Alcoholic Hepatitis
Conditions
Keywords
Canakinumab, Alcoholic Hepatitis, Alcohol Use Disorder, Interleukin, Treatment, Ilaris, Liver disease
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.
Interventions
DRUGCanakinumab 150mg/ml solution for injection
Canakinumab 150mg/ml solution for injection
DRUGPlacebo
100ml 5% Dextrose
Sponsors
Novartis Pharmaceuticals
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 0 |
| Change 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 | — |
| 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 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-18Bpa |
| CRP 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 | — |
| Number of Patients With Variceal Haemorrhage Over 90 Days | 90 days | — |
Countries
United Kingdom
Participant flow
Recruitment details
Participants were recruited at 15 sites between February 2019 and October 2020. The first participant was enrolled on 12th February 2019 and the last participant was enrolled on 19th October 2020.
Pre-assignment details
Of 76 screened participants, 55 met the inclusion criteria and were randomised to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Canakinumab A single dose of 3 mg/kg canakinumab administered intravenously at baseline. Canakinumab made up by dilution in 100ml 5% dextrose solution.
Patients with AST \> 2 x ULN on day 28 receive a second dose of 3mg/kg canakinumab administered the same way. | 28 |
| Placebo A single injection of 100ml 5% Dextrose solution at baseline.
Patients with AST \> 2 x ULN on day 28 receive a second injection of the same solution. | 27 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | COVID-19 outbreak | 2 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Canakinumab | Placebo |
|---|---|---|---|
| Age, Continuous | 49 years STANDARD_DEVIATION 8.7 | 51 years STANDARD_DEVIATION 9.1 | 46 years STANDARD_DEVIATION 7.8 |
| Body Mass Index | 29.5 kg/m^2 STANDARD_DEVIATION 6.6 | 29.8 kg/m^2 STANDARD_DEVIATION 6.2 | 29.1 kg/m^2 STANDARD_DEVIATION 7.1 |
| Chronic heart disease | 2 Participants | 2 Participants | 0 Participants |
| Chronic kidney disease | 1 Participants | 1 Participants | 0 Participants |
| Chronic lung disease | 0 Participants | 0 Participants | 0 Participants |
| Diabetic | 6 Participants | 2 Participants | 4 Participants |
| Diastolic BP | 67 mmHg STANDARD_DEVIATION 9.4 | 68.0 mmHg STANDARD_DEVIATION 10.4 | 67 mmHg STANDARD_DEVIATION 8.5 |
| Height | 172 cm STANDARD_DEVIATION 11 | 172 cm STANDARD_DEVIATION 10.8 | 171 cm STANDARD_DEVIATION 11.4 |
| Physical examination performed No | 9 Participants | 5 Participants | 4 Participants |
| Physical examination performed Yes - abnormalities | 33 Participants | 17 Participants | 16 Participants |
| Physical examination performed Yes - no abnormalities | 13 Participants | 6 Participants | 7 Participants |
| Previous admission for alcoholic hepatitis | 13 Participants | 9 Participants | 4 Participants |
| Previous diagnosis of liver cirrhosis No | 40 Participants | 20 Participants | 20 Participants |
| Previous diagnosis of liver cirrhosis Yes - Biopsy | 1 Participants | 0 Participants | 1 Participants |
| Previous diagnosis of liver cirrhosis Yes - Clinical | 14 Participants | 8 Participants | 6 Participants |
| Pulse | 83 BPM STANDARD_DEVIATION 12.5 | 81 BPM STANDARD_DEVIATION 13.1 | 85 BPM STANDARD_DEVIATION 11.7 |
| Race/Ethnicity, Customized Ethnicity Asian | 7 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Ethnicity Black | 3 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Mixed | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Other | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity White | 43 Participants | 21 Participants | 22 Participants |
| Sex: Female, Male Female | 25 Participants | 11 Participants | 14 Participants |
| Sex: Female, Male Male | 30 Participants | 17 Participants | 13 Participants |
| Source of patient referral A&E | 26 Participants | 11 Participants | 15 Participants |
| Source of patient referral GP | 1 Participants | 0 Participants | 1 Participants |
| Source of patient referral Other | 3 Participants | 3 Participants | 0 Participants |
| Source of patient referral Other hospital | 25 Participants | 14 Participants | 11 Participants |
| Surgical and medical procedures before entering the study | 5 Participants | 3 Participants | 2 Participants |
| Systolic BP | 111 mmHg STANDARD_DEVIATION 11.9 | 114 mmHg STANDARD_DEVIATION 13.4 | 109 mmHg STANDARD_DEVIATION 9.9 |
| Temperature | 36.7 Degrees Celsius STANDARD_DEVIATION 0.26 | 36.7 Degrees Celsius STANDARD_DEVIATION 0.25 | 36.7 Degrees Celsius STANDARD_DEVIATION 0.28 |
| Weight | 88 kg STANDARD_DEVIATION 24.1 | 89 kg STANDARD_DEVIATION 22.2 | 87 kg STANDARD_DEVIATION 26 |
| WHO Performance Status 0 - Asymptomatic | 5 Participants | 1 Participants | 4 Participants |
| WHO Performance Status 1 - Symptomatic but completely ambulatory | 11 Participants | 5 Participants | 6 Participants |
| WHO Performance Status 2 - Symptomatic < 50% in bed | 15 Participants | 7 Participants | 8 Participants |
| WHO Performance Status 3 - Symptomatic > 50% in bed | 22 Participants | 13 Participants | 9 Participants |
| WHO Performance Status 4 - Bedbound | 2 Participants | 2 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 28 | 2 / 27 |
| other Total, other adverse events | 26 / 28 | 24 / 27 |
| serious Total, serious adverse events | 10 / 28 | 10 / 27 |
Outcome results
Primary
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).
