IL-1 Signal Inhibition in Alcoholic Hepatitis

Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by liver failure in the context of recent and heavy alcohol consumption. The condition carries a high fatality risk; patients with severe AH have a 30% mortality rate at 90 days after presentation.

Currently there is no effective treatment for severe alcoholic hepatitis. Based on the current understanding of the disease pathogenesis IL-1 (interleukin) is a key mediator of hepatic inflammation responsible for metabolic disturbances, fibrogenesis stellate cell activation and consequently portal hypertension.

Canakinumab is a licensed monoclonal antibody inhibitor of IL-1 and may consequently reverse the adverse effects of the cytokine in patients with this disorder. Therefore, the main objective of the ISAIAH trial is to explore the potential benefits of the IL-1β antibody, Canakinumab (solution for injection), in the treatment of alcoholic hepatitis.

ISAIAH is a multicentre, double blind, randomized (1:1), placebo controlled trial. The trial will follow patients up for 90 days and will be conducted in centres across the United Kingdom. Twenty-six patients will be recruited to each arm of the trial: total 52 patients.

The main objective of the ISAIAH trial is to explore the potential benefits of the IL-1β antibody, Canakinumab (solution for injection), in the treatment of alcoholic hepatitis.

ISAIAH is a multicentre, double blind, randomized (1:1), placebo controlled trial. The trial will follow patients up for 90 days and will be conducted in centres across the United Kingdom. Twenty-six patients will be recruited to each arm of the trial: total 52 patients.

The trial will be conducted in patients with severe alcoholic hepatitis (mDF\* ≥ 32 and MELD ≤27) with treatment initiated during an index hospital admission with the condition.

The primary endpoint of the trial is histological improvement of alcoholic hepatitis on liver biopsy after 28 days of treatment compared to baseline. Histological improvement is defined as a reduction in lobular inflammation (regardless of cell type).

Patients meeting the eligibility criteria will be randomized and treated. A single dose of 3 mg/kg Canakinumab or identical placebo will be administered intravenously at baseline (Day 1). Canakinumab will be made up by dilution in 100 ml 5% Dextrose by an unblinded research personnel at each site.

Patients with AST \>2 x ULN on Day 28 will receive a second dose of 3 mg/kg study drug administered i.v. on Day 28. Patients who received placebo on baseline will receive placebo. Patients who received canakinumab on baseline will receive canakinumab.

Total follow up time for each patient is 90 days.

Eligibility Criteria:
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 weeks before 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 (as specified 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 systemic steroids (equivalent to a dose of systemic prednisolone \>20mg) within 6 weeks of screening.
* 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 renal support (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 myocardial infarction (within the last 6 weeks) or severe cardiac arrhythmias (not including atrial fibrillation)
* Pregnant or lactating women
* Patients treated with other IL-1 inhibitors and biologics or any other immunosuppressants 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 the evaluation of the benefit of canakinumab therapy
* Underlying metabolic, hematologic, renal, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions, including neutropenia (ANC \<1.5) and leukopenia, which in the opinion of the investigator immune-compromises the subject and/or places the subject at unacceptable risk for participation in an immunomodulatory therapy.
* Significant medical problems or diseases, including but not limited to the following: uncontrolled hypertension (≥160/95 mmHg), congestive heart failure \[New York Heart Association status of class III or IV\], uncontrolled diabetes
* Vaccination with a live vaccine within 3 month before baseline