Clinical trial NCT03775109: IL-1 Signal Inhibition in Alcoholic Hepatitis
Official title: IL-1 Signal Inhibition in Alcoholic Hepatitis (ISAIAH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alcoholic Hepatitis
Keywords: Canakinumab
Alcoholic Hepatitis
Alcohol Use Disorder
Interleukin
Treatment
Ilaris
Liver disease
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Novartis Pharmaceuticals
First posted: 2018-12-13
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: 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

Primary outcomes:
measure: Number of Patients Presenting Histological Improvement of Alcoholic Hepatitis on Liver Biopsy After 28 Days of Treatment Compared to Baseline.
timeFrame: Baseline and 28 days
Secondary outcomes:
measure: Difference in Proportions of Participants With Improvement of Polymorphonuclear Cell Infiltrate From Baseline to Day 28.
timeFrame: Baseline and 28 days
measure: Number of Patients Presenting Changes in Degree of Fibrosis (AHHS) From Baseline to Day 28
timeFrame: Baseline and 28 days
measure: Number of Participants Presenting Changes in Steatosis Grade (NAS) From Baseline to Day 28
timeFrame: 28 days
measure: Number of Participants Presenting Changes in Hepatic Venous Pressure Gradient (HVPG) Between Baseline and Day 28
timeFrame: 28 days
measure: Number of Participants Presenting Changes in Serum CK18-M30/M65 From Baseline to Day 7, 14, 21, 28, 42 and 90
timeFrame: Baseline and 7, 14, 21, 28, 42, 90 days
measure: Change in Serum Bilirubin Concentration From Baseline to Day 28
timeFrame: 28 days
measure: Change in MELD (Model For End-Stage Liver Disease) Score at From Baseline to Day 28
timeFrame: Day 0 to day 28
measure: Change in Glasgow Alcoholic Hepatitis Score (GAHS) From Day 28
timeFrame: Day 0 to day 28
measure: Change in Maddrey's Discriminant Function (mDF) Score From Baseline to Day 28
timeFrame: 28 days
measure: Lille Score at Day 7
timeFrame: 7 days
measure: Number of Patients With Resolution of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients With SIRS at Baseline
timeFrame: 28 days
measure: Number of Patients With Incidence of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients Without SIRS at Baseline
timeFrame: 28 days
measure: Number of Deaths at Day 90
timeFrame: 90 days
measure: Number of Patients With Infection Over 90 Days
timeFrame: 90 days
measure: Number of Patients With Acute Kidney Injury Over 90 Days
timeFrame: 90 days
measure: Number of Patients With Variceal Haemorrhage Over 90 Days
timeFrame: 90 days
measure: Number of Participants With Treatment-related Adverse Events
timeFrame: 90 days
measure: Serum and Plasma Biomarkers of Hepatic Function and Inflammation Including Cytokine Profiles Which May Indicate the Degree of Response to IL-1b Inhibition.
timeFrame: 90 days
measure: CRP Levels at Day 28
timeFrame: 28 days
measure: Length of Hospital Stay
timeFrame: 90 days
measure: Difference in Proportions of Participants With Improvement of Ballooned Hepatocytes Between Treatment Groups.
timeFrame: Day 28
measure: Difference in Proportions of Improvement of Steatosis Between Treatment Groups at Day 28
timeFrame: Day 28
measure: Number of Patients Presenting Changes in Degree of Neutrophil Infiltration (AHHS) From Baseline to Day 28
timeFrame: day 28
measure: Number of Patients Presenting Changes in Presence of Megamitochondria (AHHS) From Baseline to Day 28
timeFrame: day 28
measure: Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28
timeFrame: day 28
measure: Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28
timeFrame: day 28
measure: Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28
timeFrame: day 28
measure: Number of Patients With Sepsis Over 90 Days
timeFrame: 90 days
measure: Number of Patients With Ascites Over 90 Days
timeFrame: 90 days
measure: Number of Patients With Encephalopathy Over 90 Days
timeFrame: 90 days
Other outcomes:
Locations:
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary, Greater Glasgow & Clyde
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool and Broadgreen University Hospitals NHS Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Foundation Trust
city: London
country: United Kingdom
facility: Chelsea and Westminster Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
city: London
country: United Kingdom
facility: St George's University Hospitals NHS Foundation Trust
city: Newcastle Upon Tyne
country: United Kingdom
facility: The Newcastle Upon Tyne Hospitals NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital, Oxford University NHS Foundation Trust
city: Plymouth
country: United Kingdom
facility: Plymouth Hospitals NHS Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: Imperial College London
name: Mark Thursz
role: STUDY_DIRECTOR
References:
citation: 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.