IL-1 Signal Inhibition in Alcoholic Hepatitis

NCT03775109 | Completed Phase 2 Results DMC

• 2 other identifiers: 17SM4152231612
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 16

Brief 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.

Conditions

Alcoholic Hepatitis

Keywords

Canakinumab; Alcoholic Hepatitis; Alcohol Use Disorder; Interleukin; Treatment; Ilaris; Liver disease

Outcome Measures

Primary Outcomes (1)

• Number of Patients Presenting 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 Outcomes (30)

• Difference in Proportions of Participants With Improvement of Polymorphonuclear Cell Infiltrate From Baseline to Day 28.

  Baseline and 28 days

• Number of Patients Presenting Changes in Degree of Fibrosis (AHHS) From Baseline to Day 28

  Baseline and 28 days

• Number of Participants Presenting Changes in Steatosis Grade (NAS) From Baseline to Day 28

  28 days

• Number of Participants Presenting Changes in Hepatic Venous Pressure Gradient (HVPG) Between Baseline and Day 28

  28 days

• Number of Participants Presenting 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

Study Arms (2)

Canakinumab 150mg/ml solution for injection

ACTIVE COMPARATOR

150mg/ml solution for injection

Drug: Canakinumab 150mg/ml solution for injection

Dextrose

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Canakinumab 150mg/ml solution for injection DRUG

Canakinumab 150mg/ml solution for injection

Canakinumab 150mg/ml solution for injection

Placebo DRUG

100ml 5% Dextrose

Dextrose

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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)

Sponsors & Collaborators

• Imperial College London: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (16)

University Hospitals Bristol NHS Foundation Trust

Bristol, United Kingdom

Location

Glasgow Royal Infirmary, Greater Glasgow & Clyde

Glasgow, G4 0SF, United Kingdom

Location

Queen Elizabeth University Hospital

Glasgow, United Kingdom

Location

Leeds Teaching Hospitals NHS Trust

Leeds, United Kingdom

Location

Aintree University Hospital

Liverpool, United Kingdom

Location

Royal Liverpool and Broadgreen University Hospitals NHS Trust

Liverpool, United Kingdom

Location

Imperial College Healthcare NHS Foundation Trust

London, W2 1NY, United Kingdom

Location

Chelsea and Westminster Hospital NHS Foundation Trust

London, United Kingdom

Location

King's College Hospital NHS Foundation Trust

London, United Kingdom

Location

Royal Free London NHS Foundation Trust

London, United Kingdom

Location

St George's University Hospitals NHS Foundation Trust

London, United Kingdom

Location

The Newcastle Upon Tyne Hospitals NHS Foundation Trust

Newcastle upon Tyne, United Kingdom

Location

Nottingham University Hospitals NHS Trust

Nottingham, United Kingdom

Location

John Radcliffe Hospital, Oxford University NHS Foundation Trust

Oxford, OX3 9DU, United Kingdom

Location

Plymouth Hospitals NHS Trust

Plymouth, United Kingdom

Location

University Hospital Southampton NHS Foundation Trust

Southampton, United Kingdom

Location

Related Publications (2)

• Vergis N, Patel V, Bogdanowicz K, Czyzewska-Khan J, Fiorentino F, Day E, Cross M, Foster N, Lord E, Goldin R, Forrest E, Thursz M. IL-1 Signal Inhibition In Alcoholic Hepatitis (ISAIAH): a study protocol for a multicentre, randomised, placebo-controlled trial to explore the potential benefits of canakinumab in the treatment of alcoholic hepatitis. Trials. 2021 Nov 11;22(1):792. doi: 10.1186/s13063-021-05719-2.

  PMID: 34763711 RESULT

• Vergis N, Patel V, Bogdanowicz K, Czyzewska-Khan J, Keshinro R, Fiorentino F, Day E, Middleton P, Atkinson S, Tranah T, Cross M, Babalis D, Foster N, Lord E, Quaglia A, Lloyd J, Goldin R, Rosenberg W, Parker R, Richardson P, Masson S, Whitehouse G, Sieberhagan C, Patch D, Naoumov N, Dhanda A, Forrest E, Thursz M. IL-1 Signal Inhibition in Alcohol-Related Hepatitis: A Randomized, Double-Blind, Placebo-Controlled Trial of Canakinumab. Clin Gastroenterol Hepatol. 2025 Apr;23(5):797-807.e5. doi: 10.1016/j.cgh.2024.07.025. Epub 2024 Aug 23.

  PMID: 39181422 DERIVED

MeSH Terms

Conditions

Hepatitis, Alcoholic; Alcoholism; Liver Diseases

Interventions

canakinumab; Solutions; Injections

Condition Hierarchy (Ancestors)

Hepatitis; Digestive System Diseases; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Pharmaceutical Preparations; Drug Administration Routes; Drug Therapy; Therapeutics

Results Point of Contact

• Title: Professor Mark Thursz
• Organization: Imperial College, London

m.thursz@imperial.ac.uk

+44 (0) 203 3126454

Study Officials

• Mark Thursz

  Imperial College London

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 10, 2018
• First Posted: December 13, 2018
• Study Start: February 12, 2019
• Primary Completion: March 31, 2023
• Study Completion: March 31, 2023
• Last Updated: March 11, 2025
• Results First Posted: March 11, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (16)