IL-1 Signal Inhibition in Alcoholic Hepatitis
- Conditions
- Alcoholic Hepatitis
- Interventions
- Drug: Placebo
- Registration Number
- NCT03775109
- Lead Sponsor
- Imperial College London
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 55
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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
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Informed consent
-
Women of child-bearing potential have to use an effective contraception method (as specified in section 9.6).
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Alcohol abstinence of >6 weeks prior to randomization/baseline visit
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Duration of clinically apparent jaundice > 3 months before baseline visit
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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)
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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.
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AST >500 U/L or ALT >300 U/L (not compatible with alcoholic hepatitis)
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Patients with a serum creatinine >220 μmol/L (2.5 mg / dL) or requiring renal support (see below)
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Patients dependent upon inotropic support (adrenaline or noradrenaline). Terlipressin is allowed
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Variceal haemorrhage on this admission
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Untreated sepsis (see below)
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Patients with known hypersensitivity or contraindications to Canakinumab
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Patients with cerebral haemorrhage, extensive retinal haemorrhage, acute myocardial infarction (within the last 6 weeks) or severe cardiac arrhythmias (not including atrial fibrillation)
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Pregnant or lactating women
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Patients treated with other IL-1 inhibitors and biologics or any other immunosuppressants within 3 months of study participation.
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Known infection with HIV at screening or randomization
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History or evidence of tuberculosis (TB) (active or latent) infection
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Active ongoing inflammatory diseases other than AAH that might confound the evaluation of the benefit of canakinumab therapy
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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.
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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
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Vaccination with a live vaccine within 3 month before baseline
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Canakinumab 150mg/ml solution for injection Canakinumab 150mg/ml solution for injection 150mg/ml solution for injection Dextrose Placebo -
- Primary Outcome Measures
Name Time Method Number of Patients Presenting Histological Improvement of Alcoholic Hepatitis on Liver Biopsy After 28 Days of Treatment Compared to Baseline. Baseline and 28 days Histological improvement is defined as a reduction in lobular inflammation (regardless of cell type).
- Secondary Outcome Measures
Name Time Method Difference in Proportions of Participants With Improvement of Polymorphonuclear Cell Infiltrate From Baseline to Day 28. Baseline and 28 days Improvement will be recorded as a binary Yes/No outcome. The outcome will be analysed as the proportion of patients, within each treatment group, with improvement on each individual component (polymorphonuclear cell infiltrate, ballooned hepatocytes and steatosis).
Number of Patients Presenting Changes in Degree of Fibrosis (AHHS) From Baseline to Day 28 Baseline and 28 days Where presence of bridging fibrosis or Cirrhosis at day 28 is the outcome. Firth logistic regression model was used. An intercept term and treatment indicator are the only predictor variables.
Number of Participants Presenting Changes in Steatosis Grade (NAS) From Baseline to Day 28 28 days Number of patients in whom the histological degree of liver steatosis improved between baseline and day 28. Steatosis is assessed using an ordinal scale (1,2,3,4). There are four categories of steatosis grade: (1) \<5%, (2) 5% to 33%, (3) \>33% to 66%, and (4) \>66% Ordinal logistic regression was used for statistical analysis
Number of Participants Presenting Changes in Hepatic Venous Pressure Gradient (HVPG) Between Baseline and Day 28 28 days This outcome measure was included in the protocol as a secondary objective. However, no data was generated as HVPG is difficult to obtain and the outcome measure was therefore abandoned
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 Samples were not available. It was reported as a SAP deviation in the final statistical report.
Change in Serum Bilirubin Concentration From Baseline to Day 28 28 days Change in MELD (Model For End-Stage Liver Disease) Score at From Baseline to Day 28 Day 0 to day 28 MELD score is based on the following formula: MELD Score = (9.57 \* ln(Creatinine)) + (3.78 \* ln(Bilirubin)) + (11.2 \* ln(INR)) + 6.43. Higher score is a worse outcome. Minimum value is around 9 and maximum value is around 40.
Change in Glasgow Alcoholic Hepatitis Score (GAHS) From Day 28 Day 0 to day 28 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 5 to 12 is assigned based on age, WCC, Urea, PT ratio or INR and bilirubin. Higher score means a worse outcome and a score greater than or equal to 9 is associated with a poor prognosis.
Outcome measure is the score at day 28 - score at day 0Change in Maddrey's Discriminant Function (mDF) Score From Baseline to Day 28 28 days mDF is calculated using the following formula: mDF = 4.6 x (Prothrombin time - control time) + Serum Bilirubin (μmol/l) / 17. A higher score is associated with poorer prognosis. A value more than 32 implies poor outcome.
