Pentoxifylline as an Adjunct Therapy for Patients With Eisenmenger Syndrome

NCT ID: NCT05611268

Last Updated: 2023-12-15

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-06-03
• Study Completion Date: 2026-09-30

Brief Summary

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. Pentoxifylline 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. The main objective of this study is to verify if the chronic oral administration of pentoxifylline to Eisenmenger patients induces an increase in the circulating levels of thrombomodulin, a naturally occurring proteoglycan with anticoagulant, anti thrombotic and anti-inflammatory properties.

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.

Conditions

Eisenmenger Syndrome

Keywords

Pulmonary Hypertension; Congenital Heart Disease; Thrombosis; Pentoxifylline; Thrombomodulin; Tissue Factor

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

No treatment group

24 patients that will continue receiving routine treatment for PAH

Group Type: NO_INTERVENTION

No interventions assigned to this group

Pentoxifylline

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

Group Type: OTHER

Pentoxifylline

Intervention Type: DRUG

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

Interventions

Pentoxifylline

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Eisenmenger syndrome in functional class II, III or IV (World Health Organization for Pulmonary Hypertension).

2. Using or not oral anticoagulation with warfarin.

Exclusion Criteria

1. Hospitalized.

2. History of relevant and/or repetitive bleeding.

3. Relevant comorbidities with specific treatments.

4. Systemic syndromes, except Down syndrome.

5. Candidates for surgical treatment of any nature, except dental.

6. Clinically manifest systemic infectious or inflammatory disease.

7. Thrombocytopenia (<80x10*9 platelets/L).

8. Patients in chronic anticoagulation regimen other than warfarin.

9. Diabetics individuals.

10. Pregnancy in progress, interruption of contraception or amenorrhea.

11. History of intolerance of pentoxifylline or other xanthine derivatives.

12. "Creatinine clearance" less than or equal to 30 mL/minute.

• Minimum Eligible Age: 10 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

InCor Heart Institute

OTHER

Sponsor Role: collaborator

University of Sao Paulo General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Antonio Augusto Barbosa Lopes, MD

Role: PRINCIPAL_INVESTIGATOR

InCor Heart Institute

Locations

Antonio Augusto Barbosa Lopes

São Paulo, , Brazil

Site Status: RECRUITING

Countries

Brazil

Central Contacts

Antonio Augusto Barbosa Lopes, MD

Role: CONTACT

Phone: +55 11 2661-5409

Email: aablopes@usp.br

Mariana Cappelletti Galante, PharmD

Role: CONTACT

Phone: +55112661-5709

Email: Mariana.galante@hc.fm.usp.br

Facility Contacts

MarianaCappelletti Galante, PharmD

Role: primary

Other Identifiers

CAAE 57562322.5.0000.0068

Identifier Type: -

Identifier Source: org_study_id