Efficacy and Safety of Granulocyte-Colony Stimulating Factor Therapy in Chagas Cardiomyopathy: A Phase II Double-Blind, Randomized, Placebo-Controlled Clinical Trial

Abstract

Aim: Previous studies showed that granulocyte-colony stimulating factor (G-CSF) improved heart function in a mice model of Chronic Chagas Cardiomyopathy (CCC). Herein, we report the interim results of the safety and efficacy of G-CSF therapy vs. placebo in adults with Chagas cardiomyopathy.

Methods: Patients with CCC, New York Heart Association (NYHA) functional class II to IV and left ventricular ejection fraction (LVEF) 50% or below were included. A randomization list using blocks of 2 and 4 and an allocation rate of 1:1 was generated by R software which was stratified by functional class. Double blinding was done to both arms and assessors were masked to allocations. All patients received standard heart failure treatment for 2 months before 1:1 randomization to either the G-CSF (10 mcg/kg/day subcutaneously) or placebo group (1 mL of 0.9% saline subcutaneously). The primary endpoint was either maintenance or improvement of NYHA class from baseline to 6-12 months after treatment, and intention-to-treat analysis was used.

Results: We screened 535 patients with CCC in Salvador, Brazil, of whom 37 were randomized. Overall, baseline characteristics were well-balanced between groups. Most patients had NYHA class II heart failure (86.4%); low mean LVEF was 32 ± 7% in the G-CSF group and 33 ± 10% in the placebo group. Frequency of primary endpoint was 78% (95% CI 0.60-0.97) vs. 66% (95% CI 0.40-0.86), p = 0.47, at 6 months and 68% (95% CI 0.43-0.87) vs. 72% (95% CI 0.46-0.90), p = 0.80, at 12 months in placebo and G-CSF groups, respectively. G-CSF treatment was safe, without any related serious adverse events. There was no difference in mortality between both arms, with five deaths (18.5%) in treatment vs. four (12.5%) in the placebo arm. Exploratory analysis demonstrated that the maximum rate of oxygen consumption during exercise (VO2 max) showed an improving trend in the G-CSF group.

Conclusion: G-CSF therapy was safe and well-tolerated in 12 months of follow-up. Although prevention of symptom progression could not be demonstrated in the present study, our results support further investigation of G-CSF therapy in Chagas cardiomyopathy patients.

Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT02154269].

Keywords: Chagas cardiomyopathy; G-CSF therapy; NYHA functional class; cardiac functional analysis; safety study.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Macedo, Larocca, Noya-Rabelo, Aras, Macedo, Moreira, Caldas, Torreão, Monsão, Souza, Vasconcelos, Bezerra, Petri, Souza, Pacheco, Daher, Ribeiro-dos-Santos and Soares.

Figures

FIGURE 1

Study time chart. Patients were screened for eligibility before optimization of pharmacological therapy for at least 8 weeks. Patients included in the study were randomized to receive granulocyte-colony stimulating factor (G-CSF) or placebo and were followed up for 12 months.

FIGURE 2

Flowchart showing the flow of patients throughout the trial. ITT, intention-to-treat.

FIGURE 3

Progression of NYHA functional class at 6 and 12 months (p = 0.47 and 0.80, respectively). Favorable: Improvement of NYHA class; Unfavorable: Worsening of NYHA class.

FIGURE 4

NYHA class distributions at baseline (T = 0) (A), at 6 months (B) and 12 months (C) after treatment (p = 0.20 and 0.38, respectively).