PROlonged Corticosteroid Treatment or N-ACetylcysteine for Severe Alcoholic Hepatitis

NCT ID: NCT06956482

Last Updated: 2026-01-20

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 477 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-02-28
• Study Completion Date: 2027-01-31

Brief Summary

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.

Conditions

Alcoholic Hepatitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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

Group Type: EXPERIMENTAL

N-Acetylcysteine (NAC) Treatment

Intervention Type: DRUG

N-acetylcysteine for five days (day 1 to day 5) at a daily dose of 300mg/Kg

Prednisolone

Intervention Type: DRUG

prednisolone 40 mg/day for a total of 30 days

Placebo of Prednisolone 10mg

Intervention Type: DRUG

Placebo of prednisolone 10mg for 30 additional days

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

Group Type: ACTIVE_COMPARATOR

Prednisolone

Intervention Type: DRUG

prednisolone 40 mg/day for a total of 30 days

Placebo of N-acetylcysteine

Intervention Type: DRUG

Placebo of N-acetylcysteine for five days (day 1 to day 5)

Placebo of Prednisolone 10mg

Intervention Type: DRUG

Placebo of prednisolone 10mg for 30 additional days

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

Group Type: EXPERIMENTAL

Prednisolone

Intervention Type: DRUG

prednisolone 40 mg/day for a total of 30 days

Placebo of N-acetylcysteine

Intervention Type: DRUG

Placebo of N-acetylcysteine for five days (day 1 to day 5)

Prednisolone 10mg

Intervention Type: DRUG

prednisolone 10mg (tapering dose) for 30 additional days

Interventions

N-Acetylcysteine (NAC) Treatment

N-acetylcysteine for five days (day 1 to day 5) at a daily dose of 300mg/Kg

Intervention Type: DRUG

Prednisolone

prednisolone 40 mg/day for a total of 30 days

Intervention Type: DRUG

Placebo of N-acetylcysteine

Placebo of N-acetylcysteine for five days (day 1 to day 5)

Intervention Type: DRUG

Placebo of Prednisolone 10mg

Placebo of prednisolone 10mg for 30 additional days

Intervention Type: DRUG

Prednisolone 10mg

prednisolone 10mg (tapering dose) for 30 additional days

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Lille

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Central Contacts

Alexandre Louvet, Prof.

Role: CONTACT

alexandre.louvet@chu-lille.fr

+33 (0)3 20 44 53 03

Other Identifiers

PHRC-23-0354

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

2025-522109-39-00

Identifier Type: CTIS

Identifier Source: secondary_id

2024_0476

Identifier Type: -

Identifier Source: org_study_id