John A Tayek1, Andrew A Stolz2, Danh V Nguyen3, M Wayne Fleischman1, John A Donovan2, Joseph M Alcorn4, Daniel C-K Chao5, Aliya Asghar6, Timothy R Morgan7,8. 1. Department of Medicine, Harbor-UCLA Medical Center and Lundquist Institute, Torrance, CA, United States. 2. LAC-USC Medical Center, Los Angeles, CA and the Hepatology Section, Division of Medicine, University of Southern California, Los Angeles, CA, United States. 3. Division of General Internal Medicine, Department of Medicine, University of California, Irvine, CA, United States. 4. Division of Gastroenterology, Department of Medicine University of New Mexico, Albuquerque, New Mexico and Medical Service, Raymond G. Murphy VA Medical Center, Albuquerque, NM, United States. 5. Gastroenterology Section, Medical Service, VA Healthcare System, Loma Linda, CA, United States. 6. Research Service, VA Healthcare System, Long Beach, CA, United States. 7. Gastroenterology Section, Medical Service, VA Healthcare System, Long Beach, CA, United States. 8. Division of Gastroenterology, Department of Medicine, University of California, Irvine, CA, United States.
Abstract
Background: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Methods: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Findings: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim. Interpretation: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone. Funding: was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.
Background: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Methods: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Findings: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim. Interpretation: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone. Funding: was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.
Entities:
Keywords:
ACLF, acute on chronic liver failure; AH, alcohol-related hepatitis; AKI, acute kidney injury; Alcoholic hepatitis; CTCAE, common terminology criteria for adverse events; DF, discriminant function; DSMB, data safety monitoring board; FDA, food and drug administration; FU, follow-up; GCSF, granulocyte colony stimulating factor; HIV, human immunodeficiency virus; HRS, hepatorenal syndrome; INR, international normalized ratio; NIAAA, national institute on alcohol abuse and alcoholism; Pegfilgrastim; Phase II; Randomized clinical trial; SD, standard deviation; SOC, standard of care; WBC, white blood cell count
Authors: Cornelius Engelmann; Adam Herber; Annegret Franke; Tony Bruns; Philipp Reuken; Ingolf Schiefke; Alexander Zipprich; Stefan Zeuzem; Tobias Goeser; Ali Canbay; Christoph Berg; Jonel Trebicka; Frank E Uschner; Johannes Chang; Tobias Mueller; Niklas Aehling; Moritz Schmelzle; Katrin Splith; Frank Lammert; Christian M Lange; Christoph Sarrazin; Christian Trautwein; Michael Manns; Dieter Häussinger; Jan Pfeiffenberger; Peter R Galle; Anett Schmiedeknecht; Thomas Berg Journal: J Hepatol Date: 2021-08-05 Impact factor: 25.083