Trial Outcomes & Findings for IL-1 Signal Inhibition in Alcoholic Hepatitis (NCT NCT03775109)

NCT ID: NCT03775109

Last Updated: 2025-03-11

Results Overview

Histological improvement is defined as a reduction in lobular inflammation (regardless of cell type).

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 55 participants
• Primary outcome timeframe: Baseline and 28 days
• Results posted on: 2025-03-11

Participant Flow

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.

Of 76 screened participants, 55 met the inclusion criteria and were randomised to treatment.

Participant milestones

Measure	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.	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.
Overall Study STARTED	28	27
Overall Study Received First Dose	27	27
Overall Study COMPLETED	23	23
Overall Study NOT COMPLETED	5	4

Reasons for withdrawal

Measure	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.	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.
Overall Study Adverse Event	1	0
Overall Study COVID-19 outbreak	2	0
Overall Study Lost to Follow-up	0	2
Overall Study Withdrawal by Subject	1	1
Overall Study Death	0	1
Overall Study Lack of Efficacy	1	0

Baseline Characteristics

IL-1 Signal Inhibition in Alcoholic Hepatitis

Baseline characteristics by cohort

Measure	Canakinumab n=28 Participants 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.	Placebo n=27 Participants 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.	Total n=55 Participants Total of all reporting groups
Age, Continuous	51 years STANDARD_DEVIATION 9.1 • n=5 Participants	46 years STANDARD_DEVIATION 7.8 • n=7 Participants	49 years STANDARD_DEVIATION 8.7 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	14 Participants n=7 Participants	25 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	13 Participants n=7 Participants	30 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · White	21 Participants n=5 Participants	22 Participants n=7 Participants	43 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Mixed	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Asian	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Black	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Ethnicity · Other	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Source of patient referral GP	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Source of patient referral A&E	11 Participants n=5 Participants	15 Participants n=7 Participants	26 Participants n=5 Participants
Source of patient referral Other hospital	14 Participants n=5 Participants	11 Participants n=7 Participants	25 Participants n=5 Participants
Source of patient referral Other	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Height	172 cm STANDARD_DEVIATION 10.8 • n=5 Participants	171 cm STANDARD_DEVIATION 11.4 • n=7 Participants	172 cm STANDARD_DEVIATION 11.0 • n=5 Participants
Weight	89 kg STANDARD_DEVIATION 22.2 • n=5 Participants	87 kg STANDARD_DEVIATION 26 • n=7 Participants	88 kg STANDARD_DEVIATION 24.1 • n=5 Participants
Temperature	36.7 Degrees Celsius STANDARD_DEVIATION 0.25 • n=5 Participants	36.7 Degrees Celsius STANDARD_DEVIATION 0.28 • n=7 Participants	36.7 Degrees Celsius STANDARD_DEVIATION 0.26 • n=5 Participants
Pulse	81 BPM STANDARD_DEVIATION 13.1 • n=5 Participants	85 BPM STANDARD_DEVIATION 11.7 • n=7 Participants	83 BPM STANDARD_DEVIATION 12.5 • n=5 Participants
Systolic BP	114 mmHg STANDARD_DEVIATION 13.4 • n=5 Participants	109 mmHg STANDARD_DEVIATION 9.9 • n=7 Participants	111 mmHg STANDARD_DEVIATION 11.9 • n=5 Participants
Diastolic BP	68.0 mmHg STANDARD_DEVIATION 10.4 • n=5 Participants	67 mmHg STANDARD_DEVIATION 8.5 • n=7 Participants	67 mmHg STANDARD_DEVIATION 9.4 • n=5 Participants
Body Mass Index	29.8 kg/m^2 STANDARD_DEVIATION 6.2 • n=5 Participants	29.1 kg/m^2 STANDARD_DEVIATION 7.1 • n=7 Participants	29.5 kg/m^2 STANDARD_DEVIATION 6.6 • n=5 Participants
Physical examination performed Yes - abnormalities	17 Participants n=5 Participants	16 Participants n=7 Participants	33 Participants n=5 Participants
Physical examination performed Yes - no abnormalities	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants
Physical examination performed No	5 Participants n=5 Participants	4 Participants n=7 Participants	9 Participants n=5 Participants
WHO Performance Status 0 - Asymptomatic	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
WHO Performance Status 1 - Symptomatic but completely ambulatory	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
WHO Performance Status 2 - Symptomatic < 50% in bed	7 Participants n=5 Participants	8 Participants n=7 Participants	15 Participants n=5 Participants
WHO Performance Status 3 - Symptomatic > 50% in bed	13 Participants n=5 Participants	9 Participants n=7 Participants	22 Participants n=5 Participants
WHO Performance Status 4 - Bedbound	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Diabetic	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Previous diagnosis of liver cirrhosis Yes - Biopsy	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Previous diagnosis of liver cirrhosis Yes - Clinical	8 Participants n=5 Participants	6 Participants n=7 Participants	14 Participants n=5 Participants
Previous diagnosis of liver cirrhosis No	20 Participants n=5 Participants	20 Participants n=7 Participants	40 Participants n=5 Participants
Previous admission for alcoholic hepatitis	9 Participants n=5 Participants	4 Participants n=7 Participants	13 Participants n=5 Participants
Chronic heart disease	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Chronic lung disease	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Chronic kidney disease	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Surgical and medical procedures before entering the study	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 28 days

