Clinical trial NCT03775109
Conditions: Alcoholic Hepatitis
Keywords: Canakinumab Alcoholic Hepatitis Alcohol Use Disorder Interleukin Treatment Ilaris Liver disease
Sponsor: Imperial College London
Start date: 2019-02-12; Completion date: 2023-03-31
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 150mg/ml solution for injection arm 2: None
Interventions: intervention 1: Canakinumab 150mg/ml solution for injection intervention 2: Placebo
Intervention descriptions: intervention 1: Canakinumab 150mg/ml solution for injection intervention 2: 100ml 5% Dextrose

Protocol documents:
Prot_SAP_000.pdf: 
 
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EudraCT number: 2017-003724-79 
Sponsor: Imperial College London 
Protocol number: 17SM4152 
IRAS ID: 231612 
 
 
 
 
 
 
 
Sponsor:  
Imperial College, London 
EudraCT Number:  
 
 
2017-003724-79  
 
 
 
 
IRAS ID: 
231612 
REC reference number: 
18/LO/0745 
Development Phase: 
II 
Indications: 
Severe Alcoholic Hepatitis 
Sponsor Protocol Number: 
17SM4152 
Protocol Version: 
5.0 
Protocol Date 
03.09.2020  
Study Product:  
Canakinumab (ACZ885) 150 mg / 1 mL solution for injection 
 
 
 
 
 
Property of Imperial Clinical Trials Unit (ICTU) 
May not be used, divulged or published without the consent of ICTU 
This protocol has regard for the HRA guidance 
 


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CHIEF INVESTIGATOR 
 
Prof Mark Thursz 
SPONSOR 
Imperial College, London 
FUNDER 
Novartis Pharmaceuticals UK 
Limited 
TRIAL MANAGER 
Justyna Czyzewska-Khan 
SENIOR STATISTICIAN 
Dr Francesca Fiorentino 
 
 


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LABORATORIES 
 
 
This protocol describes the Isaiah trial and provides information about procedures for entering participants. The protocol should not be used as a guide for the treatment of other participants; 
every care was taken in its drafting, but corrections or amendments may be necessary. These will be circulated to investigators in the study, but centres entering participants for the first time 
are advised to contact the trials centre to confirm they have the most recent version. Problems relating to this trial should be referred, in the first instance, to the Trial Manager. This trial will 
adhere to the principles outlined in the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), amended regulations (SI 2006/1928) and the International Conference on 
Harmonisation Good Clinical Practice (ICH GCP) guidelines. It will be conducted in compliance with the protocol, the Data Protection Act and other regulatory requirements as appropriate.


 
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EudraCT number: 2017-003724-79 
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Protocol number: 17SM4152 
IRAS ID: 231612 
 
Table of Contents 
CONTACT LIST ............................................................................................................................. 2 
ABBREVIATIONS ............................................................................................................................... 7 
1 
Protocol Summary ................................................................................................................ 9 
1.1  
Objectives...................................................................................................................................... 9 
1.2  
Primary End Point .......................................................................................................................... 9 
1.3.  
Secondary End Points .................................................................................................................... 9 
1.4.  
Design............................................................................................................................................ 9 
1.5.  
Trial Phase ................................................................................................................................... 10 
1.6 
Main Eligibility Criteria ................................................................................................................ 10 
1.7 Treatment, formulation, route of administration and dose ............................................................... 10 
2 
Background and rationale ................................................................................................... 11 
2.1 
Rationale for IL-1b inhibition ....................................................................................................... 11 
2.2 
Rationale for dose/regimen, route of administration: ................................................................ 12 
2.4 
Rationale for this Study ............................................................................................................... 12 
2.5 
Rationale for the study population.............................................................................................. 12 
2.6 
Rationale for 16S-DNA measurement and prophylactic antibiotics ............................................. 12 
3 
Study Design ....................................................................................................................... 13 
3.1.  
Objectives.................................................................................................................................... 13 
3.2.  
Primary End Point ........................................................................................................................ 13 
3.3.  
Secondary End Points .................................................................................................................. 13 
3.4. 
Exploratory End Points ................................................................................................................ 13 
3.5.  
Design.......................................................................................................................................... 14 
3.6. 
Treatment ................................................................................................................................... 14 
4.  
Patient population .............................................................................................................. 15 
4.1 
Patient selection .......................................................................................................................... 15 
4.2 
Informed Consent ........................................................................................................................ 15 
4.3 
Incapacitated Patients ................................................................................................................. 15 
Personal legal representative ........................................................................................................... 15 
Professional legal representative ..................................................................................................... 15 
4.4 
Eligibility Criteria ......................................................................................................................... 16 
4.4.1 Inclusion criteria ...................................................................................................................... 16 
4.4.2 Exclusion criteria ..................................................................................................................... 16 
Sepsis: 17 
Renal Impairment: ........................................................................................................................... 17 
5.  
Patient Registration, Randomisation and Data Collection .................................................. 18 
5.1 Account Creation................................................................................................................................ 18 
5.2   Source Data ...................................................................................................................................... 18 
5.3  
Patient Registration ..................................................................................................................... 18 
5.4  
Patient Randomisation ................................................................................................................ 18 
5.5 
eCRF ............................................................................................................................................ 18 
5.6 
Procedure for breaking treatment code ...................................................................................... 18 
6. Concurrent Medication and Treatment ...................................................................................... 19 
6.1  
Alcohol withdrawal ..................................................................................................................... 19 


 
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6.2  
Infection / Sepsis ......................................................................................................................... 19 
6.3  
Nutrition ...................................................................................................................................... 19 
6.4  
Other treatments for Alcoholic Hepatitis .................................................................................... 19 
7.  
Investigations & Procedures ............................................................................................... 20 
7.1  
Screening ..................................................................................................................................... 20 
7.2  
Baseline (pre-randomisation) ...................................................................................................... 21 
7.3  
Evaluations During and After Treatment ..................................................................................... 21 
7.4 
 Day 90......................................................................................................................................... 22 
7.5 
Schedule of Assessments ............................................................................................................. 23 
7.6 
Assessments ................................................................................................................................ 26 
7.6.1 Patient demographics/other baseline characteristics: ............................................................ 26 
7.6.2 Physical exam: ......................................................................................................................... 26 
7.6.3 WHO Performance Status ........................................................................................................ 26 
7.6.4 Vital signs ................................................................................................................................ 26 
7.6.5 Liver biopsy ............................................................................................................................. 27 
7.6.6 Laboratory tests ...................................................................................................................... 28 
Incidence of acute kidney injury....................................................................................................... 29 
7.6.7 Infection screening .................................................................................................................. 29 
7.6.8 Monocyte oxidative burst ....................................................................................................... 29 
7.6.9 Changes in plasma bacterial DNA ............................................................................................ 30 
7.6.10 Changes in transient elastography scores .............................................................................. 30 
7.6.11 Canakinumab sample collection ............................................................................................ 30 
7.6.12 Pharmacodynamic assessments........................................................................................... 30 
7.6.13 Other assessments ................................................................................................................ 31 
8 Statistical Considerations ............................................................................................................ 31 
8.1 
Power calculation ........................................................................................................................ 31 
8.2 
Statistical Analysis Plan ............................................................................................................... 31 
9.  
Assessment of Safety .......................................................................................................... 32 
9.1  
Definitions of Adverse Events ...................................................................................................... 32 
9.2  
Recording Adverse Events ........................................................................................................... 33 
9.2.1 Exclusions to Adverse Event Recording Requirements ............................................................ 33 
9.3  
Pre-existing Conditions ................................................................................................................ 33 
9.4  
Reporting of Serious Adverse Events (SAEs, SARs and SUSARs) ................................................... 33 
9.5  
Post-treatment SAEs & Follow-Up ............................................................................................... 35 
9.6  
Pregnancy .................................................................................................................................... 35 
9.7  
Evaluation of SAEs ....................................................................................................................... 36 
9.7.1 Causality of AEs ....................................................................................................................... 36 
9.8  
Expedited Reporting ............................................................................................................ 36 
9.9   Annual reporting of Serious Adverse Events ............................................................................. 37 
9.10 Reporting urgent safety measures............................................................................................ 37 
10.  
Patient Loss from Study Post-Randomisation ..................................................................... 38 
10.1  
Patients lost................................................................................................................................. 38 
10.1.1 Withdrawn ............................................................................................................................ 38 
10.1.2 Lost to follow-up ................................................................................................................... 38 
10.1.3 Patients that have died.......................................................................................................... 38 
10.2  
Patients not lost .......................................................................................................................... 38 
11. END OF THE CLINICAL TRIAL ..................................................................................................... 39 
12 
REGULATORY, ETHICAL AND LEGAL ISSUES ........................................................................ 40 


