Male or female ≥ 18 and ≤ 70 years of age
- •Symptomatic treatment-naïve PAH patients (group I) with confirmed diagnosis of one of the following subgroups:
- •idiopathic pulmonary arterial hypertension (IPAH)
- •hereditary pulmonary arterial hypertension (HPAH)
- •Drug and toxin-induced pulmonary arterial hypertension (DPAH)
- •PAH associated with Connective Tissue Disease
- •PAH with corrected congenital heart disease
- •Intermediate-high risk patients rated acc. the simplified four-strata risk-assessment tool or intermediate-low risk with severe hemodynamic impairment as defined in current PH guidelines i.e., mean right atrial pressure (RAP) ≥ 20 mmHg, cardiac index (CI) < 2.0 L/min, stroke volume index (SVI) < 31 mL/m2 and/or pulmonary vascular resistance (PVR) ≥ 12 WU
- •Right Heart Catheterization (RHC) meeting all the following criteria:
- •Mean pulmonary arterial pressure (mPAP) > 20 mmHg
- •Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg
- •PVR > 2 Wood Units
- •Women of childbearing potential must not be pregnant or lactating, must perform regular pregnancy tests, if sexually active, agrees to continue to use reliable method(s) of contraception until study completion
排除标准
- •PAH patients (group I) belonging to one of the following subgroups:
- •Schistosomiasis
- •HIV infection
- •Portal hypertension
- •Diffuse systemic sclerosis
- •Uncorrected congenital heart disease including uncorrected systemic-to-pulmonary shunts
- •Any PAH-specific drug therapy in the past 3 months
- •Patients responding to vasoreactivity testing with calcium channel blockers (CCB)
- •Post-capillary PH and left heart disease
- •Known or suspected pulmonary veno-occlusive disease (PVOD)
- •Any PH due to lung disease
- •Any disorder of the respiratory system expressed by Diffusing Capacity of Lung for Carbon Monoxide (DLCO) <40% and a noticeable imaging result (e.g., CT) and (Total Lung Capacity) TLC <60% and (Forced Expiratory Volume) FEV1 <70% by plethysmography (a pulmonary function test)
- •Patients with need of ambulatory or long-term oxygen therapy
- •Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 480 msec at screening
- •Body mass index (BMI) > 35 (kg/m2)
- •Age > 70 years
- •History of restrictive, constrictive or congestive cardiomyopathy, atrial septostomy, any symptomatic coronary disease events within 6 months, severe uncontrolled arterial hypertension, acutely decompensated heart failure and myocardial infarction within 30 days, significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease, chronic systemic hypotension, unstable angina pectoris, permanent/persistent atrial fibrillation and/or need for pacemaker
- •Patients with acute anemia with hemoglobin (Hb) values <11g/dL
- •Cerebrovascular accident within 3 months
- •Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3× upper limit of the normal range (ULN) accompanied by aspartate aminotransferase (AST) > ULN and/or Child-Pugh Class C
- •Documented renal insufficiency with Glomerular Filtration Rate (GFR) <30 ml/min
- •Patients with untreated sleep apnea
- •Patient with other cardiovascular, liver, renal, hematologic, gastrointestinal (including active gastrointestinal ulcer), immunologic, endocrine (e.g., uncontrolled diabetes), metabolic, or central nervous system disease and acute bleeding and injuries (e.g., intracranial hemorrhage) that, in the opinion of the investigator, may adversely affect the safety of the patient and /or efficacy of the therapy or significantly limit the lifespan (< 12 months)
- •Patients with major surgery in the last 12 months
- •Known history of alcohol abuse
- •Treatment of a a cytochrome P450 (CYP)2C8 enzyme inducer (e.g., rifampicin) ≤ 28 days and/or treatment of a CYP2C8 enzyme inhibitor (e.g., gemfibrozil) ≤ 28 days
- •Treatment with another investigational drug (planned, or taken ≤ 12 weeks)
- •Hypersensitivity to any of the trial treatments or any excipient of their formulations
- •Pregnancy, breastfeeding, or intention to become pregnant during the trial
- •Any other significant disease or disorder which, in the opinion of the investigator, may put the patients at risk when participating in the trial
- •Any factor or condition likely to affect protocol compliance of the patient, as judged by the investigator.