Histological improvement is defined as a reduction in lobular inflammation (regardless of cell type).

Outcome measures

Measure	Canakinumab n=24 Participants 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.	Placebo n=24 Participants 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.
Number of Patients Presenting Histological Improvement of Alcoholic Hepatitis on Liver Biopsy After 28 Days of Treatment Compared to Baseline.	14 Participants	10 Participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=23 Participants 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.
Difference in Proportions of Participants With Improvement of Polymorphonuclear Cell Infiltrate From Baseline to Day 28.	0.652 Proportion of participants Interval 0.458 to 0.847	0.609 Proportion of participants Interval 0.409 to 0.808

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=23 Participants 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.
Number of Patients Presenting Changes in Degree of Fibrosis (AHHS) From Baseline to Day 28	23 Participants	22 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=23 Participants 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.
Number of Participants Presenting Changes in Steatosis Grade (NAS) From Baseline to Day 28	15 Participants	18 Participants

SECONDARY outcome

Timeframe: 28 days

Population: No data collected There was no measurement taken

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and 7, 14, 21, 28, 42, 90 days

Population: No data collected Data was not available as samples were not available.

Samples were not available. It was reported as a SAP deviation in the final statistical report.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 28 days

Population: Bilirubin levels at day 28 only.

Outcome measures

Measure	Canakinumab n=25 Participants 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.	Placebo n=24 Participants 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.
Change in Serum Bilirubin Concentration From Baseline to Day 28	126 micromole/litre Standard Deviation 63.1	102 micromole/litre Standard Deviation 41.5

SECONDARY outcome

Timeframe: Day 0 to day 28

Population: Patients with available day 28 MELD score only.

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.

Outcome measures

Measure	Canakinumab n=25 Participants 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.	Placebo n=24 Participants 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.
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	-5.87 MELD difference (Units on a scale) Standard Deviation 2.9

SECONDARY outcome

Timeframe: Day 0 to day 28

Population: Patients on whom the Glasgow Alcoholic Hepatitis Score was available at 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

Outcome measures

Measure	Canakinumab n=24 Participants 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.	Placebo n=24 Participants 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.
Change in Glasgow Alcoholic Hepatitis Score (GAHS) From Day 28	1.67 score on a scale	1.71 score on a scale

SECONDARY outcome

Timeframe: 28 days

Population: Day 28 results.

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.

Outcome measures

Measure	Canakinumab n=25 Participants 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.	Placebo n=24 Participants 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.
Change in Maddrey's Discriminant Function (mDF) Score From Baseline to Day 28	36 score on a scale Standard Deviation 17.7	29 score on a scale Standard Deviation 11.4

SECONDARY outcome

Timeframe: 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%.