Time frame: Baseline and 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients Presenting Histological Improvement of Alcoholic Hepatitis on Liver Biopsy After 28 Days of Treatment Compared to Baseline. | 14 Participants |
| Placebo | Number of Patients Presenting Histological Improvement of Alcoholic Hepatitis on Liver Biopsy After 28 Days of Treatment Compared to Baseline. | 10 Participants |
Comparison: It is estimated that improvement of histological alcoholic steatohepatitis will occur in 40% of patients treated with placebo and 80% of patients treated with Canakinumab. A trial with 80% power to detect a difference at the P \< 0.05 threshold would require 23 patients in each arm, 46 in total. Assuming a drop-out rate of 10%, we will recruit 52 patients in total (26 patients per group).p-value: 0.24895% CI: [-11.2, 44.5]Chi-squared
Secondary
Change in Glasgow Alcoholic Hepatitis Score (GAHS) From 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 0
Time frame: Day 0 to day 28
Population: Patients on whom the Glasgow Alcoholic Hepatitis Score was available at day 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab | Change in Glasgow Alcoholic Hepatitis Score (GAHS) From Day 28 | 1.67 score on a scale |
| Placebo | Change in Glasgow Alcoholic Hepatitis Score (GAHS) From Day 28 | 1.71 score on a scale |
95% CI: [1.558, 16.624]
Secondary
Change in Maddrey's Discriminant Function (mDF) Score From Baseline to Day 28
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.
Time frame: 28 days
Population: Day 28 results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change in Maddrey's Discriminant Function (mDF) Score From Baseline to Day 28 | 36 score on a scale | Standard Deviation 17.7 |
| Placebo | Change in Maddrey's Discriminant Function (mDF) Score From Baseline to Day 28 | 29 score on a scale | Standard Deviation 11.4 |
Comparison: Natural log transformation used for both baseline and day 28 measurements. 49 participants have mDF measurements at baseline and day 28.p-value: 0.343ANCOVA
Secondary
Change in MELD (Model For End-Stage Liver Disease) Score at From Baseline 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.
Time frame: Day 0 to day 28
Population: Patients with available day 28 MELD score only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change in MELD (Model For End-Stage Liver Disease) Score at From Baseline to Day 28 | -4.57 MELD difference (Units on a scale) | Standard Deviation 3.8 |
| Placebo | Change in MELD (Model For End-Stage Liver Disease) Score at From Baseline to Day 28 | -5.87 MELD difference (Units on a scale) | Standard Deviation 2.9 |
p-value: 0.0349ANCOVA
Secondary
Change in Serum Bilirubin Concentration From Baseline to Day 28
Time frame: 28 days
Population: Bilirubin levels at day 28 only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Change in Serum Bilirubin Concentration From Baseline to Day 28 | 126 micromole/litre | Standard Deviation 63.1 |
| Placebo | Change in Serum Bilirubin Concentration From Baseline to Day 28 | 102 micromole/litre | Standard Deviation 41.5 |
p-value: 0.27ANCOVA
Secondary
CRP Levels at Day 28
Time frame: 28 days
Population: Number of measurements at day 28
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Canakinumab | CRP Levels at Day 28 | 8 milligrams/litre |
| Placebo | CRP Levels at Day 28 | 10.2 milligrams/litre |
Secondary
Difference in Proportions of Improvement of Steatosis Between Treatment Groups at 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.
