Initial Triple Therapy Including Parenteral Treprostinil vs Initial Double Oral Therapy in PAH Group I Patients

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.

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:

1. Therapy-responder: achievement of low-risk status between week 24 and week 48
2. Therapy-non-responder:

   1. pulmonary hypertension (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 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension (2022).

Commonly used variables such as hemodynamics, echocardiogram (ECHO) and time to clinical worsening will be evaluated as secondary endpoints. In addition, the emPHasis-10 questionnaire will be used as disease specific and validated patient-reported outcome tool for PAH patients. The European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L) will be used as general patient-reported outcome tool independent from disease.

TripleTRE trial is organized as a low-intervention trial consistent with definition in Clinical Trial Regulation (Regulation (EU) No 536/2014). Participants will not undergo any invasive examinations or laboratory evaluations, diagnostic or monitoring procedures specifically for the purposes of this trial that would expose them to increased risk compared to standard of care. Trial-related procedures as well as the frequency of assessments are in alignment with ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension (2022) and are not expected to pose additional risks to patients.

Planned trial duration per patient is minimum 12 weeks and maximum 48 weeks with up to 10 visits depending on achievement of therapy responder (i.e., low risk status) or therapy non-responder status. The visits 2 and 3 can be performed on phone. Other visits will be performed on-site. The trial will only be conducted in countries where ERA and PDE-5i treatments are standard of care and treprostinil is available to patients. At the end of trial, patients will be treated according to routine medical care at the PH expert centers receiving locally reimbursed medications. Approximately 10 countries and 20 sites are planed.

Statistical considerations:

The complete statistical analysis plan (SAP) was finalized before first patient in (FPI) in meaning of first act of recruitment. A one-sided Boschloo exact test at 2.5% significance level will be used to test the following primary hypothesis:

H0: Proportion of patients achieving low risk status (therapy responders) between week 24 and week 48 after baseline in the initial Triple treatment group is less or equal to the proportion of patients achieving low risk status between week 24 and week 48 after baseline in the initial Double oral treatment group.

The null hypothesis will be rejected if the 97.5% CI of the difference of proportions of therapy responders (triple minus double) is greater than 0.

To account for the variable time on treatment of therapy responders, a secondary sensitivity analysis will be performed by comparing the median time to the achievement of the low-risk status between the treatment groups.

Further sensitivity and subgroup analyses are defined in detail the statistical analysis plan (SAP) including the handling of missing values.

Eligibility Criteria:
Inclusion Criteria:

* 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 Criteria:

* 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.