IL-1 Signal Inhibition in Alcoholic Hepatitis

Study Overview
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Brief Summary
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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 our 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.

Detailed Description
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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.

Official Title
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IL-1 Signal Inhibition in Alcoholic Hepatitis (ISAIAH)

Conditions
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Alcoholic Hepatitis

Intervention / Treatment
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* Drug: Canakinumab 150mg/ml solution for injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Canakinumab 150mg/ml solution for injection<br>150mg/ml solution for injection | Drug: Canakinumab 150mg/ml solution for injection<br>* Canakinumab 150mg/ml solution for injection<br>|
| Placebo Comparator: Dextrose<br> | Drug: Placebo<br>* 100ml 5% Dextrose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline and 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of individual components of alcoholic hepatitis on liver histology from baseline to Day 28. | Improvement will be recorded as a binary Yes/No outcome. The outcome will be analysed as the percentage of patients, within each treatment group, with improvement on each individual component (polymorphonuclear cell infiltrate, ballooned hepatocytes and steatosis). Analysis will be based on three pairs of percentages which will represent the proportion of patients with improvement for each component. | Baseline and 28 days | 
| Changes in the components of Alcoholic Hepatitis Histological Score (AHHS) from baseline to Day 28 | Four histologic features are combined to create the AHHS score: Fibrosis stage (0-3), bilirubinostasis (0-2), polymorphonuclear infiltration (0-2), and megamitochondria (0-2) for a total of 9 points (Mild 0-3; Intermediate 4-5; Severe 6-9). AHHS score will be compared between active treatment and placebo treatment groups. | Baseline and 28 days | 
| Changes in the components of Nonalcoholic fatty liver disease activity score (NAS) from baseline to Day 28 | The NAS score combines steatosis grade, lobular inflammation, and liver cell injury (ballooning). Scoring: 0-2 Not steatohepatitis; 3-4 Indeterminate; ≥5, Steatohepatitis. NAS score will be compared between active treatment and placebo treatment groups. | Baseline and 28 days | 
| Changes in hepatic venous pressure gradient (HVPG) between baseline and day 28 |  | Baseline and 28 days | 
| Changes in serum CK18-M30/M65 from baseline to Day 7, 14, 21, 28, 42 and 90 |  | Baseline and 7, 14, 21, 28, 42, 90 days | 
| Change in serum bilirubin from baseline to Day 7, 14, 28, 21, 42 and 90 |  | Baseline and 7, 14, 21, 28, 42, 90 days | 
| Change in MELD (Model For End-Stage Liver Disease) score at from baseline to Day 7, 14, 21, 28, 42 and 90 | MELD score is based on the following formula: MELD Score = 10 * ((0.957 * ln(Creatinine)) + (0.378 * ln(Bilirubin)) + (1.12 * ln(INR))) + 6.43 | Baseline and 7, 14, 21, 28, 42, 90 days | 
| Change in Glasgow Alcoholic Hepatitis Score (GAHS) from baseline to Day 7, 14, 21, 28, 42 and 90 | Predicts mortality in patients with alcoholic hepatitis by laboratory results and age. GAHS score is calculated after Forrest et al., 2007 where a score of 1-3 is assigned based on age, WCC, Urea, PT ratio or INR and bilirubin. | 90 days | 
| Change in Maddrey's Discriminant Function (mDF) score from baseline to Day 7, 14, 21, 28, 42 and 90 | mDF is calculated using the following formula: mDF = 4.6 x (Prothrombin time (PTPATIENT - PTCONTROL) + Serum Bilirubin (μmol/l) / 17.1 (PTCONTROL is defined as the mean value at each site; this mean value may be updated on a weekly or monthly basis), where a higher score is associated with poorer prognosis. | Baseline and 7, 14, 21, 28, 42, 90 days | 
| Lille score at Day 7 | Lille score is calculated as Exp(-R)/[1+exp(-R)] where R = [3.19 - (0.101*age in years)] + (1.47*albumin at baseline in g/dL) + [0.28215* (bilirubin at baseline - bilirubin at Day 8 in mg/dL)] - [0.206 * (if creatinine>=1.3 mg/dL at baseline)] - [0.11115*bilirubin baseline in mg/dL] - (0.0096*Prothrombin Time in seconds at baseline). The Lille Model predicts mortality rates within 6 months. Scores >0.45 predict a 6-month survival of 25%. Scores <0.45 predict a 6-month survival of 85%. | 7 days | 
| Resolution of Systemic Inflammatory Response Syndrome (SIRS) at Day 7, 14, 21, 28, 42 and 90 in patients with SIRS at baseline | Recommendations of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference; where SIRS represents the presence of 2 or more criteria out of following: Temperature < 36 ºC or > 38 ºC Heart rate > 90 beats/minute Respiratory rate > 20 breaths/minute or venous pCO2 <32 mmHg Leukocyte count > 12,000/mm3 or < 4,000/mm3 or band forms > 10% | Baseline and 7, 14, 21, 28, 42, 90 days | 
| Incidence of SIRS at Day 7, 14, 21, 28, 42 and 90 in patients without SIRS at baseline | Recommendations of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference; where SIRS represents the presence of 2 or more criteria out of following: Temperature < 36 ºC or > 38 ºC Heart rate > 90 beats/minute Respiratory rate > 20 breaths/minute or venous pCO2 <32 mmHg Leukocyte count > 12,000/mm3 or < 4,000/mm3 or band forms > 10% | Baseline and 7, 14, 21, 28, 42, 90 days | 
| Mortality rate at Day 90 |  | 90 days | 
| Incidence of infection and sepsis over 90 days |  | 90 days | 
| Incidence of acute kidney injury over 90 days |  | 90 days | 
| Incidence of variceal haemorrhage, ascites or encephalopathy over 90 days |  | 90 days | 
| Safety and tolerability of canakinumab | The safety and tolerability of canakinumab will be assessed through the measurement of a number of participants with treatment-related adverse events. | 90 days | 
| Serum and plasma biomarkers of hepatic function and inflammation including cytokine profiles which may indicate the degree of response to IL-1b inhibition. | The aim is to monitor baseline levels of cytokines linked to inflammasome activation and their changes after active IMP treatment. The proposed method and cytokines is as follows: MSD 7-plex kit will be used for the detection of the following cytokines: IL-18, IL-1β*, IL-1ra, IL-6, IL-8, IFNγ** and TNF-α ELLA 1-plex will be used for the detection of the following cytokines: IL-18Bpa | 90 days | 
| Changes in CRP over time |  | 90 days | 
| Length of hospital stay |  | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Canakinumab, Alcoholic Hepatitis, Alcohol Use Disorder, Interleukin, Treatment, Ilaris, Liver disease