 
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12.1 
Treatment ................................................................................................................................... 40 
12.1.1 Investigational Medicinal Product Details ..................................................................................... 40 
12.1.2 Labelling, storage and dispensing .................................................................................................. 40 
12.1.3 Accountability ............................................................................................................................... 41 
12.2 
Declaration of Helsinki ................................................................................................................ 41 
12.3 
Good Clinical Practice .................................................................................................................. 41 
12.4 
Independent Ethics Committee Approval .................................................................................... 41 
(vi) 
Initial Approval ............................................................................................................... 
41 
(vii) 
Approval of Amendments .................................................................................................... 41 
(iii) 
Annual Progress Reports ...................................................................................................... 41 
(iv) 
Annual Safety Reports and End of Trial Notification ............................................................ 41 
12.5 
Regulatory Authority Approval.................................................................................................... 42 
12.6 
HRA Approval .............................................................................................................................. 42 
12.7 
Insurance and Indemnity ............................................................................................................. 42 
12.8 
Trial Registration ......................................................................................................................... 42 
12.9 
Informed Consent ........................................................................................................................ 42 
12.10 
Non-compliance and serious breaches .................................................................................... 42 
12.11 
Contact with General Practitioner ........................................................................................... 43 
12.12 
Subject Confidentiality ............................................................................................................ 43 
12.13 
Data Protection ....................................................................................................................... 43 
12.14 
End of Trial .............................................................................................................................. 43 
12.15 
Study Documentation and Data Storage ................................................................................. 43 
13 
STUDY MANAGEMENT STRUCTURE ................................................................................................. 44 
13.1 
Trial Steering Committee ............................................................................................................. 44 
13.2 
Trial Management Group ............................................................................................................ 44 
13.3 
Data Monitoring Committee ....................................................................................................... 44 
13.4 
Early Discontinuation of the Study .............................................................................................. 44 
13.5 
Risk Assessment .......................................................................................................................... 44 
13.6  
Monitoring .................................................................................................................................. 45 
13.7 
Quality Control and Quality Assurance ........................................................................................ 46 
13.8  
Disclosure of Data and Publication .............................................................................................. 46 
13.9 
Patient and Public Involvement (PPI) .......................................................................................... 46 
13.10 
Peer review ............................................................................................................................. 46 
14 
References .......................................................................................................................... 47 
APPENDIX 1 .............................................................................................................................................. 48 
Summary of treatment plan for the Isaiah study ......................................................................................... 48 
APPENDIX 2 .............................................................................................................................................. 49 
Protocol Exempt Adverse Events ............................................................................................................. 49 
SIGNATURE PAGE 1 (Chief Investigator) ......................................................................................... 50 
SIGNATURE PAGE 2 (SPONSOR)...................................................................................................... 51 
SIGNATURE PAGE 3 (STATISTICIAN) ............................................................................................... 52 
SIGNATURE PAGE 4 (principal INVESTIGATOR) .............................................................................. 53 
 
 
 


 
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Protocol number: 17SM4152 
IRAS ID: 231612 
ABBREVIATIONS  
AE 
Adverse Event 
AH 
Alcoholic Hepatitis 
AHHS 
Alcoholic Hepatitis Histological Score 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AR 
Adverse Reaction 
AST 
Aspartate Aminotransferase 
BM 
Biomarkers 
BP 
Blood Pressure 
CAPS 
Cryopyrin-Associated Periodic Syndromes 
CI 
Chief Investigator 
CRF 
Case Report Form 
CTU 
Clinical Trials Unit 
CXR 
Chest X-ray 
DMEC 
Data Monitoring and Ethical Committee 
DNA 
Deoxyribonucleic Acid 
DSUR 
Development Safety Update Report 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FMF 
Familial Mediterranean fever 
GAHS 
Glasgow Alcoholic Hepatitis Score 
GCP 
Good Clinical Practice 
HIDS 
Hyperimmunoglobulin D Syndrome 
HIV 
Human Immunodeficiency Virus 
GI 
Gastrointestinal 
ICMJE 
International Committee of Medical Journal Editors 
ICTU 
Imperial Clinical Trials Unit 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
IMP 
Investigational Medicinal Product 
i.v. 
Intravenous 


 
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LDH 
Lactate Dehydrogenase 
MA 
Marketing Authorisation 
mDF 
 
MELD 
Model for End stage Liver Disease 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MSU 
Mid-stream urine 
NAS 
Nonalcoholic fatty liver disease activity score 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
s.c. 
Subcutaneous 
SIRS 
Systemic Inflammatory Response Syndrome 
SJIA 
Systemic Juvenile Idiopathic Arthritis 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SSAR 
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
TMF 
Trial Master File 
TMG 
Trial Management Group  
TRAPS 
Tumour necrosis factor receptor associated periodic syndrome 
TSC 
Trial Steering Committee 
ULN 
Upper Limit of Normal 
UNOS 
United Network of Organ Sharing  
UTI 
Urinary Tract Infection 
WHO 
World Health Organisation 
 


 
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EudraCT number: 2017-003724-79 
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Protocol number: 17SM4152 
IRAS ID: 231612 
1 
Protocol Summary 
 
1.1  
Objectives 
To explore the potential benefits of the IL-1  antibody, Canakinumab, in the treatment of alcoholic 
hepatitis.  
 
1.2  
Primary End Point 
Histological improvement of alcoholic hepatitis on liver biopsy after 28 days of treatment compared 
to baseline (See Section 7.6.5).  
 
1.3.  
Secondary End Points 
 Improvement of individual components of alcoholic hepatitis on liver histology from baseline 
to Day 28 
 Changes in the components of Alcoholic Hepatitis Histological Score (AHHS) (1) from baseline 
to Day 28 
 Changes in the components of Non-alcoholic fatty liver disease activity score (NAS) score from 
baseline to Day 28 
 Changes in the hepatic venous pressure gradient (HVPG) between baseline and day 28. 
 Changes in serum CK18-M30/M65 from baseline to Day 7, 14, 21, 28, 42 and 90 
 Change in serum bilirubin from baseline to Day 7, 14, 28, 21, 42 and 90  
 Change in MELD score at from baseline to Day 7, 14, 21, 28, 42 and 90 
 Change in Glasgow alcoholic hepatitis score (GAHS) from baseline to Day 7, 14, 21, 28, 42 and 
90 
 Change in mDF score from baseline to Day 7, 14, 21, 28, 42 and 90 
 Lille score at Day 7 
 Resolution of systemic inflammatory response syndrome (SIRS) at Day 7, 14, 21, 28, 42 and 90 
in patients with SIRS at baseline  
 Incidence of SIRS at Day 7, 14, 21, 28, 42 and 90 in patients without SIRS at baseline 
 Mortality rate at Day 90  
 Incidence of infection and sepsis over 90 days 
 Incidence of acute kidney injury over 90 days 
 Incidence of variceal haemorrhage, ascites or encephalopathy over 90 days 
 safety and tolerability of canakinumab  
 Changes in CRP over time 
 Length of hospital stay 
 Serum and plasma biomarkers of hepatic function and inflammation including cytokine 
profiles which may indicate the degree of response to IL-1b inhibition. 
 
 
1.4.  
Design 
Multicentre, double blind, randomized (1:1), placebo controlled trial. The trial will follow patients up 
for 90 days and will be conducted in up to 18 centres in the United Kingdom. Twenty-six patients will 
be recruited to each arm of the trial: total 52 patients.  
 