Outcome measures

Measure	Canakinumab n=24 Participants 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.	Placebo n=21 Participants 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.
Lille Score at Day 7	-1.457 score on a scale Standard Deviation 1.085	-1.540 score on a scale Standard Deviation 0.934

SECONDARY outcome

Timeframe: 28 days

Population: 6 participants had 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%

Outcome measures

Measure	Canakinumab n=2 Participants 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.	Placebo n=4 Participants 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.
Number of Patients With Resolution of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients With SIRS at Baseline	1 Participants	3 Participants

SECONDARY outcome

Timeframe: 28 days

Population: 43 participants did not have 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%

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=20 Participants 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.
Number of Patients With Incidence of Systemic Inflammatory Response Syndrome (SIRS) at Day 28 in Patients Without SIRS at Baseline	3 Participants	2 Participants

SECONDARY outcome

Timeframe: 90 days

Number of deaths per arm and hazard ratio.

Outcome measures

Measure	Canakinumab n=28 Participants 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.	Placebo n=27 Participants 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.
Number of Deaths at Day 90	2 Participants	2 Participants

SECONDARY outcome

Timeframe: 90 days

Outcome measures

Measure	Canakinumab n=28 Participants 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.	Placebo n=27 Participants 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.
Number of Patients With Infection Over 90 Days	6 Participants	8 Participants

SECONDARY outcome

Timeframe: 90 days

Outcome measures

Measure	Canakinumab n=28 Participants 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.	Placebo n=27 Participants 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.
Number of Patients With Acute Kidney Injury Over 90 Days	8 Participants	4 Participants

SECONDARY outcome

Timeframe: 90 days

Outcome measures

Measure	Canakinumab n=28 Participants 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.	Placebo n=27 Participants 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.
Number of Patients With Variceal Haemorrhage Over 90 Days	1 Participants	1 Participants

SECONDARY outcome

Timeframe: 90 days

The safety and tolerability of canakinumab will be assessed through the measurement of a number of participants with treatment-related adverse events.

Outcome measures

Measure	Canakinumab n=28 Participants 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.	Placebo n=27 Participants 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.
Number of Participants With Treatment-related Adverse Events	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 90 days

Population: Data were not available as serum samples required for the cytokine measurements were lost in a freezer failure.

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 28 days

Population: Number of measurements at day 28

Outcome measures

Measure	Canakinumab n=25 Participants 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.	Placebo n=24 Participants 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.
CRP Levels at Day 28	8 milligrams/litre Interval 6.2 to 16.0	10.2 milligrams/litre Interval 6.1 to 27.0

SECONDARY outcome

Timeframe: 90 days

Outcome measures

Measure	Canakinumab n=25 Participants 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.	Placebo n=26 Participants 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.
Length of Hospital Stay	22 days Interval 17.0 to 34.0	22 days Interval 15.0 to 27.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=23 Participants 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.
Difference in Proportions of Participants With Improvement of Ballooned Hepatocytes Between Treatment Groups.	0.652 Proportion of participants Interval 0.458 to 0.847	0.609 Proportion of participants Interval 0.409 to 0.808

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=23 Participants 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.
Difference in Proportions of Improvement of Steatosis Between Treatment Groups at Day 28	0.652 Proportion of participants Interval 0.458 to 0.847	0.783 Proportion of participants Interval 0.614 to 0.951

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=23 Participants 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.
Number of Patients Presenting Changes in Degree of Neutrophil Infiltration (AHHS) From Baseline to Day 28	21 Participants	17 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=23 Participants 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.
Number of Patients Presenting Changes in Presence of Megamitochondria (AHHS) From Baseline to Day 28	21 Participants	19 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=23 Participants 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.
Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28 No or hepatocellular only	14 Participants	16 Participants
Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28 Ductular or canalicular	3 Participants	3 Participants
Number of Patients Presenting Changes in Type of Bilirubinostasis (AHHS) From Baseline to Day 28 Ductular or canalicular plus Hepatocellular	6 Participants	4 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=23 Participants 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.
Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 < 2 foci per 200x field	10 Participants	14 Participants
Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 No foci	1 Participants	0 Participants
Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 2 to 4 foci per 200x field	11 Participants	7 Participants
Number of Patients Presenting Changes in Lobular Inflammation (NAS) From Baseline to Day 28 > 4 foci per 200x field	1 Participants	2 Participants

SECONDARY outcome

Timeframe: day 28

There are three categories: (1) none, (2) few balloon cells, and (3) many cells/prominent ballooning. Ordinal logistic regression was used.

