PROlonged Corticosteroid Treatment or N-ACetylcysteine for Severe Alcoholic Hepatitis (PROCORNAC)

Only patients suffering from a severe form of alcoholic hepatitis (Maddrey's discriminant function greater than 32) require medical treatment. Oral prednisolone for 28 days is the only treatment which has been proven to improve short-term survival over placebo in patients with severe alcoholic hepatitis. However, prednisolone alone cannot be regarded as an ideal treatment because some patients still have a bad outcome despite being treated with corticosteroids. Response to treatment can be predicted by the Lille score, a simple tool that is calculated after 7 days of prednisolone course. The ideal binary cut-off of the Lille is 0.45, responders having a Lille score < 0.45 and non-responders having a Lille score ≥0.45. In terms of treatment management, approximately 30% of patients with severe alcoholic hepatitis do not take benefit from prednisolone and are classified as null responders by a Lille score greater than 0.56. In them, there is a consensus for stopping prednisolone after a 7-day course of treatment (Lille score is calculated after 7 days) while patients with a Lille score <0.56 continue treatment for a total of 30 days.

Numerous trials have attempted to test the impact of other strategies in association with prednisolone, but none of them has shown an improvement in survival (primary endpoint) as compared to prednisolone alone. These strategies include for instance pentoxifylline, amoxicillin-clavulanic acid and enteral nutrition.

Because oxidative stress is a major driver of liver injury during alcohol-related liver disease, antioxidants, especially N-acetylcysteine, have been tested for many years to treat alcoholic hepatitis. N-acetylcysteine alone does not seem to bring a survival benefit over placebo while it may improve outcome when combined to prednisolone.

Historically in severe alcoholic hepatitis, treatment is only given for one month. However, a significant proportion of patients still disclose impaired hepatic function after treatment has been stopped (e.g. 50% of patients still have a MELD score ≥17 after 60 days in). It is thus tempting to hypothesize that a proportion of patients will recover slowly and may take benefit from a prolonged treatment. Such strategy has been proposed in some old studies with relatively limited sample size but never tested with a rigorous approach.

In the present study, for the first time in alcoholic hepatitis, we will take into account the recent recommendations of international experts by choosing an innovative primary endpoint that does not only include mortality and evaluate this endpoint at the preferred timepoint of 90 days.

After more than 30 years of negative trials in severe alcoholic hepatitis, the present study is aimed to evaluate two important new strategies to decrease both mortality and liver impairment.

Study Overview

• Status: Recruiting
• Conditions: Alcoholic Hepatitis
• Intervention / Treatment: Drug: N-Acetylcysteine (NAC) Treatment; Drug: Prednisolone; Drug: Placebo of N-acetylcysteine; Drug: Placebo of Prednisolone 10mg; Drug: Prednisolone 10mg

• Study Type: Interventional
• Enrollment (Estimated): 477
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Alexandre Louvet, Prof.; Phone Number: +33 (0)3 20 44 53 03; Email: alexandre.louvet@chu-lille.fr

Study Locations

• France
  • Lille, France, 59037
    • Recruiting
    • CHU de Lille, Hôpital Huriez
    • Contact: Alexandre Louvet, PhD; Phone Number: +33320445597; Email: alexandre.louvet@chu-lille.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged 18-75
• Alcohol consumption of more than 40g/day (women) and 50g/day (men)
• Recent onset of jaundice (<3 months)
• Biopsy proven alcoholic hepatitis (transjugular liver biopsy)
• Maddrey's discriminant function ≥ 32, defining severe alcoholic hepatitis
• MELD score ≥ 17
• Patients covered with social insurance
• Patients having provided written informed consent to participate

Exclusion Criteria:

• Hepatocellular carcinoma
• Uncontrolled gastrointestinal bleeding
• Previous severe allergy or hypersensitivity to N-acetylcysteine (anaphylactic shock, Quincke edema, severe urticaria)
• Hypersensitivity to any component of the medication
• MELD score <17
• Type 1 hepatorenal syndrome before the initiation of treatment
• Severe extrahepatic disease, with life expectancy < 6 months
• Any malignant tumor < 2 years (except skin carcinomas)
• Ongoing viral or parasitic infection
• Untreated bacterial infection
• Tuberculosis < 5 years
• Positive blood PCR in patients with positive antibodies against HCV
• Patient carrying HBV or HIV
• Treatment with corticosteroids, immunosuppression therapy or budesonide within 6 months before the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NAC/Prednisolone/Placebo; N-acetylcysteine for five days (day 1 to day 5) in combination with prednisolone 40 mg/day for a total of 30 days, followed by a placebo for 30 additional days	Drug: N-Acetylcysteine (NAC) Treatment; N-acetylcysteine for five days (day 1 to day 5) at a daily dose of 300mg/Kg; Drug: Prednisolone; prednisolone 40 mg/day for a total of 30 days; Drug: Placebo of Prednisolone 10mg; Placebo of prednisolone 10mg for 30 additional days
Active Comparator: Placebo/Prednisolone/Placebo; Placebo for five days (day 1 to day 5) in combination with prednisolone 40 mg/day for a total of 30 days, followed by a placebo for 30 additional days	Drug: Prednisolone; prednisolone 40 mg/day for a total of 30 days; Drug: Placebo of N-acetylcysteine; Placebo of N-acetylcysteine for five days (day 1 to day 5); Drug: Placebo of Prednisolone 10mg; Placebo of prednisolone 10mg for 30 additional days
Experimental: Placebo/Prednisolone/Prednisolone; Placebo for five days (day 1 to day 5) in combination with prednisolone 40 mg/day for a total of 30 days, followed by prednisolone (tapering dose) for 30 additional days	Drug: Prednisolone; prednisolone 40 mg/day for a total of 30 days; Drug: Placebo of N-acetylcysteine; Placebo of N-acetylcysteine for five days (day 1 to day 5); Drug: Prednisolone 10mg; prednisolone 10mg (tapering dose) for 30 additional days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of patients alive with compensated liver disease	Rate of patients alive with compensated liver disease defined as a MELD score <17 at 90 days. MELD score will be calculated according to the formula given in Dunn et al. Hepatology 2005: MELD = 9.57 x ln (creatinine in mg/dL) + 3.78 x ln (bilirubin in mg/dL) + 11.2 x ln (INR) + 6.43	90 days

Collaborators and Investigators

• Sponsor: University Hospital, Lille

Study record dates

Study Major Dates

• Study Start (Actual): May 22, 2026
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): May 1, 2030

Study Registration Dates

• First Submitted: April 25, 2025
• First Submitted That Met QC Criteria: April 25, 2025
• First Posted (Actual): May 4, 2025

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: N-acetylcysteine; Alcoholic hepatitis; survival, prednisolone; liver insufficiency
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Substance-Related Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Hepatitis; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Hepatic Insufficiency; Hepatitis, Alcoholic; Amino Acids, Peptides, and Proteins; Sulfur Compounds; Organic Chemicals; Polycyclic Compounds; Amino Acids; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Pregnadienetriols; Cysteine; Amino Acids, Sulfur; Prednisolone; Acetylcysteine; Therapeutics
• Other Study ID Numbers: 2024_0476; PHRC-23-0354 (Other Grant/Funding Number: DGOS, France); 2025-522109-39-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No