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

Pulmonary Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03835676
• Other study ID #: Treprostinil RV
• Status: Recruiting
• Phase: Phase 4
• Start date: May 1, 2019
• Est. completion date: December 1, 2025

Study information

• Verified date: December 2022
• Source: Magdi Yacoub Heart Foundation
• Contact: Ahmed M ElGuindy, MD, MRCP
• Phone: +201001615151
• Email: ahmed_elguindy[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 1, 2025
• Est. primary completion date: June 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• 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.

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Arterial Hypertension
• Pulmonary Hypertension

Intervention

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)

Locations

Country	Name	City	State
Egypt	Aswan Heart Centre - Magdi Yacoub Heart Foundation	Aswan

Sponsors (1)

Lead Sponsor	Collaborator
Magdi H. Yacoub

Country where clinical trial is conducted

Egypt, 

References & Publications (20)

Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jobsis MM, Blackburn SD, Shortino D, Crow JW; Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996 Feb 1;334(5):296-301. doi: 10.1056/NEJM199602013340504. — View Citation

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Gomberg-Maitland M, Tapson VF, Benza RL, McLaughlin VV, Krichman A, Widlitz AC, Barst RJ. Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med. 2005 Dec 15;172(12):1586-9. doi: 10.1164/rccm.200505-766OC. Epub 2005 Sep 8. — View Citation

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Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M. Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers. J Cardiovasc Pharmacol. 2004 Aug;44(2):209-14. doi: 10.1097/00005344-200408000-00010. — View Citation

McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J; American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009 Apr 28;53(17):1573-619. doi: 10.1016/j.jacc.2009.01.004. No abstract available. — View Citation

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Quaife RA, Chen MY, Lynch D, Badesch DB, Groves BM, Wolfel E, Robertson AD, Bristow MR, Voelkel NF. Importance of right ventricular end-systolic regional wall stress in idiopathic pulmonary arterial hypertension: a new method for estimation of right ventricular wall stress. Eur J Med Res. 2006 May 5;11(5):214-20. — View Citation

Roeleveld RJ, Vonk-Noordegraaf A, Marcus JT, Bronzwaer JG, Marques KM, Postmus PE, Boonstra A. Effects of epoprostenol on right ventricular hypertrophy and dilatation in pulmonary hypertension. Chest. 2004 Feb;125(2):572-9. doi: 10.1378/chest.125.2.572. — View Citation

Sebbag I, Rudski LG, Therrien J, Hirsch A, Langleben D. Effect of chronic infusion of epoprostenol on echocardiographic right ventricular myocardial performance index and its relation to clinical outcome in patients with primary pulmonary hypertension. Am J Cardiol. 2001 Nov 1;88(9):1060-3. doi: 10.1016/s0002-9149(01)01995-6. No abstract available. — View Citation

Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ; Treprostinil Study Group. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002 Mar 15;165(6):800-4. doi: 10.1164/ajrccm.165.6.2106079. — View Citation

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Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000 Nov 28;102(22):2700-6. doi: 10.1161/01.cir.102.22.2700. Erratum In: Circulation 2001 Jan 23;103(3):476. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Assessment of Treprostinil effects on right ventricular structure and function using echocardiography	Assessment of RV structure and function by echocardiography	through study completion, an average of 5 years
Primary	Assessment of Treprostinil effects on right ventricular structure and function using Cardiac Magnetic Resonance Imaging (CMR).	Assessment of RV structure and function by cardiac magnetic resonance imaging (CMR).	through study completion, an average of 5 years
Secondary	Correlate changes in RV structure and function with World Health Organisation (WHO) Class.	correlate changes in RV structure and function with the WHO class.	through study completion, an average of 5 years
Secondary	Correlate changes in RV structure and function with the Six-minute walk test results	correlate changes in RV structure and function with the Six-minute walk test results	through study completion, an average of 5 years
Secondary	Correlate changes in RV structure and function with QoL	correlate changes in RV structure and function with the Quality of life (QoL)	through study completion, an average of 5 years
Secondary	Correlate changes in RV structure and function with prespecified biomarkers	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