 
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Protocol number: 17SM4152 
IRAS ID: 231612 
1.5.  
Trial Phase  
Phase II  Exploring the benefits of IL-1 inhibition in alcoholic hepatitis 
 
1.6 
Main Eligibility Criteria 
 
(Full eligibility criteria listed in Section 4.4) 
Inclusion criteria 
 Male and female patients aged 18 years or older at screening 
 Clinical diagnosis of alcoholic hepatitis at screening: 
- 
 
- 
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: 
o Evidence of chronic viral hepatitis (Hepatitis B or C) 
o Biliary obstruction 
o 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) 
 
below) 
 Patients dependent upon inotropic support (adrenaline or noradrenaline).  Terlipressin is 
allowed 
 Variceal haemorrhage on this admission 
 Untreated sepsis (see 4.4.2 Exclusion Criteria) 
 
1.7 Treatment, formulation, route of administration and dose 
Consenting eligible patients will be included, randomized and treated before the histology result is 
available because histology results usually come back within 5 to 7 days depending on the hospital. If 
the histology is negative then the patient will be discontinued from the study, will not undergo any 
further treatment or the second biopsy and will not be included into the efficacy analysis but will be 
followed up for safety assessment. For each patient with a negative histology, another patient will be 
recruited to ensure that the sample of positive histology patients is 52. Additionally, recruitment will 
be continued until both biopsies (at Baseline and Day28) from 48 patients will be collected. 
 


 
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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. 
2 
Background and rationale 
Alcohol consumption causes a spectrum of liver abnormalities and leads to over 2 million deaths per 
year (1). Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by 
liver failure (jaundice and coagulopathy) in the context of recent and heavy alcohol consumption (2). 
The condition carries a high fatality risk; patients with severe AH have a 30% mortality rate at 90 days 
after presentation. Moderate AH carries a mortality rate of 6-10% at 90 days. Currently there are no 
effective treatments for alcoholic hepatitis although clinical guidelines currently recommend 
prednisolone(3). Prednisolone therapy improves survival in patients with severe AH up to 28 days but 
beyond this timepoint a higher incidence of infection results in no survival advantage at 90 days 
compared to placebo treatment (4-6)  
Alcoholic hepatitis is a clinical syndrome associated with steatohepatitis on liver histology. Severity 
and prothrombin time), Glasgow alcoholic hepatitis score (based on age, white blood cell count, urea, 
prothrombin time and bilirubin) or Model for End Stage Liver Disease (MELD) score (based on 
creatinine, bilirubin and INR)(2, 6). Alcoholic hepatitis is classified as severe when the mDF is  32. In 
the recent STOPAH trial we identified a group of patients with DF  32and MELD < 25, representing 
60% of the trial population in whom the 90 day mortality rate was 18%. In patients with mDF 32 and 
MELD 27 the 90 day mortality was marginally higher at 22%. This group of patients was less 
susceptible to infection even when treated with prednisolone (6). 
 
2.1 
Rationale for IL-1b inhibition 
 IL-1 levels are significantly increased in both serum and liver in patients with alcoholic hepatitis as 
well as in animal models of the disease. Patients with alcoholic hepatitis have serum levels almost 10 
times higher than found in healthy controls(7). IL-1 is thought to be responsible for many of the 
clinical and metabolic characteristics of alcoholic hepatitis including fever, neutrophilia, monocyte 
activation, anorexia and muscle catabolism (8). In animal models, inhibition of IL-1 signaling 
considerably attenuates disease severity (9, 10)  
IL-1 inhibition using Canakinumab is currently licensed therapy for cryopyrin-associated periodic 
syndromes, TRAPS, HIDS, systemic juvenile idiopathic arthritis, FMF and gouty arthritis. Canakinumab 
has demonstrated a favorable risk-benefit profile in patients with these diseases. Previous studies 
with anti-cytokine therapy in alcoholic hepatitis, targeting the TNF  system, have failed to show a 
survival benefit due to the increased risk of infection and possibly due to the removal of a 
regenerative signal provided by TNF
The current protocol will stratify the risk of infection 
and use prophylactic antibiotics to reduce the risk of sepsis (13). 
The current protocol seeks to explore the potential use of Canakinumab in the treatment of AH. AH 
is a complex disorder in which liver dysfunction results from inflammatory liver injury and cirrhosis 
and the patient outcome is also determined by susceptibility to infection or the development of acute 


 
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kidney injury. In the first instance, it is therefore essential to establish the efficacy of Canakinumab in 
a proof-of-principle Phase II) study in alcoholic hepatitis. This is best achieved by demonstrating 
improvement of the hepatic tissue injury histologically.  
There is a considerable unmet clinical need in alcoholic hepatitis. At present there is no treatment for 
patients with this condition which influences mortality rates at 90 days (5). A severe patient 
population defined by a DF  32 and MELD 27 is an ideal group in which to evaluate a new modality 
of treatment as this group of patients are less susceptible to infection and acute kidney injury could 
complicate the analysis of a treatment response.  
Treatment of alcoholic hepatitis is usually delivered for a 4 week period. Assessment of clinical 
response can be made after 7 days and is demonstrated by a reduction in the serum bilirubin or the 
Lille score (14). 
 
2.2 
Rationale for dose/regimen, route of administration: 
Canakinumab has been administered in clinical trials as an intravenous (i.v.) infusion and 
subcutaneous (s.c.) injection. The doses administered i.v. ranged from 0.03 mg/kg to 10 mg/kg or a 
fixed dose of 600 mg. The safety, tolerability and efficacy data of canakinumab administered i.v. in 
completed Novartis sponsored interventional studies are available from more than 800 male or 
female subjects. Data from completed clinical studies demonstrate strong efficacy as well as a good 
safety profile. In acute alcoholic hepatitis, immediate disease control is important to decrease the risk 
for acute kidney injury and other disease related complications. Therefore, canakinumab will be 
administered intravenously at a dose regimen of 3 mg/kg at Baseline to rapidly reach Cmax.  
 
2.4 
Rationale for this Study 
Currently there is no effective treatment for severe alcoholic hepatitis. Based on our current 
understanding of the disease pathogenesis IL-1  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. 
 
2.5 
Rationale for the study population 
 
of around 30% at 90 days after admission. In the recent STOPAH trial we found that patients with a 
7 had 90 day mortality around 22% but had significantly less complications. In particular the 
incidence of on-treatment infection in patients with a MELD score < 27 was substantially lower in this 
group of patients. As it is possible that Canakinumab will increase the risk of infection we have chosen 
to investigate the potential benefit of IL-1b inhibition in patients with less risk of this complication. 
 
2.6 
Rationale for 16S-DNA measurement and prophylactic antibiotics 
The overall risk of infection in alcoholic hepatitis is 20-30% but this is increased 3  4 fold in patients 
treated with immunosuppressive drugs such as prednisolone when the pre-treatment bacterial 16S 
ribosomal DNA (16S-DNA) in blood is > 18.5 pg/ml(13). In order to reduce the risk of infection we will 
place all patients on prophylactic antibiotics for 14 days from baseline and measure 16S DNA changes 
throughout the study.  
 
 


 
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3 
Study Design 
3.1.  
Objectives 
To explore the potential benefits of the IL-
hepatitis.  
 
3.2.  
Primary End Point 
Histological improvement of alcoholic hepatitis on liver biopsy after 28 days of treatment 
compared to baseline. (See Section 7.6.5). Histological improvement is defined as a reduction 
in lobular inflammation (regardless of cell type). 
 
3.3.  
Secondary End Points 
 Improvement of individual components (polymorphonuclear cell infiltrate, ballooned 
hepatocytes and steatosis) of alcoholic hepatitis on liver histology from baseline to Day 28. 
 Changes in the components of Alcoholic Hepatitis Histological Score (AHHS) (1) from baseline 
to Day 28 
 Changes in the components of Nonalcoholic fatty liver disease activity score (NAS) score from 
baseline to Day 28 
 Changes in hepatic venous pressure gradient (HVPG) between baseline and day 28 
 Changes in serum CK18-M30/M65 from baseline to Day 7, 14, 21, 28, 42 and 90 
 Change in serum bilirubin from baseline to Day 7, 14, 28, 21, 42 and 90  
 Change in MELD score at from baseline to Day 7, 14, 21, 28, 42 and 90 
 Change in Glasgow alcoholic hepatitis score (GAHS) from baseline to Day 7, 14, 21, 28, 42 and 
90 
 Change in mDF score from baseline to Day 7, 14, 21, 28, 42 and 90 
 Lille score at Day 7 
 Resolution of systemic inflammatory response syndrome (SIRS) at Day 7, 14, 21, 28, 42 and 90 
in patients with SIRS at baseline  
 Incidence of SIRS at Day 7, 14, 21, 28, 42 and 90 in patients without SIRS at baseline 
 Mortality rate at Day 90  
 Incidence of infection and sepsis over 90 days 
 Incidence of acute kidney injury over 90 days 
 Incidence of variceal haemorrhage, ascites or encephalopathy over 90 days 
 safety and tolerability of canakinumab  
 Serum and plasma biomarkers of hepatic function and inflammation including cytokine 
profiles which may indicate the degree of response to IL-1b inhibition.  
 Changes in CRP over time 
 Length of hospital stay 
 
