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

Pulmonary Arterial Hypertension Clinical Trial

— TripleTRE  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06317805
• Other study ID #: TREV1-10P.401
• Secondary ID: 2023-504351-26-0
• Status: Recruiting
• Phase: Phase 4
• Start date: December 6, 2023
• Est. completion date: June 30, 2027

Study information

• Verified date: March 2024
• Source: AOP Orphan Pharmaceuticals AG
• Contact: Clinical Project Manager
• Phone: +43676 3464650
• Email: tripletre[@]aoporphan.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 110
• Est. completion date: June 30, 2027
• Est. primary completion date: June 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Generic treprostinil sodium + 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.
• Standard of Care - Double Oral
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

Country	Name	City	State
Austria	Ordensklinikum Linz	Linz
Austria	Medical University Vienna	Vienna
Czechia	Fakultní Nemocnice Olomouc	Olomouc
Czechia	Všeobecná fakultní nemocnice v Praze	Praha
France	Hôpital Bicêtre-- Assistance Publique Hopitaux de Paris	Paris
France	Hôpitaux Universitaires de Strasbourg	Strasbourg
Germany	DRK Kliniken Berlin Westend	Berlin
Germany	University Hospital Carl Gustav Carus of Technical University Dresden	Dresden
Germany	Universitätsmedizin Greifswald	Greifswald
Hungary	Gottsegen National Cardiovascular lnstitute	Budapest
Hungary	Medical University of Szeged	Szeged
Italy	Sapienza University of Rome	Rome
Poland	John Paul II Hospital Krakow	Kraków
Poland	Fryderyk Chopin Hospital in European Health Centre Otwock	Otwock
Portugal	Centro Hospitalar Lisboa Norte - Santa Maria University Hospital	Lisboa
Romania	Emergency Institute for Cardiovascular Diseases Prof. Dr. C.C.Iliescu	Bucharest
Romania	Emergency Clinical County Hospital of Targu Mures	Târgu-Mures
Spain	Hospital Clinic of Barcelona	Barcelona
Spain	Hospital Ramon y Cajal	Madrid

Sponsors (5)

Lead Sponsor	Collaborator
AOP Orphan Pharmaceuticals AG	Aixial s.r.o., ANOVA CRO s.r.o., GCP-Service International Ltd. & Co. KG, PharmaLex Belgium

Countries where clinical trial is conducted

Austria,  Czechia,  France,  Germany,  Hungary,  Italy,  Poland,  Portugal,  Romania,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety outcomes:	Number of Adverse events (AE) and Adverse reactions (ADR); Number of Serious Adverse events (SAE) and Serious Adverse Drug Reactions (SADR); Number of Suspected unexpected serious adverse reactions (SUSAR)	between baseline and week 48
Primary	Patients achieving (non-)response status to the assigned treatment in terms of achievement of low-risk status	Therapy-responder: achievement of low-risk status between week 24 and week 48; Therapy-non-responder: PH related deterioration to high-risk status, lung transplantation or death between week 12 and week 48 and/or; additional medication or change of initial PH specific medication due to unsatisfactory efficacy between week 12 and week 48 and/or; 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.	between week 12 and week 48 from baseline (BL)
Secondary	Change in hemodynamic parameters by means of right heart catheterization (RHC) - PVR	Pulmonary Vascular Resistance (PVR) measured in WU	at week 24 from baseline (BL)
Secondary	Change in hemodynamic parameters by means of right heart catheterization (RHC) - mPAP	Mean pulmonary arterial pressure (mPAP) measured in mmHg	at week 24 from baseline (BL)
Secondary	Change in hemodynamic parameters by means of right heart catheterization (RHC) - mRAP	Mean right atrial pressure (mRAP) measured in mmHg	at week 24 from baseline (BL)
Secondary	Change in hemodynamic parameters by means of right heart catheterization (RHC) - CI	Cardiac index (CI) measured in liters per minute per square meter	at week 24 from baseline (BL)
Secondary	Change in hemodynamic parameters by means of right heart catheterization (RHC) - CO	Cardiac output (CO) measured in liters per minute	at week 24 from baseline (BL)
Secondary	Change in hemodynamic parameters by means of right heart catheterization (RHC) - RAP	Right atrial pressure (RAP) measured in mmHg	at week 24 from baseline (BL)
Secondary	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)	at week 24 from baseline (BL)
Secondary	Change in right heart structure and function assessed by echocardiography - RVEDA	RV end-diastolic area (RVEDA) measured in square centimeters	at week 24 from baseline (BL)
Secondary	Change in right heart structure and function assessed by echocardiography - RVESA	RV end-systolic area (RVESA) measured in square centimeters	at week 24 from baseline (BL)
Secondary	Change in right heart structure and function assessed by echocardiography - RVFAC	RV fractional area change (RVFAC) calculated in %	at week 24 from baseline (BL)
Secondary	Change in right heart structure and function assessed by echocardiography - RA	Right Atrium (RA) area in square centimeters	at week 24 from baseline (BL)
Secondary	Change in right heart structure and function assessed by echocardiography - Pericardial effusion	Pericardial effusion assessment will be done and rated as yes/no	at week 24 from baseline (BL)
Secondary	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 from baseline (BL) up to week 48
Secondary	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	between baseline and week 48
Secondary	Change in the number of low-risk criteria based on the French PH Network Registry (FPHR) risk assessment tool		between baseline and week 24
Secondary	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%	between baseline and week 24
Secondary	Rate of change in WHO-FC		between baseline and week 48
Secondary	Rate of change in 6MWD		between baseline and week 48
Secondary	Rate of change in NT-proBNP/BNP levels		between baseline and week 48
Secondary	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	between baseline and week 48
Secondary	Overall and transplant free survival		between baseline and week 48
Secondary	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.	between baseline and week 48
Secondary	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.	between baseline and week 48