粒细胞集落刺激因子治疗恰加斯心肌病的疗效与安全性：一项II期双盲、随机、安慰剂对照临床试验

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

作者信息

Macedo Carolina T, Larocca Ticiana F, Noya-Rabelo Márcia, Aras Roque, Macedo Cristiano R B, Moreira Moisés I, Caldas Alessandra C, Torreão Jorge A, Monsão Victor M A, Souza Clarissa L M, Vasconcelos Juliana F, Bezerra Milena R, Petri Daniela P, Souza Bruno S F, Pacheco Antônio G F, Daher André, Ribeiro-Dos-Santos Ricardo, Soares Milena B P

机构信息

Department of Cardiology, Hospital São Rafael, Salvador, Brazil.

Gonçalo Moniz Institute, Oswaldo Cruz Foundation, Salvador, Brazil.

出版信息

Front Cardiovasc Med. 2022 Jun 9;9:864837. doi: 10.3389/fcvm.2022.864837. eCollection 2022.

DOI:10.3389/fcvm.2022.864837

PMID:35757326

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9222127/

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), = 0.47, at 6 months and 68% (95% CI 0.43-0.87) vs. 72% (95% CI 0.46-0.90), = 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 (VO 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].

摘要

目的

先前的研究表明，粒细胞集落刺激因子（G-CSF）可改善慢性恰加斯心肌病（CCC）小鼠模型的心脏功能。在此，我们报告G-CSF治疗与安慰剂相比，在成年恰加斯心肌病患者中的安全性和有效性的中期结果。

方法

纳入纽约心脏协会（NYHA）心功能II至IV级且左心室射血分数（LVEF）为50%或更低的CCC患者。使用R软件生成了2和4的区组随机列表，分配率为1:1，并按心功能分级进行分层。对两组均进行双盲，评估者对分配情况不知情。所有患者在1:1随机分组至G-CSF组（皮下注射10 mcg/kg/天）或安慰剂组（皮下注射1 mL 0.9%生理盐水）之前，先接受2个月的标准心力衰竭治疗。主要终点是从基线到治疗后6至12个月NYHA分级维持或改善情况，并采用意向性分析。

结果

我们在巴西萨尔瓦多筛查了535例CCC患者，其中37例被随机分组。总体而言，两组间基线特征均衡。大多数患者为NYHA II级心力衰竭（86.4%）；G-CSF组的平均LVEF较低，为32±7%，安慰剂组为33±10%。在6个月时，主要终点的发生率在安慰剂组和G-CSF组分别为66%（95%CI 0.40-0.86）和78%（95%CI 0.60-0.97），P = 0.47；在12个月时，分别为72%（95%CI 0.46-0.90）和68%（95%CI 0.43-0.87），P = 0.80。G-CSF治疗是安全的，未出现任何相关严重不良事件。两组间死亡率无差异，治疗组有5例死亡（18.5%），安慰剂组有4例死亡（12.5%）。探索性分析表明，G-CSF组运动期间最大耗氧率（VO max）呈改善趋势。