 
3.4. 
Exploratory End Points 
 Changes in monocyte oxidative burst function over time 
 Changes in circulating monocyte phenotype over time 
 Changes in circulating bacterial DNA over time 
 Changes in transient elastography (Fibroscan) scores from baseline at Day 28 and Day 90 
 Canakinumab PK/PD profile 


 
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 Changes in tissue gene expression from baseline to Day 28 
 Immunohistochemistry 
 Gene variant interaction of PNPLA3 with treatment outcome 
 
3.5.  
Design 
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.  
 
3.6. 
Treatment 
Patients will be included and randomized and treated before histology result is available. If the 
histology is negative then patient will be withdrawn. 
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. The drug or placebo (5% Dextrose alone) will be labelled by the 
designated unblinded team member.  
Patients with moderate to severe ascites should undergo large volume paracentesis prior to 
administration of Canakinumab.  
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. 
The second dose of study drug (or placebo) should not be administered if the patient experienced an 
incident of infection during the prior 28 days, MELD >27 or in cases where the PI is concerned about 
 
Randomisation will be via the trial InForm database which will enable the unblinded research team 
to ensure the right dosing and drug preparation in respect of the AST assessment on D28.  
 
 
 
 
 


 
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4.  
Patient population 
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.  
 
4.1 
Patient selection 
Potential patients will be identified after admission for treatment of severe alcoholic hepatitis and 
the details of the study explained to them. Patients will receive a written explanation (Patient 
Information Sheet and Informed Consent Form) of the study and must freely give their informed 
consent in writing.  Following consent, patients will be screened for eligibility for the trial and must 
fulfil the inclusion and exclusion criteria in order to be randomised into the trial, receive study drug 
and followed-up for further evaluations as per schedule of assessments (see Table 1).  
 
4.2 
Informed Consent  
 
 
4.3 
Incapacitated Patients 
Potential patients for the trial who present with hepatic encephalopathy may be unable to consent 
for themselves, but are not excluded from the trial.  Special arrangements are in place to ensure that 
the interests of such patients are protected.  Such patients should be considered for the trial as a 
patient group likely to receive maximum benefit from the trial interventions, if received soon after 
confirmation of eligibility. 
 
When considering a patient who is unable to consent for themselves for suitability for the trial, the 
presumed wishes. The type and hierarchy of legal representative who should be approached to give 
informed consent on behalf of an incapacitated adult, prior to inclusion of the subject in the trial, is 
given following: 
 
Personal legal representative 
- A person not connected with the conduct of the trial who is:  
(a) suitable to act as the legal representative by virtue of their relationship with the adult, and  
(b) available and willing to do so. 
 
Professional legal representative  
A person not connected with the conduct of the trial who is:  
 
(b) a person nominated by the relevant health care provider (e.g. an acute NHS Trust or Health Board).  


 
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A professional legal representative may be approached if no suitable personal legal representative is 
available. 
The appropriate legal representative will be provided with the approved Legal Representative 
Information Sheet and Legal Representative Informed Consent Form, to document the consent 
process.  
The consent given by the legal representative remains valid in law until such time as the as the patient 
recovers capacity. At this point, the patient will be informed about the trial and asked to decide 
whether or not they want to continue in the trial, and consent to continue will be sought from the 
patient themselves.  
 
4.4 
Eligibility Criteria 
4.4.1 Inclusion criteria 
 Male and female patients aged 18 years or older at screening 
 Clinical diagnosis of alcoholic hepatitis at screening: 
- 
 
- 
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). 
 
4.4.2 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: 
o Evidence of chronic viral hepatitis (Hepatitis B or C) 
o Biliary obstruction 
o 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 c
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 


 
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 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: 
Association status of class III or IV], uncontrolled diabetes 
 Vaccination with a live vaccine within 3 month before baseline 
 
Sepsis:  
As per standard of care all patients will be screened for infection prior to randomization.  Diagnosis 
of infection is based on the criteria outlined by Bajaj and colleagues and will involve chest 
radiography, urinalysis (mid-stream urine (MSU) culture if urinalysis positive), ascitic tap (if ascites 
present) and blood cultures if pyrexial.  Positive culture and initiation of antibiotics with clinical or 
radiological signs of infection, as well as clinical suspicion, will be recorded as sepsis. 
Blood culture negative pyrexia and a leucocytosis will not be regarded as signs of active sepsis on 
their own, as these are often co-existent findings with alcoholic hepatitis. Patients with evidence of 
sepsis will be treated for a minimum of 2 days with appropriate antibiotics before re-screening. Once 
the local Principal Investigator (PI) considers that the sepsis is under control, the patient may be re-
screened and randomised if eligible. All patients will be treated with prophylactic antibiotics (e.g. co-
trimoxazole, co-amoxyclav,ciprofloxacin) for the first 14 days treatment irrespective of whether they 
are randomized to Canakinumab or placebo. Details of the prescribed prophylactic antibiotics must 
be noted in the Concomitant Medication form in eCRF. 
Patients to have screening for infection at baseline and on a weekly basis until the patient is 
discharged from hospital. 
 
Renal Impairment:  
Patients who are oligo-anuric, have a creatinine >220 uM/L (2.5 mg/dL) or who require renal support, 
will be given appropriate resuscitation therapy for up to 1 week. These patients may then be re-
screened and considered for randomisation, once they meet eligibility criteria. 
 
 
 


 
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5.  
Patient Registration, Randomisation and Data Collection 
The principal means of data collection from participant visits will be Electronic Data Capture (EDC) via 
the internet using the InForm database.  Data is entered into the EDC system via site personnel.  All 
source data recorded in the electronic case report form (eCRF) will be signed by the Investigator or 
his/her appropriate designee.  All changes made following the electronic signing will have an 
electronic audit trail with a signature and date.  Specific instructions and further details will be 
outlined in the eCRF manual. 
 
5.1 Account Creation 
Each local user at the study sites must complete user training (appropriate to their role in the trial) 
for InForm after which an account will be created for them on the ISAIAH InForm database. 
 
5.2   Source Data 
Source documents include original documents related to the trial, to medical treatment and to the 
history of the participant, and adequate source documentation must be maintained to allow reliable 
verification and validation of the trial data. What constitutes the source data for this trial will be 
outlined in the study Monitoring Plan. 
 
5.3  
Patient Registration 
After informed consent has been obtained each patient must be registered for the study via the 
ISAIAH InForm database.  Registered patients will be allocated a unique Subject ID number. Each 
patient will retain this number for the duration of the study. The unique Subject ID number and 
patients  age will be the patient identifiers in the study data. 
 
5.4  
Patient Randomisation 
After the patient is registered, the screening assessments will take place; please refer to the 
assessment schedule in section 7 for detailed description of screening assessments.  
If eligible for the study, the patient will be electronically randomised via the ISAIAH InForm database 
to a study treatment group, but this will be blinded to the site staff (with the exception of designated 
unblinded study personnel) and the patient, by means of a unique code. If the patient is not eligible 
for the study, they are deemed a 'screening failure', and will receive treatment as per local standard 
care.  
 
5.5 
eCRF 
Data will be collected through the electronic case report forms (eCRF) on the ISAIAH InForm database 
at each patient visit as scheduled below in Section 7. Details of procedures for eCRF completion will 
be provided in a study manual. 
 
5.6 
Procedure for breaking treatment code 
In the event of a medical emergency where breaking the blind is required to provide medical care to 
the subject, the local principal investigators will have access to a mechanism that permits rapid un-
blinding should they feel this is necessary and are unable to contact the study team.  Local SOPs 
describing the emergency unblinding procedure will be in place. The chief investigator recommends, 
but does not require, that the investigator contact him before breaking the blind. Treatment 
assignment should remain blinded unless that knowledge is necessary to determine subject 


 
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emergency medical care. The rationale for unblinding must be clearly explained in source 
documentation and on the electronic case report form (eCRF), along with the date on which the 
treatment assignment was obtained.  
 