Outcome measures

Measure	Canakinumab n=23 Participants 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.	Placebo n=23 Participants 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.
Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28 None	1 Participants	3 Participants
Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28 Few balloon cells	15 Participants	11 Participants
Number of Patients Presenting Changes in Hepatocyte Ballooning (NAS) From Baseline to Day 28 Many cells/prominent ballooning	7 Participants	9 Participants

SECONDARY outcome

Timeframe: 90 days

Outcome measures

Measure	Canakinumab n=28 Participants 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.	Placebo n=27 Participants 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.
Number of Patients With Sepsis Over 90 Days	1 Participants	1 Participants

SECONDARY outcome

Timeframe: 90 days

Outcome measures

Measure	Canakinumab n=28 Participants 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.	Placebo n=27 Participants 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.
Number of Patients With Ascites Over 90 Days	26 Participants	21 Participants

SECONDARY outcome

Timeframe: 90 days

Outcome measures

Measure	Canakinumab n=28 Participants 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.	Placebo n=27 Participants 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.
Number of Patients With Encephalopathy Over 90 Days	9 Participants	6 Participants

Adverse Events

Canakinumab

Serious events: 10 serious events

Other events: 26 other events

Deaths: 2 deaths

Placebo

Serious events: 10 serious events

Other events: 24 other events

Deaths: 2 deaths

Serious adverse events

Measure	Canakinumab n=28 participants at risk 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.	Placebo n=27 participants at risk 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.
Blood and lymphatic system disorders Anaemia	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Cardiac disorders Cardiac arrest	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Cardiac disorders Palpitations	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Gastrointestinal disorders Abdominal distension	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Gastrointestinal disorders Abdominal pain	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Gastrointestinal disorders Haematemesis	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Gastrointestinal disorders Pancreatitis acute	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Gastrointestinal disorders Rectal haemorrhage	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
General disorders Oedema	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Hepatobiliary disorders Alcoholic liver disease	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Hepatobiliary disorders Ascites	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Hepatobiliary disorders Hepatic failure	7.1% 2/28 • Number of events 2 • 90 days	14.8% 4/27 • Number of events 5 • 90 days
Hepatobiliary disorders Hepatic encephalopathy	7.1% 2/28 • Number of events 2 • 90 days	0.00% 0/27 • 90 days
Hepatobiliary disorders Oesophageal varices haemorrhage	3.6% 1/28 • Number of events 2 • 90 days	0.00% 0/27 • 90 days
Infections and infestations Peritonitis bacterial	0.00% 0/28 • 90 days	7.4% 2/27 • Number of events 2 • 90 days
Infections and infestations Pneumonia	3.6% 1/28 • Number of events 1 • 90 days	7.4% 2/27 • Number of events 2 • 90 days
Infections and infestations Urinary tract infection	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Injury, poisoning and procedural complications Haemoperitoneum	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Injury, poisoning and procedural complications Post procedural haemorrhage	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 2 • 90 days
Injury, poisoning and procedural complications Skull fracture	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Injury, poisoning and procedural complications Subarachnoid haemorrhage	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Metabolism and nutrition disorders Hypernatraemia	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/28 • 90 days	7.4% 2/27 • Number of events 2 • 90 days
Metabolism and nutrition disorders Metabolic acidosis	3.6% 1/28 • Number of events 1 • 90 days	0.00% 0/27 • 90 days
Nervous system disorders Hypoaesthesia	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.6% 1/28 • Number of events 1 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Renal and urinary disorders Acute kidney injury	3.6% 1/28 • Number of events 1 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Vascular disorders Haematoma	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Vascular disorders Hypotension	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days
Vascular disorders Soft tissue necrosis	0.00% 0/28 • 90 days	3.7% 1/27 • Number of events 1 • 90 days

Other adverse events

Measure	Canakinumab n=28 participants at risk 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.	Placebo n=27 participants at risk 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.
General disorders General AE	92.9% 26/28 • Number of events 114 • 90 days	88.9% 24/27 • Number of events 102 • 90 days

Additional Information

Professor Mark Thursz

Imperial College, London

Phone: +44 (0) 203 3126454

Email: m.thursz@imperial.ac.uk

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place