Time frame: Day 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab | Difference in Proportions of Improvement of Steatosis Between Treatment Groups at Day 28 | 0.652 Proportion of participants |
| Placebo | Difference in Proportions of Improvement of Steatosis Between Treatment Groups at Day 28 | 0.783 Proportion of participants |
95% CI: [-0.388, 0.127]
Secondary
Difference in Proportions of Participants With Improvement of Ballooned Hepatocytes Between Treatment Groups.
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.
Time frame: Day 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab | Difference in Proportions of Participants With Improvement of Ballooned Hepatocytes Between Treatment Groups. | 0.652 Proportion of participants |
| Placebo | Difference in Proportions of Participants With Improvement of Ballooned Hepatocytes Between Treatment Groups. | 0.609 Proportion of participants |
95% CI: [-0.235, 0.322]
Secondary
Difference in Proportions of Participants With Improvement of Polymorphonuclear Cell Infiltrate From Baseline to 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 improvement on each individual component (polymorphonuclear cell infiltrate, ballooned hepatocytes and steatosis).
Time frame: Baseline and 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canakinumab | Difference in Proportions of Participants With Improvement of Polymorphonuclear Cell Infiltrate From Baseline to Day 28. | 0.652 Proportion of participants |
| Placebo | Difference in Proportions of Participants With Improvement of Polymorphonuclear Cell Infiltrate From Baseline to Day 28. | 0.609 Proportion of participants |
95% CI: [-0.235, 0.322]
Secondary
Length of Hospital Stay
Time frame: 90 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Canakinumab | Length of Hospital Stay | 22 days |
| Placebo | Length of Hospital Stay | 22 days |
Secondary
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%.
Time frame: 7 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Canakinumab | Lille Score at Day 7 | -1.457 score on a scale | Standard Deviation 1.085 |
| Placebo | Lille Score at Day 7 | -1.540 score on a scale | Standard Deviation 0.934 |
95% CI: [-0.529, 0.696]
Secondary
Number of Deaths at Day 90
Number of deaths per arm and hazard ratio.
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Deaths at Day 90 | 2 Participants |
| Placebo | Number of Deaths at Day 90 | 2 Participants |
95% CI: [0.147, 7.424]
Secondary
Number of Participants Presenting Changes in Hepatic Venous Pressure Gradient (HVPG) Between Baseline and Day 28
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
Time frame: 28 days
Population: No data collected There was no measurement taken
Secondary
Number of Participants Presenting Changes in Serum CK18-M30/M65 From Baseline to Day 7, 14, 21, 28, 42 and 90
Samples were not available. It was reported as a SAP deviation in the final statistical report.
Time frame: Baseline and 7, 14, 21, 28, 42, 90 days
Population: No data collected Data was not available as samples were not available.
Secondary
Number of Participants Presenting Changes in Steatosis Grade (NAS) From Baseline to Day 28
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
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Participants Presenting Changes in Steatosis Grade (NAS) From Baseline to Day 28 | 15 Participants |
| Placebo | Number of Participants Presenting Changes in Steatosis Grade (NAS) From Baseline to Day 28 | 18 Participants |
95% CI: [0.357, 9.965]
Secondary
Number of Participants With Treatment-related Adverse Events
The safety and tolerability of canakinumab will be assessed through the measurement of a number of participants with treatment-related adverse events.
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Participants With Treatment-related Adverse Events | 0 Participants |
| Placebo | Number of Participants With Treatment-related Adverse Events | 0 Participants |
Secondary
Number of Patients Presenting Changes in Degree of Fibrosis (AHHS) From Baseline to Day 28
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.
Time frame: Baseline and 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients Presenting Changes in Degree of Fibrosis (AHHS) From Baseline to Day 28 | 23 Participants |
| Placebo | Number of Patients Presenting Changes in Degree of Fibrosis (AHHS) From Baseline to Day 28 | 22 Participants |
95% CI: [0.121, 81.004]
Secondary
Number of Patients Presenting Changes in Degree of Neutrophil Infiltration (AHHS) From Baseline to 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.
Time frame: day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients Presenting Changes in Degree of Neutrophil Infiltration (AHHS) From Baseline to Day 28 | 21 Participants |
| Placebo | Number of Patients Presenting Changes in Degree of Neutrophil Infiltration (AHHS) From Baseline to Day 28 | 17 Participants |
95% CI: [0.693, 23.219]
Secondary
Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28
There are three categories: (1) none, (2) few balloon cells, and (3) many cells/prominent ballooning. Ordinal logistic regression was used.