6. Concurrent Medication and Treatment 
Many additional medications may be required. Concomitant medication may be given as medically 
indicated. Forbidden treatments are listed under section 6.4.   
 
6.1  
Alcohol withdrawal 
Alcohol withdrawal therapy as required is allowed. 
 
6.2  
Infection / Sepsis 
Patients who have infection or sepsis at screening or at any time during the study should be treated 
with antibiotics. Patients presenting with infection at screening visit will be eligible for randomization 
once the infection is under control. Antibiotics should be continued/given for the first two weeks 
after initiation in all patients. See Section 4.4 for further details. 
 
Regular surveillance for infection or sepsis should be conducted throughout the study. Infection 
screening will be performed at every study visit.  
 
6.3  
Nutrition 
All patients will receive supportive nutritional therapy. Patients will be offered nutritional 
supplements in the first instance. If they are unable to take these, they will be offered enteral 
nutrition via a nasogastric tube. An attempt should be made to provide 35-40 kcal/kg/day non-protein 
energy with 1.5g/kg/day protein. The responsible clinician will decide upon the use of other 
treatments such as terlipressin, for patients who are developing hepatorenal failure, acid suppression 
for prophylaxis against gastro-intestinal haemorrhage, antibiotics and vitamin supplementation. 
 
6.4  
Other treatments for Alcoholic Hepatitis 
N-acetyl cysteine should not be used.  
 
Patients must NOT be prescribed pentoxifylline or prednisolone during the treatment period of the 
study. 
 
Other immunosuppressive treatments must not be used. 
 
 
 


 
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7.  
Investigations & Procedures 
 
Please also refer to the tabulated Schedule of Assessments (Table 1) and the summary of treatment 
plan in appendix 1.  
 
All patients must have freely given their informed consent before any trial-related procedures can 
be conducted. 
 
*Procedures marked *  written in italics are part of routine clinical practice and are listed only to 
denote that the data will be collected in the CRF 
 
7.1  
Screening  
 Informed consent from patient/legal representative 
 Demographic details 
 Inclusion and Exclusion criteria 
 HIV test 
 *Hep B & Hep C screening 
 Genetic sequencing for gene variant PNPL3 
 Pregnancy test^ (serum)  
 *Alcohol consumption 
 Urinary ethyl glucuronide 
 *Liver ultrasound (USS) 
 Past medical history including general history using the Charlson Index, liver-specific history 
(history of jaundice in past 3 months) and smoking history 
 Prior/Concomitant medication 
 *Complete physical examination, including height, weight, WHO performance status  
 *Vital signs (Temperature, systolic and diastolic blood pressure (BP), pulse rate) 
 *Laboratory tests: haematology, clinical chemistry (including electrolytes, creatinine, eGFR, 
LFTs [must include AST and GGT]), CRP and prothrombin time  
 *Disease scores: mDF, MELD, GAHS 
 *Evidence of GI bleed or sepsis in previous 7 days 
 *Acute kidney injury 
 *Infection/ sepsis/ SIRS screening including 
o Chest X-ray (CXR) 
o Blood cultures  
o Hepatic encephalopathy 
o Ascitic tap (in case required) 
o MSU 
o Urine culture  
 EDTA sample for host & bacterial DNA (16S) 
 
^ Not required in post-menopausal females.  
 
 
 


 
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7.2  
Baseline (pre-randomisation) 
 Inclusion and Exclusion criteria 
 Urinary ethyl glucuronide 
 Concomitant medication 
 *Dietary calorie and protein consumption 
 *Complete physical examination including WHO performance status  
 *Vital signs (Temperature, systolic and diastolic blood pressure (BP), pulse rate) 
 *Laboratory tests: haematology, clinical chemistry (including electrolytes, creatinine, eGFR, 
LFTs), CRP and prothrombin time  
 *Disease scores: mDF, MELD, GAHS 
 *Evidence of GI bleed or sepsis in previous 7 days 
 *Acute kidney injury 
 *Infection/ sepsis/ SIRS screening including 
o Chest X-ray (CXR) 
o Blood cultures (in case of fever) 
o Hepatic encephalopathy 
o Ascitic tap (in case required) 
o MSU 
o Urine culture (in case required) 
 EDTA sample for host & bacterial DNA (16S) 
 Heparinised sample for PBMC (Monocyte oxidative burst + Monocyte phenotype) 
 Serum CK18-M30/M65 
 Liver Biopsy at screening/pre-randomisation is Standard of Care 
 HVPG measurement during trans-jugular biopsy procedure 
 Gene expression tissue sample 
 Fibroscan 
 PK/PD 
 Exploratory/inflammatory BM serum 
 Duration since admission to hospital 
 Adverse events 
 Stool and saliva sample 
 
 
See Schedule of Assessments and Footnote Table for timeframe allowances and full notes relating 
to sample collection.  
 
7.3  
Evaluations During and After Treatment  
Treatment Day 7, 14, 21, 28 and 42 Assessments.  
 
 Alcohol consumption on Day 28 and 42 
 Urinary ethyl glucuronide on Day 28 and 42  
 Concomitant medication 
 *Dietary calorie and protein consumption 


 
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 *Complete physical examination including WHO performance (and weight on day of 
discharge) 
 *Vital signs (Temperature, systolic and diastolic blood pressure (BP), pulse rate) 
 *Laboratory tests: haematology, clinical chemistry (including electrolytes, creatinine, eGFR, 
LFTs), CRP and prothrombin time 
 *Disease scores: mDF, MELD, GAHS 
 *Lille score at Day 7 
 *Evidence of GI bleed or sepsis in previous 7 days 
 *Acute kidney injury 
 *Infection/ sepsis/ SIRS screening including 
o Chest X-ray (CXR) 
o Blood cultures (in case of fever) 
o Hepatic encephalopathy 
o Ascitic tap (in case required) 
o MSU 
o Urine culture (in case required) 
 EDTA sample for host & bacterial DNA (16S)+ 
 Heparinised sample for PBMC (Monocyte oxidative burst + Monocyte phenotype)# 
 Serum CK18-M30/M65 
 Liver Biopsy at Day 28 (incl. HVPG measurement during  trans-jugular biopsy) 
 Gene expression tissue sample at Day 28 
 Fibroscan at Day 28 
 PK/PD 
 Exploratory/inflammatory BM serum 
 Administration of study drug for patients presenting with AST > 2 x ULN at Day 28 
 Duration of hospital stay on day of discharge 
 Adverse events 
 Stool and saliva sample# 
 
 
# PBMC sample not required at on day 21 and 42 or at discharge.  
+ 16S DNA sample not required on day 42 or at discharge.  
# Stool and saliva collected at (baseline and) day 14, 28 and 90.  
 
See Schedule of Assessments and Footnote Table for timeframe allowances and full notes relating 
to sample collection.  
 
 
 
7.4 
 Day 90 
 *Alcohol consumption  
 Urinary ethyl glucuronide 
 Pregnancy test^ (urinary)  
 Concomitant medication 
 Dietary calorie and protein consumption 
 *Complete physical examination including weight, WHO performance status 
 *Vital signs (Temperature, systolic and diastolic blood pressure (BP), pulse rate) 


 
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 *Laboratory tests: haematology, clinical chemistry (including electrolytes, creatinine, eGFR, 
LFTs), CRP and prothrombin time  
 Disease scores: mDF, MELD, GAHS 
 *Evidence of GI bleed or sepsis in previous 7 days 
 *Acute kidney injury 
 *Infection/ sepsis/ SIRS screening including 
o Chest X-ray (CXR) 
o Blood cultures (in case of fever) 
o Hepatic encephalopathy 
o Ascitic tap (in case required) 
o MSU 
o Urine culture (in case required) 
 EDTA sample for host & bacterial DNA 
 Heparinised sample for PBMC (Monocyte oxidative burst + Monocyte phenotype) 
 Serum CK18-M30/M65 
 Fibroscan  
 PK/PD 
 Exploratory/inflammatory BM serum 
 Adverse events 
 Stool and saliva sample 
 
^ Not required in post-menopausal females. 
 
See Schedule of Assessments and Footnote Table for timeframe allowances and full notes relating 
to sample collection.  
 
