IL-1 Signal Inhibition in Alcoholic Hepatitis

Inclusion Criteria:

• Male and female patients aged 18 years or older at screening

• Clinical diagnosis of alcoholic hepatitis at screening:

• Serum bilirubin > 80μmol/L

• History of excess alcohol (> 80g/day male, > 60g/day female) to within 6 weeksbefore screening visit

• Less than 4 weeks since admission to hospital at baseline visit

• mDF* ≥ 32 and MELD ≤ 27 at baseline visit

• Informed consent

• Women of child-bearing potential have to use an effective contraception method (asspecified in section 9.6).

Exclusion Criteria:

• Alcohol abstinence of >6 weeks prior to randomization/baseline visit

• Duration of clinically apparent jaundice > 3 months before baseline visit

• Other causes of liver disease including:

• Evidence of chronic viral hepatitis (Hepatitis B or C)

• Biliary obstruction

• Hepatocellular carcinoma

• Evidence of current malignancy (except non-melanotic skin cancer)

• Previous entry into the study, or use of either prednisolone or any systemicsteroids (equivalent to a dose of systemic prednisolone >20mg) within 6 weeks ofscreening.

• AST >500 U/L or ALT >300 U/L (not compatible with alcoholic hepatitis)

• Patients with a serum creatinine >220 μmol/L (2.5 mg / dL) or requiring renalsupport (see below)

• Patients dependent upon inotropic support (adrenaline or noradrenaline).Terlipressin is allowed

• Variceal haemorrhage on this admission

• Untreated sepsis (see below)

• Patients with known hypersensitivity or contraindications to Canakinumab

• Patients with cerebral haemorrhage, extensive retinal haemorrhage, acute myocardialinfarction (within the last 6 weeks) or severe cardiac arrhythmias (not includingatrial fibrillation)

• Pregnant or lactating women

• Patients treated with other IL-1 inhibitors and biologics or any otherimmunosuppressants within 3 months of study participation.

• Known infection with HIV at screening or randomization

• History or evidence of tuberculosis (TB) (active or latent) infection

• Active ongoing inflammatory diseases other than AAH that might confound theevaluation of the benefit of canakinumab therapy

• Underlying metabolic, hematologic, renal, pulmonary, neurologic, endocrine, cardiac,infectious or gastrointestinal conditions, including neutropenia (ANC <1.5) andleukopenia, which in the opinion of the investigator immune-compromises the subjectand/or places the subject at unacceptable risk for participation in animmunomodulatory therapy.

• Significant medical problems or diseases, including but not limited to thefollowing: uncontrolled hypertension (≥160/95 mmHg), congestive heart failure [NewYork Heart Association status of class III or IV], uncontrolled diabetes

• Vaccination with a live vaccine within 3 month before baseline