A phase II, multicenter, open-label, randomized trial of pegfilgrastim for patients with alcohol-associated hepatitis

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.

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.

Conflict of interest statement

TRM reports grants from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), personal fees from the University of California, Irvine, during the conduct of the study. JAT and AAS received funding from the NIAAA to perform this clinical trial. AAS received funding from the NIDDK to conduct the Drug Induced Liver Injury (DILI) clinical center. TRM received funding to his institution to perform clinical trials by AbbVie, Gilead, Merck and Genfit (not related to alcoholic liver disease). JAD is on the governing board of the Southern California Society of Gastroenterology, a non-profit organization focused on education of gastroenterologists.

Figures

Figure 1

Consort flow diagram.

Figure 2

Kaplan Meier survival estimates for all enrolled subjects through Week 24. Survival was not significantly different between SOC and SOC + GCSF at Day 31 (p = 0.27), Day 90 (p = 0.48), or Week 24 (p = 0.97)(log-rank test). SOC: standard of care (solid line); pegfilgrastim (dotted line).