 
7.5 
Schedule of Assessments 
Table 1 lists all of the assessments and indicates with an 
x
 at which visits the assessments are 
performed. Patients should be seen for all visits on the designated day, or as close to it as possible  
the visit window/tolerance for each visit is given below the table. At a minimum, patients will be 
contacted for safety evaluations during the 90 days following randomisation to the study. At this final 
visit the adverse event and concomitant medications should be reconciled on the CRF. 
Documentation of attempts to contact the patient should be recorded in the source documentation. 
 


 
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Table 1: Assessment schedule 
 
Screening 
Baseline
6, 9, 11 
Day 74
Day 
144 
Day 
214 
Day 
28 2, 11 
Day  
42 1,4 
On 
Dischar
ge 10 
Day  
903 
Unsche-
duled 
Informed Consent
X
Demographic data
X
Inclusion/Exclusion criteria  
X 
X 
 
 
 
 
 
 
 
 
HIV test^ 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test+ 
X5 
 
 
 
 
 
 
 
X 
 
Hepatitis B & C serology^
X
Genetic sequencing (PNPLA3) 
X 
 
 
 
 
 
 
 
 
 
Urinary ethyl glucuronide 
X 
X 
 
 
 
X 
X 
 
X 
 
Alcohol consumption 
X 
 
 
 
 
X 
X 
 
X 
 
Duration since admission to 
hospital 
 
X 
 
 
 
 
 
X 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Prior/Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
 
 
 
 
X1 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Calorie and protein intake 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
IMP / placebo administration 
 
X 
 
 
 
X 
 
 
 
 
Prothrombin time 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Haematology% 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry% 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum CK18-M30/M65 sample
X
X
X
X
X
X
X
X
DF, MELD, GAHS scores
X
X
X
X
X
X
X
X
X
Lille score
X
Overt GI Haemorrhage assessment$ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Acute kidney injury assessment$ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EDTA sample for DNA (16S) 
X 
X 
X 
X 
X 
X 
 
 
X 
 
PBMC sample~ 
 
X 
X 
X 
 
X 
 
 
X 
 
Infection/ Sepsis/ SIRS screen 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
USS Liver assessment$ 
X 
 
 
 
 
 
 
 
 
 
Fibroscan measurement$ 
 
X 
 
 
 
X 
 
 
X 
 
Gene expression sample 
 
X 
 
 
 
X 
 
 
 
 
Liver biopsy (incl. HVPG 
measurement*)8 
 
X 
 
 
 
X 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK/PD samples in blood and ascites 
fluid # 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biomarker serum 
X
X
X
X
X
X
X
X
Stool & saliva sample
X
X
X
X
 
 
 


 
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Footnotes to Schedule of Assessments 
 
1 
Day 42 visit 
Required for patients who received second dose study drug at Day 28 
2 
Day 28 visit 
A Day 28 assessment/follow up treatment/biopsy can be performed between 
Day 25 and Day 35 
3 
Day 90 visit 
A Day 90 assessment can be performed 14 days either side of the target date 
4 
Day 7, 14, 21, 42 visits 
For Day 7, 14, 21 and 42 assessments a tolerance of 48 hrs in time window 
either way is accepted 
5 
Screening pregnancy test 
Needs to be performed as serum test 
6 
Screening and baseline samples 
If baseline visit is performed within 72 hours since screening, then screening 
samples which repeat at baseline may be accepted on baseline date. 
7 
Screening and Baseline visit 
The maximum time between screening and date baseline is 7 days 
8 
Baseline liver biopsy acceptance 
window 
The maximum timeframe for a baseline biopsy to be accepted into the trial is 7 
days before baseline visit (day of Randomisation and study drug 
administration). 
9 
Baseline visit 
Allowance of -1 day is accepted to allow for blood results to come through for 
re-confirmation of eligibility before randomisation and IMP/Placebo 
administration.  Baseline date of visit should always be the date of 
randomisation and IMP administration.  
10 
Discharge 
Patients who are discharged during the follow-up period are not required to 
attend further weekly visits other than on Day 28 (when the potential second 
IMP dose and second biopsy is taking place), Day 42 (if second Imp dose was 
administered) and Day 90, which is the end of study visit. Patients due to be 
discharged will have the samples collected on discharge, as specified in the 
schedule of assessments below 
11 
Baseline; Day 28 
Sample collection is pre-IMP administration.  
# 
Pharmacokinetic and 
pharmacodynamics samples - blood 
and ascitic fluid 
In case of ascites, ascites fluid sample needs to be collected only once, at the 
time when patient is having ascites tapped for clinical purposes. 
* 
TJ liver biopsy 
HVPG measurement should be collected in all TJ liver biopsies. 
^ 
Virology screening 
Results within 6 months of screening may be accepted without the need to 
repeat 
+ 
Screening and Day 90 pregnancy tests 
Pregnancy test required only for females of reproductive age only 
~ 
PMBC 
PBMC, which are to be sent to a central lab immediately after collection, should 
not be collected on Friday or Saturday in order to avoid loss of sample due to a 
weekend staff cover at the central laboratory. When PMBCs are posted out, an 
email notification must be sent, as per study Lab Manual.  
% 
Haematology & Biochemistry 
± 1 day of screening date 
$ 
Overt GI haemorrhage assessment, 
AKI assessment; Fibroscan, USS 
From day of admission onwards 
 
 


 
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7.6 
Assessments 
7.6.1 Patient demographics/other baseline characteristics: 
Patient demographic and baseline characteristic data to be collected on all patients include: age, 
gender, ethnicity, source of patient referral, relevant medical history/ current medical condition 
present before signing informed consent. Where possible diagnoses but not symptoms will be 
recorded. 
to be recorded as part of prior medication), 
disease diagnosis and disease related prior medications, surgical and medical procedures that 
occurred before signing informed consent will also be collected. 
Investigators will have the discretion to record abnormal test findings on the medical history CRF 
whenever in their judgment, the test abnormality occurred prior to the informed consent signature. 
 
7.6.2 Physical exam: 
A complete physical examination will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular and neurological. If indicated based on medical history and/or symptoms, rectal, external 
genitalia, breast, and pelvic exams will be performed. Weight and height will be measured as per the 
visit schedule. Physical exam includes WHO performance status. 
 
7.6.3 WHO Performance Status 
 
0 
Asymptomatic (Fully active, able to carry on all pre-disease activities without restriction) 
1 
Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature. For example, light housework, office work)
2 
Symptomatic, <50% in bed during the day (Ambulatory and capable of all self-care but unable to 
carry out any work activities. Up and about more than 50% of waking hours) 
3 
Symptomatic, >50% in a chair or in bed, but not bedbound (Capable of only limited self-care, 
confined to bed or chair 50% or more of waking hours) 
4 
Bedbound (Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair) 
5 
Death 
 
                 
                                                                                       
7.6.4 Vital signs 
Vital signs will include blood pressure (BP), pulse and body temperature measurements. Systolic and 
diastolic BP and radial pulse rate will be assessed after the patient has rested in the supine position 
for at least 3 minutes. Blood pressure should be assessed on the same arm each time measurements 
are taken. Body temperature should be measured by validated thermometers as commonly used by 
sites in the respective patient population. The same type of thermometer should be used throughout 
the study.  
 


 
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7.6.5 Liver biopsy  
A liver biopsy is required at baseline visit prior to randomization and on day 28. This may be obtained 
via a transcutaneous or transjugular route depending on the 
 coagulation status and local 
expertise. Additionally, where a transjugular liver biopsy is performed, HVPG measurements will also 
be obtained. The liver biopsy is performed under local anaesthetic and requires the use of X-rays to 
guide the position of the needle that is inserted to take samples. Two biopsy specimens will be 
obtained with each liver biopsy; one for histology and one, snap frozen, for gene expression analysis.  
 
All histology samples will be read and scored locally as per usual routine, as well as centrally by Prof 
Goldin at Imperial. Sites should use the widest gauge needle available for biopsy collection. 
Depending on the size of the needle, up to six passes may be performed; aggregate length of greater 
than 3cms is necessary and preferably (but not necessarily) obtained in one pass. The sample is to be 
used for: 
 a) Local histology assessment to confirm AH eligibility at baseline and for day 28 comparisons 
 b) At the time of liver sample collection, at least 3 and preferably 6 unstained slides (or block) 
should be prepared for central histology assessment for calculation of primary/secondary 
outcomes 
c) Snap-frozen sample for gene expression analysis, which is to be prepared from the 
remaining sample and with at least one or two cores present. The snap-frozen sample should 
be stored frozen in liquid nitrogen (or at -80) in local sites until batch shipment is arranged at 
the end of the study.   
 