Lille Score at Day 7 7 days 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%.Number of Patients With Resolution of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients With SIRS at Baseline 28 days 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%Number of Patients With Incidence of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients Without SIRS at Baseline 28 days 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%Number of Deaths at Day 90 90 days Number of deaths per arm and hazard ratio.
Number of Patients With Infection Over 90 Days 90 days Number of Patients With Acute Kidney Injury Over 90 Days 90 days Number of Patients With Variceal Haemorrhage Over 90 Days 90 days Number of Participants With Treatment-related Adverse Events 90 days The safety and tolerability of canakinumab will be assessed through the measurement of a number of participants with treatment-related adverse events.
Serum and Plasma Biomarkers of Hepatic Function and Inflammation Including Cytokine Profiles Which May Indicate the Degree of Response to IL-1b Inhibition. 90 days Data were not available at time of final analysis.
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-18BpaCRP Levels at Day 28 28 days Length of Hospital Stay 90 days Difference in Proportions of Participants With Improvement of Ballooned Hepatocytes Between Treatment Groups. Day 28 Improvement will be recorded as a binary Yes/No outcome. The outcome will be analysed as the proportion of patients, within each treatment group, with 95% confidence intervals.
Difference in Proportions of Improvement of Steatosis Between Treatment Groups at Day 28 Day 28 Improvement will be recorded as a binary Yes/No outcome. The outcome will be analysed as the proportion of patients, within each treatment group, with 95% confidence intervals.
Number of Patients Presenting Changes in Degree of Neutrophil Infiltration (AHHS) From Baseline to Day 28 day 28 Where no/mild polymorphonuclear infiltration at day 28 is the outcome. A logistic regression model was used. An intercept term, baseline measurement and treatment indicator are the only predictor variables.
Number of Patients Presenting Changes in Presence of Megamitochondria (AHHS) From Baseline to Day 28 day 28 Where no megamitochondria at day 28 is the outcome. Firth logistic regression model was used. An intercept term, baseline measurement and treatment indicator are the only predictor variables.
Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28 day 28 Where there are 3 outcomes: (1) no or hepatocellular only, (2) ductular or canalicular, (3) canalicular or ductular plus hepatocellular. An ordinal logistic regression model was used. An intercept term, baseline measurement and treatment indicator are the only predictor variables.
Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 day 28 There are four categories: (1) No foci, (2) \< 2 foci per 200x field, (3) 2 to 4 foci per 200x field, and (4) \> 4 foci per 200x field. Ordinal logistic regression was used.
Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28 day 28 There are three categories: (1) none, (2) few balloon cells, and (3) many cells/prominent ballooning. Ordinal logistic regression was used.
Number of Patients With Sepsis Over 90 Days 90 days Number of Patients With Ascites Over 90 Days 90 days Number of Patients With Encephalopathy Over 90 Days 90 days
Trial Locations
- Locations (16)
University Hospitals Bristol NHS Foundation Trust
🇬🇧Bristol, United Kingdom
Glasgow Royal Infirmary, Greater Glasgow & Clyde
🇬🇧Glasgow, United Kingdom
Queen Elizabeth University Hospital
🇬🇧Glasgow, United Kingdom
Leeds Teaching Hospitals NHS Trust
🇬🇧Leeds, United Kingdom
Aintree University Hospital
🇬🇧Liverpool, United Kingdom
Royal Liverpool and Broadgreen University Hospitals NHS Trust
🇬🇧Liverpool, United Kingdom
Imperial College Healthcare NHS Foundation Trust
🇬🇧London, United Kingdom
Chelsea and Westminster Hospital NHS Foundation Trust
🇬🇧London, United Kingdom
King's College Hospital NHS Foundation Trust
🇬🇧London, United Kingdom
Royal Free London NHS Foundation Trust
🇬🇧London, United Kingdom
St George's University Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
The Newcastle Upon Tyne Hospitals NHS Foundation Trust
🇬🇧Newcastle Upon Tyne, United Kingdom
Nottingham University Hospitals NHS Trust
🇬🇧Nottingham, United Kingdom
John Radcliffe Hospital, Oxford University NHS Foundation Trust
🇬🇧Oxford, United Kingdom
Plymouth Hospitals NHS Trust
🇬🇧Plymouth, United Kingdom
University Hospital Southampton NHS Foundation Trust
🇬🇧Southampton, United Kingdom