Effects of Treprostinil on Right Ventricular Structure and Function in Patients With Pulmonary Arterial Hypertension

December 14, 2022 updated by: Magdi H. Yacoub
In a group of patients with PAH treated with treprostinil, the current study aims to investigate the effect of treatment on RV structure and function; and correlate changes in RV structure and function with: World Health Organisation (WHO) class, Six-minute walk test, Quality of life (QoL), and Pre-specified biomarkers (N-terminal B-type natriuretic peptide (NT-ProBNP), Tissue growth factor-B B-type natriuretic peptide BNP, and Profibrotic markers)

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

A) Right ventricle (RV) in pulmonary hypertension

RV failure is the main cause of death in patients with pulmonary arterial hypertension (PAH), and the ability of the RV to adapt to the progressive increase in pulmonary vascular resistance associated with changes to the pulmonary vasculature in PAH is the main determinant of a patient's functional capacity and survival.

The response of the right ventricle (RV) to the increase in afterload produced by the pulmonary vascular changes characteristic of PAH is the key factor in the development of symptoms and in determining survival. Structurally, rising systolic and diastolic ventricular pressures increase diastolic and systolic stretch on the RV wall, which leads initially to an increase in muscle mass (adaptive hypertrophy) due to increased protein synthesis and an increase in cardiomyocyte size through the addition of sarcomeres. However, the RV cannot maintain adaptive hypertrophy in the face of sustained pressure overload, and eventually there is a transition to dilatation. At this stage there is no further increase, or even a decrease, in RV contractility, despite a further increase in load. One consequence of RV dilatation is an increase in wall tension, which increases myocardial oxygen demand and simultaneously decreases RV perfusion, leading to further compromised contractility and dilatation.

The exact mechanisms leading to the development of RV failure in patients with PAH are still unclear. Several mechanisms have been hypothesized: RV myocardial ischaemia, microvascular endothelial cell dysfunction, and myocyte apoptosis. In severe end-stage PAH, the RV changes its shape from the normal conformation to a more spherical one, and RV wall stress increases because RV wall thickness does not increase proportionally.

Given the importance of the RV in PAH, preservation and improvement of its function should be important aspects of therapy; however, there are currently few data specifically related to this aspect of treatment response.

B) Vasodilator therapy and RV in pulmonary hypertension Although RV failure is the main cause of death in patients with pulmonary arterial hypertension (PAH), there is insufficient data about the effects of PAH treatment on RV geometry and function mainly because the RV assessment has been hampered by its complex crescentic shape, large infundibulum, and its trabecular nature. . This is specifically true for vasodilator therapies. Such therapies may affect the RV via direct cardiac-specific effects or indirect effects by reducing RV load. In a meta-analysis of clinical studies of PAH-specific therapies, active treatment was associated with a reduction in pulmonary vascular resistance which was accompanied by a decrease in pulmonary artery pressure, and an increase in stroke volume, but without an increase in contractility, suggesting that current PAH therapies have predominantly pulmonary vasodilating effects and have limited cardiac-specific effects. In a study of epoprostenol therapy, beneficial effects on RV structure and function (RV dilatation, curvature of the interventricular septum and maximal tricuspid regurgitant jet velocity) compared with placebo were reported following 12 weeks of treatment, with change in 6-min walk distance between baseline and 12 weeks being inversely related to the change in diastolic eccentricity index and pericardial effusion size. Such improvements may contribute to the clinical improvement and prolonged survival observed with epoprostenol in other studies.

Other evidence of improvements in RV parameters has come from descriptive studies using a number of PAH-specific therapies; however, these generally include a small number of patients, and this, together with the fact that such studies evaluated different parameters (both in terms of functional parameters and measures of RV size/mass), makes the assessment of results difficult. longer term studies of epoprostenol have not shown a positive treatment effect on RV size/mass although without a comparator arm it is not possible to determine whether long-term therapy slowed down the rate of RV hypertrophy or dilatation.

Overall, therefore, the effects of PAH-specific therapies on RV function remain to be fully investigated.

C) Treprostinil Treprostinil is a tricyclic benzindene analogue of prostacyclin, and has as such similar anti-platelet and vasodilatory actions, including acute pulmonary vasodilation.

Treprostinil, a stable prostacyclin analog, has similar pharmacologic effects to epoprostenol, However, in contrast to epoprostenol, treprostinil is chemically stable at room temperature and neutral 'power of hydrogen' (pH) and has a longer half-life (elimination half-life of 4.5 h with distribution half-life of 40 min, compared with 2 to 3 min for epoprostenol) permitting continuous subcutaneous infusion (16). Treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and quality of life in patients with pulmonary arterial hypertension.