The prepared unstained slides, together with residual formalin fixed paraffin embedded block should 
be sent to the central laboratory at Imperial College for central histology assessment. When samples 
are posted, a notification should be sent to Isaiah@imperial.ac.uk and Prof Goldin  please refer to 
the laboratory manual for more information.  
 
There should be an H and E (hematoxylin and eosin) and Sirius Red stained sample to enable the local 
pathologist to confirm the presence of steatohepatitis and 3-6 unstained slides for central lab 
analysis, which will stained and digitalized and either returned to the referring sites (if requested by 
local pathology lab) or stored centrally at 
. Any remaining material will be used 
for biomarker analysis.  
 
Biopsies will be assessed initially to confirm that all features of alcoholic hepatitis are present (based 
on locally histology). The primary endpoint, histological improvement will be measured in the central 
laboratory and is defined as a reduction in lobular inflammation (regardless of cell type). It will be 
read by one pathologist, who is blinded with regard to histology slide chronology, type of therapy, 
and patient clinical status. In addition a sensitivity analysis will be employed by having the histology 
slide read independently by 2 readers, who are blinded with regard to histology slide chronology, 
type of therapy, and patient clinical status. Histological improvement will be assessed by direct 
comparison of pre and post treatment biopsies and recorded as a binary answer, either there is less 
inflammation present in the biopsy or not. This method of blind biopsy comparison has been used 
previously (15).  Secondary endpoints - AHHS and NAS score- will be measured and compared 
between active treatment and placebo treatment groups. Further the specimens will be stained and 
immunohistological findings will be assessed and compared between treatment groups.   


 
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7.6.6 Laboratory tests 
The haematology panel will include: Hemoglobin, white blood cell count with differential including 
lymphocytes, monocytes, neutrophils and platelet count will be measured. Absolute Neutrophil 
Count (ANC) will be determined by the laboratory. Prothrombin time will be assessed as well. 
The clinical chemistry panel will include: alkaline phosphatase, total bilirubin, total cholesterol, LDLC, 
HDL-C, creatinine,  aspart
-amylase, 
sodium, potassium, lactate dehydrogenase (LDH), triglycerides, transferrin and CRP; The estimated 
creatinine clearance will be calculated using the Cockcroft-Gault equation for each creatinine 
creatinine levels.   
Urine samples will be assessed: Urinalysis (MSU) + assessment for urinary tract infection (UTI); urine 
white blood cell count with either positive urine gram stain or culture. Urinary ethyl glucuronide will 
be assessed to control patients' abstinence. 
 
Standard laboratory assessments will be used to determine:  
 
Maddrey Discriminant function (mDF) 
mDF = 4.6 x (Prothrombin time (PTPATIENT  PTCONTROL
 
(PTCONTROL is defined as the mean value at each site; this mean value may be updated on a weekly or 
monthly basis). 
Model for End-Stage Liver Disease (MELD) 
MELD Score = 10 * ((0.957 * ln(Creatinine)) + (0.378 * ln(Bilirubin)) + (1.12 * ln(INR))) + 6.43 
MELD scores should be UNOS-modified (United Network of Organ Sharing). It is recommended that 
mdcalc.com (MELD Score - Original, Pre-2016, Model for End-Stage Liver Disease) is used to calculate 
scores. The Pre-2016 UNOS modification is as follows: 
 If the patient has been dialyzed twice within the last 7 days, then the value for serum 
creatinine used should be 4.0 mg/dL 
 Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8 a value of 1.0 is used) 
to prevent subtraction from any of the three factors, since the natural logarithm of a 
positive number below 1 (greater than 0 and less than 1) yields a negative value. 
NOTE:  Pre-2016 MELD does not include serum sodium level. Values used for MELD calculations must 
be noted in eCRF.  
 
GAHS score 
Will be calculated after Forrest et al., 2007 
Score given 
1 
2 
3 
Age 
<50 
50 
 
WCC (109/l) 
<15 
15 
 
Urea (mmol/l) 
<5 
5 
 
PT ratio or INR 
<1.5 
1.5 2.0 
>2.0 
 
<125 
125 250 
>250 


 
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Lille score  
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 7 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) 
Change in bilirubin after 7 days 
A fall of > 25% will be taken to be a clinically significant fall 
 
Incidence of acute kidney injury  
Defined as  
 Rise in blood creatinine by 26 micromoles per liter or more within 48 hours 
 Rise in blood creatinine over time by 50% or more within the past 7 days 
 Urine output less than 0.5ml per kg per hour for more than 6 hours 
SIRS 
Recommendations of the American College of Chest Physicians/Society of Critical Care Medicine 
Consensus Conference; 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% 
 
7.6.7 Infection screening 
Diagnosis of infection is based on the criteria outlined by Bajaj and colleagues:  
1) spontaneous bacteremia: positive blood cultures without a source of infection; 2) SBP: ascitic fluid 
ons: new pulmonary infiltrate in 
the presence of: i) at least one respiratory symptom (cough, sputum production, dyspnea, pleuritic 
pain) with ii) at least one finding on auscultation (rales or crepitation) or one sign of infection (core 
body temperature >38°C or less than 36°C, shivering, or leukocyte count >10,000/mm3 or 
<4,000/mm3) in the absence of antibiotics; 4) Clostridium difficile Infection: diarrhea with a positive 
C. difficile assay; 5) bacterial entero-colitis: diarrhea or dysentery with a positive stool culture for 
Salmonella, Shigella, Yersinia, Campylobacter, or pathogenic E. coli; 6) soft-tissue/skin Infection: fever 
with cellulitis; 7) urinary tract infection (UTI): urine white blood cell >15/high-power field with either 
positive urine gram stain or culture; 8) intra-abdominal infections: diverticulitis, appendicitis, 
cholangitis, etc.; 9) other infections not covered above; and 10) fungal infections as a separate 
category. Infection screening will involve chest radiography, urinalysis (mid-stream urine (MSU) 
culture if urinalysis positive), ascitic tap (if ascites present) and blood cultures if pyrexial. 
 
7.6.8 Monocyte oxidative burst 
Monocyte oxidative burst is assessed ex vivo 
manufacturers  instructions (Glycotrope, Germany). 
is incubated with 2x107 E. coli 
for 20 minutes at both 37°C (test condition) and on ice (control condition). 
-
dihydrorhodamine (1,2,3DHR) is then added for a further 20 minutes at 37°C and the oxidation to 
rhodamine within CD14+ monocytes is measured by flow cytometry. 


 
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7.6.9 Changes in plasma bacterial DNA 
DNA extraction is performed on 400 l of blood using Qiagen (Hilden, Germany) QIAamp DNA Mini 
kits under aseptic conditions.  The quantity of 16S ribosomal bacterial DNA (bDNA) is determined and 
measured by real-time polymerase chain reaction (qPCR). Primers directed against the V7-V9 variable 
-
 sequence AACTGGAGGAAGGTGGGGAT, reverse: 
DG74.R; -
 sequence AGGAGGTGATCCAACCGCA) are combined with a custom fluorescent probe 
(6-FAM- TACAAGGCCCGGGAACGTATTCACCG-TAMRA; Life Technologies, Carlsbad, USA) at final 
concentrations of 0.5 M and 0.25 M, respectively.  This is combined with 10ul of Taqman Gene 
Expression mix (Applied Biosceiences, Foster City, USA), 4ul of extracted DNA and PCR-grade water 
to give a final reaction volume of 20ul.  PCR is performed on a StepOne Plus PCR machine (Applied 
Biosciences, Foster City, USA) with hot-start activation (2 minutes at 50°C, 10 minutes at 95°C) and 
40 reaction cycles (15 seconds at 95°C, 30 seconds at 60°C and 60 seconds at 72°C to collect 
fluorescence).  Serial 10-fold dilutions of E.coli DNA (0.08 ng/
 to 0.000008 ng/
 and a negative 
control are run to generate a standard curve. 
 
7.6.10 Changes in transient elastography scores 
Fibroscan will be used to obtain elastography scores at baseline, Day 28 and Day 90. Changes in scores 
from baseline will be compared between the two treatment groups. 
 
