Cornelius Engelmann1, Adam Herber2, Annegret Franke3, Tony Bruns4, Philipp Reuken5, Ingolf Schiefke6, Alexander Zipprich7, Stefan Zeuzem8, Tobias Goeser9, Ali Canbay10, Christoph Berg11, Jonel Trebicka12, Frank E Uschner13, Johannes Chang14, Tobias Mueller15, Niklas Aehling2, Moritz Schmelzle16, Katrin Splith16, Frank Lammert17, Christian M Lange18, Christoph Sarrazin19, Christian Trautwein20, Michael Manns21, Dieter Häussinger22, Jan Pfeiffenberger23, Peter R Galle24, Anett Schmiedeknecht3, Thomas Berg25. 1. 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. 2. Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany. 3. Clinical Trial Centre (ZKS) Leipzig, Faculty of Medicine, University Leipzig, Leipzig, Germany. 4. Department of Medicine III, Aachen University Hospital, Aachen, Germany; Clinic for Internal Medicine IV, University Hospital Jena, Jena, Germany. 5. Clinic for Internal Medicine IV, University Hospital Jena, Jena, Germany. 6. Clinic for Gastroenterology, Hepatology and Endocrinology, St. Georg Hospital, Leipzig, Germany. 7. University Hospital for Internal Medicine 1, Martin-Luther-University Halle-Wittenberg, Halle, Germany. 8. Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany. 9. Clinic for Gastroenterology and Hepatology, University Hospital Cologne, Cologne, Germany. 10. Medical Department, University Hospital Ruhr-University Bochum, Bochum, Germany. 11. Department of Internal Medicine I, University Hospital Tuebingen, Tuebingen, Germany. 12. 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. 13. Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; Department of Internal Medicine I, University of Bonn, Bonn, Germany. 14. Department of Internal Medicine I, University of Bonn, Bonn, Germany. 15. Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany. 16. Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinik, Charité - Universitätsmedizin Berlin, Berlin, Germany. 17. Department of Medicine II, Saarland University Medical Center, Homburg, Germany. 18. Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; Clinic for Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany. 19. Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt, Germany; Medical Clinic 2, St. Josefs Hospital Wiesbaden, Wiesbaden, Germany. 20. Department of Medicine III, Aachen University Hospital, Aachen, Germany. 21. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 22. Clinic and Policlinic of Gastroenterology, Hepatology and Infectious Disease, Heinrich Heine University Duesseldorf, Düsseldorf, Germany. 23. Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany. 24. Department of Internal Medicine, University Medical Center Mainz, Mainz, Germany. 25. Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany. Electronic address: thomas.berg@medizin.uni-leipzig.de.
Abstract
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.
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.
Authors: John A Tayek; Andrew A Stolz; Danh V Nguyen; M Wayne Fleischman; John A Donovan; Joseph M Alcorn; Daniel C-K Chao; Aliya Asghar; Timothy R Morgan Journal: EClinicalMedicine Date: 2022-10-12