D) Assessment of RV with cardiac magnetic resonance imaging Currently, the most widely used noninvasive techniques are echocardiography and cardiac magnetic resonance imaging), and a number of potential indicators assessed using these methods have been proposed. Cardiac magnetic resonance imaging provides a higher spatial resolution, and is not limited by factors affecting echocardiography (e.g. acoustic window). Cardiac magnetic resonance imaging allows for the visualisation and measurement of complex three-dimensional geometry and it is therefore particularly suited to the complex morphology of the RV. Precise, noninvasive assessment of cardiac volumes and function is possible, without the need for geometric approximations, while assessments such as flow measurements in the heart and great vessels using techniques such as cine phase-contrast provide more comprehensive data on cardiac function than echocardiography.

Study Type

Interventional

Enrollment (Anticipated)

30

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Egypt
      • Aswan, Egypt
        • Recruiting
        • Aswan Heart Centre - Magdi Yacoub Heart Foundation
        • Contact:
        • Contact:
        • Principal Investigator:
          • Magdi H Yacoub, OM FRS

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • Inclusion Criteria:

    • PAH defined as a mean pulmonary artery pressure >25 mmHg on right heart catheterization at rest in the setting of a normal pulmonary arterial wedge pressure ≤15 mm Hg
    • PAH that is idiopathic, familial, or associated with connective tissue disease.
    • WHO class III or class IV despite the use of Endothelin receptor antagonists (ERA) and/or phosphodiesterase-5 inhibitors
    • Age > 18 years
    • Sinus rhythm

  • Exclusion Criteria:

    • Patients with PAH associated with HIV infection, portal hypertension, congenital heart disease, schistosomiasis, chronic haemolytic anaemia
    • Patients with pulmonary hypertension due to veno-occlusive disease and/or pulmonarycapillary haemangiomatosis, thromboembolism.
    • Patients with left side heart disease that may contribute to pulmonary hypertension. Those patients are identified by having pulmonary wedge pressure >15 mmHg or elevated Left Ventricle (LV) end-diastolic pressure
    • Patients who are severely disabled and will not be able to complete the study
    • Patients with significant lung disease as shown by forced vital capacity (FVC) < 70% predicted, or forced expiratory volume at one second (FEV1)/FVC < 50% - Life expectancy <1 year due to severe PAH or any other forms of terminal disease.
    • Pregnant women
    • Refusal to give informed consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pulmonary hypertension treated with Treprostinil
Thirty patients who will be treated with Treprostinil.
Drug: Treprostinil

After inclusion and baseline measurements, patients will receive treprostinil in addition to background therapy for 24 months. Follow-up assessment will include:

  • Clinical, echocardiographic, laboratory assessments will be repeated at 1, 3, 6, 12, 18, and 24 month (or when there is clinical indication)
  • CMR will be performed at 6 monthly intervals for 2 years.
  • Peak power output at 6,12, 18 and 24 month
  • Right-side cardiac catheterization will be performed at 6, 12 , 18 and 24 months (or when there is clinical indication)
Other Names:
  • Remodulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assessment of Treprostinil effects on right ventricular structure and function using echocardiography
Time Frame: through study completion, an average of 5 years
Assessment of RV structure and function by echocardiography
through study completion, an average of 5 years
Assessment of Treprostinil effects on right ventricular structure and function using Cardiac Magnetic Resonance Imaging (CMR).
Time Frame: through study completion, an average of 5 years
Assessment of RV structure and function by cardiac magnetic resonance imaging (CMR).
through study completion, an average of 5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlate changes in RV structure and function with World Health Organisation (WHO) Class.
Time Frame: through study completion, an average of 5 years
correlate changes in RV structure and function with the WHO class.
through study completion, an average of 5 years
Correlate changes in RV structure and function with the Six-minute walk test results
Time Frame: through study completion, an average of 5 years
correlate changes in RV structure and function with the Six-minute walk test results
through study completion, an average of 5 years
Correlate changes in RV structure and function with QoL
Time Frame: through study completion, an average of 5 years
correlate changes in RV structure and function with the Quality of life (QoL)
through study completion, an average of 5 years
Correlate changes in RV structure and function with prespecified biomarkers
Time Frame: through study completion, an average of 5 years
correlate changes in RV structure and function with the Pre-specified biomarkers (NT-ProBNP, Tissue growth factor-B BNP, and Profibrotic markers)
through study completion, an average of 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Magdi H. Yacoub

Investigators

  • Study Chair: Magdi H Yacoub, OM FRS, Magdi Yacoub Heart Foundation - Aswan Heart Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2019

Primary Completion (Anticipated)

June 1, 2025

Study Completion (Anticipated)

December 1, 2025

Study Registration Dates

First Submitted

February 6, 2019

First Submitted That Met QC Criteria

February 6, 2019

First Posted (Actual)

February 8, 2019

Study Record Updates

Last Update Posted (Actual)

December 15, 2022

Last Update Submitted That Met QC Criteria

December 14, 2022

Last Verified

December 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Treprostinil RV

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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