Ignite Creation Date:
2024-05-06 @ 12:43 PM
Last Modification Date:
2024-10-26 @ 1:03 PM
Study NCT ID:
NCT03835676
Status:
RECRUITING
Last Update Posted:
2022-12-15
First Post:
2019-02-06
Brief Title:
Effects of Treprostinil on Right Ventricular Structure and Function in Patients With Pulmonary Arterial Hypertension
Sponsor:
Magdi H Yacoub
Organization:
Magdi Yacoub Heart Foundation
Study Overview
Official Title:
Effects of Treprostinil on Right Ventricular Structure and Function in Patients With Pulmonary Arterial Hypertension
Status:
RECRUITING
Status Verified Date:
2022-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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
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 patients 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 sizemass makes the assessment of results difficult longer term studies of epoprostenol have not shown a positive treatment effect on RV sizemass 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 45 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 eg 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
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 patients 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 sizemass makes the assessment of results difficult longer term studies of epoprostenol have not shown a positive treatment effect on RV sizemass 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 45 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 eg 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None