Efficacy of granulocyte colony stimulating factor in patients with severe alcoholic hepatitis with partial or null response to steroid (GRACIAH trial): study protocol for a randomized controlled trial

Abstract

Background: Alcoholic hepatitis (AH) has the most severe presentation among alcohol-related liver diseases. Corticosteroids are the most widely recommended treatment for severe AH. However, more innovative, refined treatment measures are required because of its high mortality despite corticosteroid treatment. This study aims to determine whether granulocyte colony stimulating factor (G-CSF) treatment increases short-term survival in patients with severe AH refractory to corticosteroid treatment.

Methods/design: Patients with severe AH whose Maddrey's discriminant function (MDF) score is ≥ 32 and who will be treated with prednisolone (40 mg/day) for 1 week will be screened. Among them, 190 subjects with a partial response (PR) (Lille score 0.16-0.56), and 78 subjects with a null response (NR) (Lille score ≥ 0.56) will be enrolled. Subjects with PR will be randomized to steroid plus placebo or steroid plus 12 G-CSF injections (5 μg/kg/day for 5 days followed by every 3 days) at a ratio of 1:1. Subjects with a NR will be randomized to the placebo or G-CSF group (1:1). Study subjects in the PR group will be treated with prednisolone for 28 days followed by dose tapering for an additional 2 weeks. The primary endpoint is the 2-month survival rate in the NR group and the 6-month survival rate in the PR group. Child-Turcotte-Pugh, model for end-stage liver disease score, and the change in the proportion of peripheral circulating CD34-positive cells will be analyzed as risk factors for mortality. Preliminary safety data for the initial 10 study subjects enrolled in the PR study will be assessed to determine whether the PR study would be continued, according to the G-CSF-mobilized, peripheral-blood stem cell donor assessment protocol of the National Marrow Donor Program.

Discussion: We hypothesized that G-CSF would prolong short-term survival of patients with severe AH refractory to corticosteroid treatment. This is a proof-of-concept trial designed to assess the efficacy of Lille-score-guided G-CSF treatment. This trial is also designed to identify a special subgroup in whom G-CSF rescue treatment would improve liver function and prolong survival.

Trial registration: ClinicalTrials.gov, NCT02442180 . Prospectively registered on 13 May 2015.

Keywords: Alcoholic hepatitis; Discriminant function; G-CSF; Prednisolone.

Conflict of interest statement

Ethics approval and consent to participate

The trial has been approved by the Institutional Review Board (IRB) of Seoul National University Boramae Medical Center and by the IRBs of the 14 participating centers (Hallym University Medical Center-Chuncheon, Pusan National University Hospital, Pusan National University Yangsan Hospital, Daegu Catholic University Medical Center, Ulsan University Hospital, St. Vincent’s Hospital, Korea University Ansan Hospital, Hanyang University Guri Hospital, Chonbuk National University Hospital, Yonsei University Wonju Severance Christian Hospital, GangNeung Asan Hospital, Uijeongbu St. Mary’s Hospital, Wonkwang University Hospital, and Gyeongsang National University Hospital). Informed consent will be obtained from all participants in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Flowchart for study participants. Abbreviations: G-CSF, granulocyte colony stimulating factor; AFP, alpha-fetoprotein; HVPG, hepatic venous pressure gradient; D, day

Fig. 2

Study schedule of enrollment, intervention, and assessment. Abbreviations: G-CSF, granulocyte colony stimulating factor; AUDIT-K, Alchol Use Disorder Identification Test-Korea; USG, ultrasonography; CT, computed tomography; MRI, magnetic resonance imaging; CTP, Child–Turcotte–Pugh, MELD, model for end-stage liver disease; CLIF-SOFA, chronic liver failure sequential organ failure assessment; D, day