Evaluation of Prolonged Prednisolone and N-Acetylcysteine in Severe Alcoholic Hepatitis: A Randomized Controlled Trial

The primary objective is to determine the efficacy of adding a 5‑day infusion of N‑acetylcysteine to standard therapy with oral prednisolone (30 days) or to a prolonged course (60 days) versus standard prednisolone alone, using the proportion of patients alive with compensated liver disease at 90 days as the primary endpoint.

Secondary objectives include:

• Evaluation of the impact of the combination therapy on median and long‑term survival, on the proportion of patients alive with compensated liver disease at 60, 180 and 360 days, and on the incidence of infections and hepatorenal syndrome within 90 days.
• Assessment of early therapeutic response at day 7 and of the proportion alive with compensated liver disease at 30 days, comparing the combination arm with pooled standard‑ and prolonged‑prednisolone arms.
• Safety analysis of the combination regimen relative to standard prednisolone treatment, focusing on adverse event rates.

The sponsor did not provide information on the total number of enrolled participants. Eligible individuals were adults aged 18–75 years of either sex who met criteria for severe alcoholic hepatitis. Inclusion required a documented history of heavy alcohol intake (>40 g/day for women, >50 g/day for men), onset of jaundice within the preceding three months, and confirmation by transjugular liver biopsy. Additional laboratory thresholds were a Maddrey’s discriminant function of ≥ 32 and a Model for End‑Stage Liver Disease (MELD) score of ≥ 17, indicating advanced disease. Participants were required to have social insurance coverage and to provide written informed consent. Selection was based on these clinical and laboratory parameters; lifestyle considerations centered on recent excessive alcohol consumption, while other habits such as diet or physical activity were not specified.

The PROCORNAC study is a multicentre, prospective, randomized, double‑blind, placebo‑controlled trial with three parallel arms evaluating standard prednisolone for 30 days, prolonged prednisolone for 60 days, or a 5‑day course of N‑acetylcysteine combined with prednisolone for 30 days in patients with alcoholic hepatitis. After obtaining written informed consent, participants undergo a screening visit to verify inclusion criteria (age 18‑75, heavy alcohol use, recent jaundice, biopsy‑confirmed disease, Maddrey’s discriminant function ≥ 32, MELD score ≥ 17) and baseline assessments. Randomization occurs at the baseline visit (day 0) followed by administration of the assigned study medication. Follow‑up visits are scheduled on days 7, 30, 60, 90, 180 and 360 to assess safety, laboratory parameters, and efficacy outcomes, including the primary endpoint of survival with compensated liver function defined as a MELD score < 17 at 90 days. The end‑of‑study visit at day 360 completes the participant’s involvement, which therefore spans approximately 12 months. Early termination may occur if a participant experiences a serious adverse event, develops a contraindication to study drugs, withdraws consent, is lost to follow‑up, or exhibits major protocol non‑compliance.

The investigational intravenous agent HIDONAC 5 g/25 ml is supplied as a solution for injection/infusion. Each dose contains acetylcysteine 300 mg/kg, administered by slow intravenous infusion once daily for a total of five consecutive days. Dosing is calculated on the participant’s body weight at screening, and the infusion is performed under clinical supervision with vital signs monitored before, during, and after administration.

Micronized Prednisolone is provided as oral capsules containing 40 mg of prednisolone. The medication is taken once daily by mouth. In the standard‑treatment arm, the course continues for 30 days; in the prolonged‑treatment arm, dosing is extended to a total of 60 days. Capsule intake is recorded in a patient‑completed dosing diary and verified by pill count at each study visit.

SOLUPRED 20 mg is an orodispersible tablet containing prednisolone metasulfobenzoate sodium, used as an auxiliary background therapy. The tablet is administered orally at a dose of 40 mg (two tablets) once daily. Administration is observed by study staff at the initial visit to ensure proper dissolution and ingestion.

The placebo for the intravenous arm consists of a solution of 5 % dextrose combined with 10 % normal saline, identical in appearance to the active infusion. It is delivered by the same infusion protocol as HIDONAC, with identical monitoring procedures.

The oral placebo comprises a tablet matching the appearance of a 10 mg prednisolone tablet. It is administered orally once daily using the same schedule as the active prednisolone capsules, and compliance is assessed by the same diary and pill‑count methods.

All study medications are stored according to manufacturer specifications. Administration times are documented in the electronic case report form. Compliance monitoring includes direct observation of the first dose, review of infusion logs, pill‑count reconciliation, and review of patient‑reported dosing diaries at each scheduled visit.

Efficacy will be evaluated using both primary and secondary clinical endpoints. The primary endpoint is the proportion of patients who are alive with compensated liver disease, defined by a MELD score of less than 17 at day 90. The Model for End‑Stage Liver Disease (MELD) will be calculated according to the formula published by Dunn et al. (Hepatology 2005), requiring serum creatinine, bilirubin, and INR values measured in the laboratory.

Secondary efficacy assessments include overall survival at days 90 and 360; the proportion of patients alive with compensated liver disease (<17 MELD) at days 30, 60, 180, and 360; therapeutic response at day 7 assessed by the proportion of patients with a Lille score below 0.45 and by the Lille score as a continuous variable; and the cumulative incidence of infection, hepatorenal syndrome, and serious adverse events within the first 90 days. The Lille score will be derived from laboratory parameters obtained at baseline and day 7.

Laboratory tests for creatinine, bilirubin, INR, and other variables required for the Lille calculation will be performed at screening, day 7, and at each scheduled follow‑up visit (days 30, 60, 90, 180, 360). Data will be collected in the trial database, and efficacy analyses will compare the rates and scores between treatment arms using appropriate statistical methods for time‑to‑event and proportion outcomes.