Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study),Journal of Hepatology

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Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study)
Journal of Hepatology ( IF 26.8 ) Pub Date : 2021-08-05 , DOI: 10.1016/j.jhep.2021.07.033
Cornelius Engelmann ₁ , Adam Herber ₂ , Annegret Franke ₃ , Tony Bruns ₄ , Philipp Reuken ₅ , Ingolf Schiefke ₆ , Alexander Zipprich ₇ , Stefan Zeuzem ₈ , Tobias Goeser ₉ , Ali Canbay ₁₀ , Christoph Berg ₁₁ , Jonel Trebicka ₁₂ , Frank E Uschner ₁₃ , Johannes Chang ₁₄ , Tobias Mueller ₁₅ , Niklas Aehling ₂ , Moritz Schmelzle ₁₆ , Katrin Splith ₁₆ , Frank Lammert ₁₇ , Christian M Lange ₁₈ , Christoph Sarrazin ₁₉ , Christian Trautwein ₂₀ , Michael Manns ₂₁ , Dieter Häussinger ₂₂ , Jan Pfeiffenberger ₂₃ , Peter R Galle ₂₄ , Anett Schmiedeknecht ₃ , Thomas Berg ₂

Affiliation

Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany; Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany.
Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.
Clinical Trial Centre (ZKS) Leipzig, Faculty of Medicine, University Leipzig, Leipzig, Germany.
Department of Medicine III, Aachen University Hospital, Aachen, Germany; Clinic for Internal Medicine IV, University Hospital Jena, Jena, Germany.
Clinic for Internal Medicine IV, University Hospital Jena, Jena, Germany.
Clinic for Gastroenterology, Hepatology and Endocrinology, St. Georg Hospital, Leipzig, Germany.
University Hospital for Internal Medicine 1, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany.
Clinic for Gastroenterology and Hepatology, University Hospital Cologne, Cologne, Germany.
Medical Department, University Hospital Ruhr-University Bochum, Bochum, Germany.
Department of Internal Medicine I, University Hospital Tuebingen, Tuebingen, Germany.
Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain; Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; Clinic for Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany.
Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; Medical Clinic 2, St. Josefs Hospital Wiesbaden, Wiesbaden, Germany.
Department of Medicine III, Aachen University Hospital, Aachen, Germany.
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Clinic and Policlinic of Gastroenterology, Hepatology and Infectious Disease, Heinrich Heine University Duesseldorf, Düsseldorf, Germany.
Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany.
Department of Internal Medicine, University Medical Center Mainz, Mainz, Germany.

Background & Aims

Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF.

Methods

In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 μg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n = 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period.

Results

Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711–1.551; p = 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697–1.430; p = 0.992 and HR 1.058; 95% CI 0.727–1.548; p = 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation.

Conclusions

In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF.

ClinicalTrials.gov number

NCT02669680

Lay summary

Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.

中文翻译：

粒细胞集落刺激因子 (G-CSF) 治疗慢加急性肝衰竭：一项多中心随机试验（GRAFT 研究）

背景与目标

基于小型单中心研究的积极结果，粒细胞集落刺激因子 (G-CSF) 正在广泛用于治疗慢加急性肝衰竭 (ACLF) 患者。在此，我们旨在评估 G-CSF 在 ACLF 患者中的安全性和有效性。

方法

在这项多中心、前瞻性、对照、开放标签的 II 期研究中，176 名 ACLF（EASL-CLIF 标准）患者被随机分配接受 G-CSF（前 5 天每天 5 μg/kg，此后每三天一次，直到第26) 加上标准药物治疗 (SMT) (n = 88) 或单独的 SMT。主要疗效终点是通过 Cox 回归模型分析的 90 天无移植生存期。关键的次要终点是 360 天后的总体和无移植生存、ACLF 相关并发症的发展以及整个观察期间的肝功能评分过程。

结果

接受 G-CSF 治疗的患者 90 天无移植生存率为 34.1%，而 SMT 组为 37.5%（风险比 [HR] 1.05；95% CI 0.711–1.551；p = 0.805）。360 天的无移植生存期和总生存期在 2 组之间没有差异（HR 0.998；95% CI 0.697–1.430；p = 0.992 和 HR 1.058；95% CI 0.727–1.548；p =0.768，分别）。G-CSF 未改善无感染、酒精相关 ACLF 或 APASL 标准定义的 ACLF 患者亚组的肝功能评分、感染发生率或存活率。G-CSF+SMT 组报告了 61 例严重不良事件，SMT 组报告了 57 例。G-CSF组共发生7例药物相关的严重不良反应。该研究在条件功效计算后因无效而提前终止。