研究组 & 干预措施
Initial triple therapy
Assigned treatment: double oral (background therapy consisting of 1 endothelin receptor antagonist ERA and 1 phosphodiesterase type-5 inhibitor PDE-5i) with subcutaneous (SC)/intravenous (IV) treprostinil on top
干预措施: Generic treprostinil sodium + Standard of Care (Double Oral) (Drug)
Initial triple therapy
Assigned treatment: double oral (background therapy consisting of 1 endothelin receptor antagonist ERA and 1 phosphodiesterase type-5 inhibitor PDE-5i) with subcutaneous (SC)/intravenous (IV) treprostinil on top
干预措施: Standard of Care - Double Oral (Drug)
• Initial double therapy
double oral (background therapy consisting of 1 endothelin receptor antagonist ERA and 1 phosphodiesterase type-5 inhibitor PDE-5i)
干预措施: Standard of Care - Double Oral (Drug)
结局指标
主要结局
Patients achieving (non-)response status to the assigned treatment in terms of achievement of low-risk status
时间窗: between week 12 and week 48 from baseline (BL)
1. Therapy-responder: achievement of low-risk status between week 24 and week 48 2. Therapy-non-responder: 1. PH related deterioration to high-risk status, lung transplantation or death between week 12 and week 48 and/or 2. additional medication or change of initial PH specific medication due to unsatisfactory efficacy between week 12 and week 48 and/or 3. low risk status not achieved up to week 48 Risk status is assessed with the simplified four-strata risk-assessment tool as per PH guidelines.
次要结局
- Change in hemodynamic parameters by means of right heart catheterization (RHC) - mPAP(at week 24 from baseline (BL))
- Change in hemodynamic parameters by means of right heart catheterization (RHC) - PVR(at week 24 from baseline (BL))
- Change in the number of low-risk criteria based on the French PH Network Registry (FPHR) risk assessment tool(between baseline and week 24)
- Change in hemodynamic parameters by means of right heart catheterization (RHC) - mRAP(at week 24 from baseline (BL))
- Change in hemodynamic parameters by means of right heart catheterization (RHC) - CI(at week 24 from baseline (BL))
- Change in hemodynamic parameters by means of right heart catheterization (RHC) - CO(at week 24 from baseline (BL))
- Change in hemodynamic parameters by means of right heart catheterization (RHC) - RAP(at week 24 from baseline (BL))
- Change in right heart structure and function assessed by echocardiography - TAPSE/sPAP(at week 24 from baseline (BL))
- Change in right heart structure and function assessed by echocardiography - RVEDA(at week 24 from baseline (BL))
- Change in right heart structure and function assessed by echocardiography - RVESA(at week 24 from baseline (BL))
- Change in right heart structure and function assessed by echocardiography - RVFAC(at week 24 from baseline (BL))
- Change in right heart structure and function assessed by echocardiography - RA(at week 24 from baseline (BL))
- Change in right heart structure and function assessed by echocardiography - Pericardial effusion(at week 24 from baseline (BL))
- Time to achievement of low-risk status(time from baseline (BL) up to week 48)
- Rate of change of risk status(between baseline and week 48)
- Rate of change in NT-proBNP/BNP levels(between baseline and week 48)
- Change in REVEAL 2.0 risk score(between baseline and week 24)
- Rate of change in WHO-FC(between baseline and week 48)
- Rate of change in 6MWD(between baseline and week 48)
- Total number of clinical worsening(s)(between baseline and week 48)
- Overall and transplant free survival(between baseline and week 48)
- Rate of change in quality of life - emPHasis-10(between baseline and week 48)
- Rate of change in quality of life - EQ-5D-5L(between baseline and week 48)