Pentoxifylline as an Adjunct Therapy for Patients With Eisenmenger Syndrome

Sponsor

University of Sao Paulo General Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT05611268

Collaborator

InCor Heart Institute (Other)

Enrollment

Location

Arms

51.9

Anticipated Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Condition or Disease	Intervention/Treatment	Phase
Eisenmenger Syndrome	Drug: Pentoxifylline	N/A

Detailed Description

The Eisenmenger syndrome corresponds to the most advanced form of pulmonary arterial hypertension associated with congenital heart disease. The syndrome causes chronic hypoxemia, with an increase in erythrocyte mass, which predisposes to thrombotic complications. It also involves endothelial dysfunction characterized by increase in the circulating levels of von Willebrand factor, tissue-type plasminogen activator and P-selectin, with a reduction in the plasma concentration of thrombomodulin. The usual drug treatment is represented by the use of prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors and, eventually, anticoagulation with warfarin. However, the difficulty of controlling the chronic use of warfarin and the few studies with other oral anticoagulants, brings the possibility of using drugs not specifically designated as coagulation inhibitors, such as pentoxifylline. This drug is a xanthine derivative and it is considered as a hemorrheological agent with described effects of reduction in erythrocyte and platelet aggregation, adhesion and activation of leukocytes, and endothelial damage. It is, therefore, considered as an agent capable of reducing blood viscosity and improving erythrocyte deformability probably due to an increase in intracellular adenosine triphosphate (ATP), with a reduction in Ca++ and phosphorylation of membrane proteins. The objective of this study is to verify if the chronic oral administration of pentoxifylline: 1) induces an increase in the circulating levels of thrombomodulin, a naturally occurring proteoglycan with anticoagulant, anti thrombotic and anti-inflammatory properties; 2) stabilizes or induces a reduction in circulating tissue factor and thrombin-antithrombin complexes; 3) changes the expression of thrombomodulin and tissue factor in circulating monocytes; 4) offers protection against the occurrence of predefined clinical events; 5) provides improvement in physical capacity, peripheral oxygen saturation, hematocrit level and right ventricular function. The main study outcome is biochemical: change from baseline (increase) in circulating levels of thrombomodulin at 3 months and 6 months of oral use of pentoxifylline. It will be a prospective, single-center, randomized study. Forty-eight adult patients with Eisenmenger syndrome who are already using specific therapies for pulmonary arterial hypertension will be included and these will be randomized to receive pentoxifylline as an adjunctive treatment or remain under routine therapeutic measures for pulmonary arterial hypertension. Oral pentoxifylline will be started at the dose of 400 mg/day for 30 days, followed by 800 mg/day for 5 months, completing the 6-month period of the study. The routine treatment for pulmonary arterial hypertension will be maintained for all patients.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

48 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

Single (Outcomes Assessor)

Masking Description:

The professional responsible for obtainment of laboratory data including outcome measures will not have access to any clinical data or patient allocation to the study groups.

Primary Purpose:

Treatment

Official Title:

Pentoxifylline as an Adjunct Therapy for Patients With Eisenmenger Syndrome: a Randomized Study

Actual Study Start Date :

Jun 3, 2022

Anticipated Primary Completion Date :

Sep 30, 2024

Anticipated Study Completion Date :

Sep 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: No treatment group 24 patients that will continue receiving routine treatment for PAH
Other: Pentoxifylline 24 patients that will receive pentoxifylline and the routine treatment for PAH	Drug: Pentoxifylline Oral Pentoxifylline 400 mg/day for 30 days, followed by 800 mg/day for 150 days

Arm

Intervention/Treatment

No Intervention: No treatment group

24 patients that will continue receiving routine treatment for PAH

Other: Pentoxifylline

24 patients that will receive pentoxifylline and the routine treatment for PAH

Drug: Pentoxifylline

Oral Pentoxifylline 400 mg/day for 30 days, followed by 800 mg/day for 150 days

Outcome Measures

Primary Outcome Measures

Plasma concentration of Thrombomodulin [3 months and 6 months]
Change in plasma concentration of thrombomoduin at 3 months and 6 months of pentoxifylline therapy compared to baseline.

Secondary Outcome Measures

Plasma concentration of tissue factor [3 months and 6 months]
Change in plasma concentration of tissue factor at 3 months and 6 months of pentoxifylline therapy compared to baseline.
Monocyte thrombomodulin content [3 months and 6 months]
Change in mean fluorescence intensity (MFI) for thrombomodulin in circulating (blood) monocytes measured by flow cytometry 3 months and 6 months of pentoxifylline therapy compared to baseline.
Monocyte tissue factor content [3 months and 6 months]
Change in mean fluorescence intensity (MFI) for tissue factor in circulating (blood) monocytes measured by flow cytometry 3 months and 6 months of pentoxifylline therapy compared to baseline.
Plasma concentration of other markers of thrombosis [3 months and 6 months]
Change in plasma concentration of D-dimer and thrombin-antithrombin complexes at 3 months and 6 months of pentoxifylline therapy compared to baseline.

Eligibility Criteria

Criteria

Ages Eligible for Study:

10 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Eisenmenger syndrome in functional class II, III or IV (World Health Organization for Pulmonary Hypertension).
Using or not oral anticoagulation with warfarin.