A Phase 4 interventional study of Generic treprostinil sodium + Standard of Care (Double Oral) and Standard of Care - Double Oral in Pulmonary Arterial Hypertension, sponsored by AOP Orphan Pharmaceuticals AG. Recruiting at 19 sites in 10 countries. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2024-03-19.
Sponsored by AOP Orphan Pharmaceuticals AG · Phase 4, Interventional, and Treatment
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:
Therapy-non-responder:
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.
761 studies on the registry are indexed under Pulmonary Arterial Hypertension; 142 are open to participants now.
This study's planned enrollment of 110 is above the median of 38 across 509 interventional studies indexed under Pulmonary Arterial Hypertension.
Browse Pulmonary Arterial Hypertension studies →AOP Orphan Pharmaceuticals AG is the lead sponsor of 16 studies on the registry; 4 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Symptomatic treatment-naïve PAH patients (group I) with confirmed diagnosis of one of the following subgroups:
Right Heart Catheterization (RHC) meeting all the following criteria:
Exclusion Criteria:
PAH patients (group I) belonging to one of the following subgroups:
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
Drug: Generic treprostinil sodium + Standard of Care (Double Oral) · Drug: Standard of Care - Double Oral
double oral (background therapy consisting of 1 endothelin receptor antagonist ERA and 1 phosphodiesterase type-5 inhibitor PDE-5i)
Drug: Standard of Care - Double Oral
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.
Also known as: Trisuva, Tresuvi, Treposa, Treprostinil Orpha-Devel, Treprostinil Amomed, Treprostinil OrPha, Treposuvi
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)
Patients achieving (non-)response status to the assigned treatment in terms of achievement of low-risk status
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.
Time frame: between week 12 and week 48 from baseline (BL)
Change in hemodynamic parameters by means of right heart catheterization (RHC) - PVR
Pulmonary Vascular Resistance (PVR) measured in WU
Time frame: at week 24 from baseline (BL)
Change in hemodynamic parameters by means of right heart catheterization (RHC) - mPAP
Mean pulmonary arterial pressure (mPAP) measured in mmHg
Time frame: at week 24 from baseline (BL)
Change in hemodynamic parameters by means of right heart catheterization (RHC) - mRAP
Mean right atrial pressure (mRAP) measured in mmHg
Time frame: at week 24 from baseline (BL)
Change in hemodynamic parameters by means of right heart catheterization (RHC) - CI
Cardiac index (CI) measured in liters per minute per square meter
Time frame: at week 24 from baseline (BL)
Change in hemodynamic parameters by means of right heart catheterization (RHC) - CO
Cardiac output (CO) measured in liters per minute
Time frame: at week 24 from baseline (BL)
Change in hemodynamic parameters by means of right heart catheterization (RHC) - RAP
Right atrial pressure (RAP) measured in mmHg
Time frame: at week 24 from baseline (BL)
Change in right heart structure and function assessed by echocardiography - TAPSE/sPAP
RV-PA coupling estimated by the ratio of tricuspid annular plane systolic excursion by pulmonary artery systolic pressure (TAPSE/sPAP)
Time frame: at week 24 from baseline (BL)
Change in right heart structure and function assessed by echocardiography - RVEDA
RV end-diastolic area (RVEDA) measured in square centimeters
Time frame: at week 24 from baseline (BL)
Change in right heart structure and function assessed by echocardiography - RVESA
RV end-systolic area (RVESA) measured in square centimeters
Time frame: at week 24 from baseline (BL)
Change in right heart structure and function assessed by echocardiography - RVFAC
RV fractional area change (RVFAC) calculated in %
Time frame: at week 24 from baseline (BL)
Change in right heart structure and function assessed by echocardiography - RA
Right Atrium (RA) area in square centimeters
Time frame: at week 24 from baseline (BL)
Change in right heart structure and function assessed by echocardiography - Pericardial effusion
Pericardial effusion assessment will be done and rated as yes/no
Time frame: at week 24 from baseline (BL)
Time to achievement of low-risk status
Time from baseline to achievement of low-risk status assessed by the simplified four-strata risk-assessment tool
Time frame: time from baseline (BL) up to week 48
Rate of change of risk status
by means of the simplified four-strata risk-assessment tool categorizing patients in low (1), intermediate-low (2), intermediate-high (3) and high risk (4) based on the outcome in WHO FC class assessment, 6MWD and BNP/NT-proBNP
Time frame: between baseline and week 48
Change in the number of low-risk criteria based on the French PH Network Registry (FPHR) risk assessment tool
Time frame: between baseline and week 24
Change in REVEAL 2.0 risk score
REVEAL Registry Risk Score 2.0 for Pulmonary Arterial Hypertension (PAH) predicts survival in patients with pulmonary arterial hypertension. It classifies patients in 3 risk groups: * Low: REVEAL score ≤6 meaning a predicted 1-year survival of ≥94% * Intermediate: REVEAL score 7-8 meaning a predicted 1-year survival of 70% to \<94% * High: REVEAL score ≥9 meaning a predicted 1-year survival of \<70%
Time frame: between baseline and week 24
Rate of change in WHO-FC
Time frame: between baseline and week 48
Rate of change in 6MWD
Time frame: between baseline and week 48
Rate of change in NT-proBNP/BNP levels
Time frame: between baseline and week 48
Total number of clinical worsening(s)
where clinical worsening is defined as: * PAH related death (including all deaths where PAH cannot be excluded as cause) and lung transplantation due to PAH * PH-related hospitalization * Post baseline (screening visit) decrease in 6MWD by 15% * Post baseline (screening visit) worsening of WHO FC
Time frame: between baseline and week 48
Overall and transplant free survival
Time frame: between baseline and week 48
Rate of change in quality of life - emPHasis-10
Emphasis meaning something of special importance or significance. Please translate using the most appropriate term. The PH in emPHasis represents the condition Pulmonary Hypertension. The number 10 refers to the number of items in the questionnaire. This questionnaire is designed to determine how Pulmonary Hypertension (PH) affects patient's life. It refers to how PH affects or the impact that PH has on the patient's life.
Time frame: between baseline and week 48
Rate of change in quality of life - EQ-5D-5L
The EQ-5D-5L questionnaire consists of 2 parts - the EQ-5D-5L descriptive system and the EQ Visual Analogue scale. The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number expressing the level selected for that dimension. The digits for 5 dimensions can be combined in a 5-digit number describing the respondent's health state. It should be noted that the numerals 1-5 have no arithmetic properties and should not be used as a cardinal score.
Time frame: between baseline and week 48
Safety outcomes:
1. Number of Adverse events (AE) and Adverse reactions (ADR) 2. Number of Serious Adverse events (SAE) and Serious Adverse Drug Reactions (SADR) 3. Number of Suspected unexpected serious adverse reactions (SUSAR)
Time frame: between baseline and week 48
Plan to share: No
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AOP Orphan Pharmaceuticals AG