Time frame: day 28
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Canakinumab | Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28 | None | 1 Participants |
| Canakinumab | Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28 | Few balloon cells | 15 Participants |
| Canakinumab | Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28 | Many cells/prominent ballooning | 7 Participants |
| Placebo | Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28 | None | 3 Participants |
| Placebo | Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28 | Few balloon cells | 11 Participants |
| Placebo | Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28 | Many cells/prominent ballooning | 9 Participants |
95% CI: [0.238, 2.479]
Secondary
Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to 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.
Time frame: day 28
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Canakinumab | Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 | No foci | 1 Participants |
| Canakinumab | Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 | < 2 foci per 200x field | 10 Participants |
| Canakinumab | Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 | 2 to 4 foci per 200x field | 11 Participants |
| Canakinumab | Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 | > 4 foci per 200x field | 1 Participants |
| Placebo | Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 | > 4 foci per 200x field | 2 Participants |
| Placebo | Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 | No foci | 0 Participants |
| Placebo | Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 | 2 to 4 foci per 200x field | 7 Participants |
| Placebo | Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 | < 2 foci per 200x field | 14 Participants |
95% CI: [0.281, 3.397]
Secondary
Number of Patients Presenting Changes in Presence of Megamitochondria (AHHS) From Baseline to 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.
Time frame: day 28
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients Presenting Changes in Presence of Megamitochondria (AHHS) From Baseline to Day 28 | 21 Participants |
| Placebo | Number of Patients Presenting Changes in Presence of Megamitochondria (AHHS) From Baseline to Day 28 | 19 Participants |
95% CI: [0.543, 38.043]
Secondary
Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to 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.
Time frame: day 28
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Canakinumab | Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28 | Ductular or canalicular plus Hepatocellular | 6 Participants |
| Canakinumab | Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28 | No or hepatocellular only | 14 Participants |
| Canakinumab | Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28 | Ductular or canalicular | 3 Participants |
| Placebo | Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28 | No or hepatocellular only | 16 Participants |
| Placebo | Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28 | Ductular or canalicular | 3 Participants |
| Placebo | Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28 | Ductular or canalicular plus Hepatocellular | 4 Participants |
95% CI: [0.456, 6.558]
Secondary
Number of Patients With Acute Kidney Injury Over 90 Days
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients With Acute Kidney Injury Over 90 Days | 8 Participants |
| Placebo | Number of Patients With Acute Kidney Injury Over 90 Days | 4 Participants |
Secondary
Number of Patients With Ascites Over 90 Days
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients With Ascites Over 90 Days | 26 Participants |
| Placebo | Number of Patients With Ascites Over 90 Days | 21 Participants |
Secondary
Number of Patients With Encephalopathy Over 90 Days
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients With Encephalopathy Over 90 Days | 9 Participants |
| Placebo | Number of Patients With Encephalopathy Over 90 Days | 6 Participants |
Secondary
Number of Patients With Incidence of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 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%
Time frame: 28 days
Population: 43 participants did not have SIRS at baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients With Incidence of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients Without SIRS at Baseline | 3 Participants |
| Placebo | Number of Patients With Incidence of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients Without SIRS at Baseline | 2 Participants |
p-value: 1Fisher Exact
Secondary
Number of Patients With Infection Over 90 Days
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients With Infection Over 90 Days | 6 Participants |
| Placebo | Number of Patients With Infection Over 90 Days | 8 Participants |
Secondary
Number of Patients With Resolution of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 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%
Time frame: 28 days
Population: 6 participants had SIRS at baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients With Resolution of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients With SIRS at Baseline | 1 Participants |
| Placebo | Number of Patients With Resolution of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients With SIRS at Baseline | 3 Participants |
p-value: 1Fisher Exact
Secondary
Number of Patients With Sepsis Over 90 Days
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients With Sepsis Over 90 Days | 1 Participants |
| Placebo | Number of Patients With Sepsis Over 90 Days | 1 Participants |
Secondary
Number of Patients With Variceal Haemorrhage Over 90 Days
Time frame: 90 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Canakinumab | Number of Patients With Variceal Haemorrhage Over 90 Days | 1 Participants |
| Placebo | Number of Patients With Variceal Haemorrhage Over 90 Days | 1 Participants |
Secondary
Serum and Plasma Biomarkers of Hepatic Function and Inflammation Including Cytokine Profiles Which May Indicate the Degree of Response to IL-1b Inhibition.
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-18Bpa
Time frame: 90 days
Population: Data were not available as serum samples required for the cytokine measurements were lost in a freezer failure.