Phase 2 N=55 Randomized Quadruple-blind Treatment

IL-1 Signal Inhibition in Alcoholic Hepatitis

Alcoholic Hepatitis

Bottom Line

View on ClinicalTrials.gov: NCT03775109 ↗

Enrolled (actual)

Serious AEs

36.4%

Results posted

Mar 2025

Primary outcome: Primary: Number of Patients Presenting Histological Improvement of Alcoholic Hepatitis on Liver Biopsy After 28 Days of Treatment Compared to Baseline. — 14; 10 Participants — p=0.248

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: Canakinumab 150mg/ml solution for injection (Drug); Placebo (Drug)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: Imperial College London
Primary completion: Mar 2023

Outcome Measures

Outcome	Result	p-value
PRIMARY Number of Patients Presenting Histological Improvement of Alcoholic Hepatitis on Liver Biopsy After 28 Days of Treatment Compared to Baseline.	14; 10	0.248
SECONDARY Difference in Proportions of Participants With Improvement of Polymorphonuclear Cell Infiltrate From Baseline to Day 28.	0.652; 0.609	—
SECONDARY Number of Patients Presenting Changes in Degree of Fibrosis (AHHS) From Baseline to Day 28	23; 22	—
SECONDARY Number of Participants Presenting Changes in Steatosis Grade (NAS) From Baseline to Day 28	15; 18	—
SECONDARY Number of Participants Presenting Changes in Hepatic Venous Pressure Gradient (HVPG) Between Baseline and Day 28	—	—
SECONDARY Number of Participants Presenting Changes in Serum CK18-M30/M65 From Baseline to Day 7, 14, 21, 28, 42 and 90	—	—
SECONDARY Change in Serum Bilirubin Concentration From Baseline to Day 28	126; 102	0.270
SECONDARY Change in MELD (Model For End-Stage Liver Disease) Score at From Baseline to Day 28	-4.57; -5.87	0.03490 sig
SECONDARY Change in Glasgow Alcoholic Hepatitis Score (GAHS) From Day 28	1.67; 1.71	—
SECONDARY Change in Maddrey's Discriminant Function (mDF) Score From Baseline to Day 28	36; 29	0.343
SECONDARY Lille Score at Day 7	-1.457; -1.540	—
SECONDARY Number of Patients With Resolution of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients With SIRS at Baseline	1; 3	1.000
SECONDARY Number of Patients With Incidence of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients Without SIRS at Baseline	3; 2	1.000
SECONDARY Number of Deaths at Day 90	2; 2	—
SECONDARY Number of Patients With Infection Over 90 Days	6; 8	—
SECONDARY Number of Patients With Acute Kidney Injury Over 90 Days	8; 4	—
SECONDARY Number of Patients With Variceal Haemorrhage Over 90 Days	1; 1	—
SECONDARY Number of Participants With Treatment-related Adverse Events	0; 0	—
SECONDARY Serum and Plasma Biomarkers of Hepatic Function and Inflammation Including Cytokine Profiles Which May Indicate the Degree of Response to IL-1b Inhibition.	—	—
SECONDARY CRP Levels at Day 28	8; 10.2	—
SECONDARY Length of Hospital Stay	22; 22	—
SECONDARY Difference in Proportions of Participants With Improvement of Ballooned Hepatocytes Between Treatment Groups.	0.652; 0.609	—
SECONDARY Difference in Proportions of Improvement of Steatosis Between Treatment Groups at Day 28	0.652; 0.783	—
SECONDARY Number of Patients Presenting Changes in Degree of Neutrophil Infiltration (AHHS) From Baseline to Day 28	21; 17	—
SECONDARY Number of Patients Presenting Changes in Presence of Megamitochondria (AHHS) From Baseline to Day 28	21; 19	—
SECONDARY Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28	14; 16; 3; 3; 6; 4	—
SECONDARY Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28	1; 0; 10; 14; 11; 7	—
SECONDARY Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28	1; 3; 15; 11; 7; 9	—
SECONDARY Number of Patients With Sepsis Over 90 Days	1; 1	—
SECONDARY Number of Patients With Ascites Over 90 Days	26; 21	—
SECONDARY Number of Patients With Encephalopathy Over 90 Days	9; 6	—

Summary

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.

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

View full record on ClinicalTrials.gov →

Data sourced from ClinicalTrials.gov (NCT03775109). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.