Initial Triple Therapy Including Parenteral Treprostinil vs Initial Double Oral Therapy in PAH Group I Patients
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)
AOP Orphan Pharmaceuticals AG
110 participants
Dec 6, 2023
INTERVENTIONAL
Conditions
Summary
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.
Eligibility
Inclusion Criteria13
- 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 4. 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
Exclusion Criteria31
- 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.
Interventions
Treprostinil (prostacyclin analogue) solution for continuous subcutaneous (SC) or intravenous (IV) infusion (1 mg/ml; 2.5 mg/ml; 5 mg/ml; 10 mg/ml in 10 mL glass vial) will be administered by an infusion pump system and up-titrated to ≥40 ng/kg/min or to the maximum tolerated dose within 24 weeks. Further up-titration shall be performed until trial completion according to the discretion of the investigator.
All patients will receive standard of care double oral background treatment consisting of one Phosphodiesterase type 5 inhibitor (i.e., tadalafil or sildenafil) and one Endothelin Receptor Antagonist (i.e. ambrisentan, bosentan or macitentan)
Locations(19)
View Full Details on ClinicalTrials.gov
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NCT06317805