7.6.11 Canakinumab sample collection 
Blood samples (1 mL) will be collected into SST tubes. The blood sample will be allowed to clot over 
a minimum of 30 minutes at room temperature prior to harvesting of the serum. The serum will be 
obtained by centrifugation at approximately 2500 rpm for 10 minutes. Serum samples will be split 
into 2 aliquots (polypropylene tubes) and then stored (within 30 min of preparation) at -20°C or -70°C 
(approximately) prior to shipment. Canakinumab is stable in serum samples for 12 months at -20°C 
or at -70°C. All samples will be given a unique sample number. The actual sample collection date and 
time will be entered on the PK blood collection page of the CRF. Sampling problems will be 
commented in the CRFs. 
 
7.6.12 Pharmacodynamic assessments 
1. Total IL-
: Pharmacodynamic assessments (IL-
serum as per the Assessment Schedule, pre-dose (trough levels). 
2. Pharmacodynamic sample collection and processing: Blood samples (1.5 mL) will be collected into 
SST tubes. The blood sample will be allowed to clot over a minimum of 30 minutes at room 
temperature prior to harvesting of the serum. The serum will be obtained by centrifugation at 
approximately 2500 rpm for 10 minutes. Serum samples will be split into 2 aliquots (polypropylene 
tubes) and then stored (within 30 min. of preparation) at -20°C or -70°C (approximately) prior to 
shipment. IL-
-20°C or -70°C. 
 


 
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7.6.13 Other assessments 
1. HIV test: An HIV test will be performed at screening (HIV test conducted within 6 months of 
screening may be accepted). Patients with a known infection with HIV at screening or 
randomisation will be excluded from participating in the trial. 
2. Pregnancy Test (in females of reproductive age): A pregnancy test will be performed as a serum 
test at screening and pregnant patients excluded from participation. A urinary pregnancy test will 
be performed at day 90. If a subject or his partner becomes pregnant whilst taking part in the trial 
they will be followed up according to Section 9.6. 
3. Hepatitis B & C Serology: Serology will be undertaken at screening (Hep B/C result performed 
within 6 months of screening may be accepted) and evidence of chronic viral hepatitis (B or C) will 
exclude the patient from participation. 
4. Genetic sequencing: Genetic sequencing will be carried out at screening. 
5. Alcohol consumption: Details on alcohol consumption will be collected at screening, day 28, day 
42 and day 90. 
6. Calorie and protein intake: Details on calorie and protein intake will be collected at all visits apart 
from screening. 
7. Liver ultrasound (USS): A liver ultrasound will take place at screening only and is part of Standard 
of Care for the patients. 
8. Stool and saliva samples will be collected at baseline and days 14, 28 and 90.  
9. Exploratory BM serum to be collected (2 x 500ul) at baseline and all subsequent visits.  
 
 
8 Statistical Considerations 
 
8.1 
Power calculation 
 
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). Patients will be 
included and randomized and treated before histology result is available. If the histology is negative, 
then patient will be withdrawn and another patient recruited. Additionally, to meet the study power 
we will continue recruitment until we have paired biopsies in 48 patients. 
 
8.2 
Statistical Analysis Plan 
A statistical analysis plan will be drafted prior to the first data extraction.  
 
The primary analysis will estimate the difference between the groups in proportion of patients with 
improvement of the disease using a chi square test. Logistic regression, adjusted for histology baseline 
values, will investigate the relationship between disease histological improvement and other 
independent variables including the baseline severity (MELD score), age and gender. All statistical 
tests will be two-tailed with a 5% significance level. Further details of the planned analysis of the 


 
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secondary outcomes and methods for dealing with missing data will be given in the Statistical Analysis 
Plan. 
 
There is no planned interim or subgroup analyses. Any deviations from the statistical analysis plan 
will be dealt with in accordance with Imperial Clinical Trial 
 statistical Standard Operating 
Procedures.  
9.  
Assessment of Safety 
9.1  
Definitions of Adverse Events 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (UK), as amended, provides the 
following definitions relating to adverse events in trials with an investigational medicinal product: 
 
Adverse Event (AE):  
Any untoward medical occurrence in a subject to whom a medicinal product has been administered 
including occurrences which are not necessarily caused by or related to that product. 
 
Adverse Reaction (AR):  
Any untoward and unintended response in a subject to an investigational medicinal product, which 
is related to any dose administered to that subject. All AEs judged by either the reporting investigator 
or the sponsor as having reasonable causal relationship to a medicinal product qualify as adverse 
reactions. 
 
Serious Adverse Event (SAE):  
Any adverse event that: 
 
results in death; 
 
is life-threatening; 
 
requires hospitalisation or prolongation of existing hospitalisation; 
 
results in persistent or significant disability or incapacity, or 
 
consists of a congenital anomaly or birth defect 
 
Is medically significant 
 
-
was at risk of death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe.  
Hospitalisation means any unexpected admission to a hospital department. It does not usually apply 
to scheduled admissions that were planned before study inclusion or visits to casualty (without 
admission). 
medical or surgical intervention. 
 
Serious Adverse Reaction (SAR) 
A SAR is defined as a SAE that is judged to be related to any dose of study drug administered to the 
subject or withdrawn from the subject. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 


 
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Any SAR that is NOT consistent with the applicable product information as set out in the Investigator 
Brochure (IB) or Summary of Product Characteristics (SmPC) i.e. is unexpected as per Appendix 2. 
 
9.2  
Recording Adverse Events 
The Imperial Clinical Trials Unit (ICTU) has been delegated by the Sponsor to undertake all sponsor 
duties relating to pharmacovigilance. 
All non-serious AR/AEs, whether expected or not, should be recorded in the adverse event section of 
the relevant Case Report Form. All new SAEs regardless of causality, occurring after the patient has 
signed informed consent and until the last patient visit must be reported to ICTU within 24 hours of 
learning of its occurrence and must also be recorded on Adverse Event Case Report Form (AE CRF) 
within the InForm database 
 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to 
the original episode, regardless of when the event occurs. This report must be submitted according 
to the study specific reporting procedures.  
An SAE that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
At each contact with the subject during the treatment period, the Investigator must seek information 
on adverse events by specific questioning and, as appropriate, by examination. Information elicited 
should be recorded immediately in the source document, and the AE CRF.  All clearly related signs, 
symptoms, and abnormal diagnostic procedures results should be recorded in the source document 
using the event terms and grading given in the relevant eCRF pages. 
The clinical course of each event should be followed until resolution or stabilisation. 
 
9.2.1 Exclusions to Adverse Event Recording Requirements  
Many clinical events are likely to occur which would ordinarily need recording as adverse events.  
However, events that are recognised and expected complications of the condition (listed in Appendix 
1) 
(section 9.1).   
 
9.3  
Pre-existing Conditions 
A pre-existing condition should not be reported as an AE unless the condition worsens during the 
trial.  The condition, however, must be reported in the Medical History Form.   
 
9.4  
Reporting of Serious Adverse Events (SAEs, SARs and SUSARs) 
 
All serious adverse events and reactions must be reported immediately by the Principal Investigator 
or delegate to the ICTU. In turn, ICTU will inform the Sponsor (within 24hrs of becoming aware of the 
event) and the Funder (as soon as becoming aware and not more than 15 calendar days).    
 
Summary of product characteristics (SmPC) should be used as the Reference Safety Information. 
Serious adverse events expected to occur with Canakinumab should be recorded on an SAE/SUSAR 
Report Form on InForm and the ICTU/Sponsor informed within 24 hours. A submitted SAE form on 
InForm will automatically send alert emails to the Chief Investigator, the Project Manager and the 
Sponsor. Adverse Events considered to be expected for Reporting purposes are detailed in Appendix 


 
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2. These reports should be followed by further detailed SAE/SUSAR Report Forms until resolution of 
the event.  
 
N.B. The SAE/SUSAR Report Form should be completed as though the patients were taking active 
form of IMP, even though all parties are blinded. 
 
Study specific SAE reporting instructions will be available and provide full detail on reporting 
requirements. An overview of the Safety Reporting Process is detailed in the diagram below. 
 
 
Contact details for reporting SAEs and SUSARs 
Follow the study specific procedure for reporting SAEs and SUSARs and complete an SAE form & 
submit to the Study Coordination Centre (ICTU) as soon as possible (within 24 hrs). SAE forms are 
available on the InForm eCRF system.  
 
ICTU Trial Manager: isaiah@imperial.ac.uk 
 
jrco.ctimp.team@imperial.ac.uk (contact only by ICTU) 
ct_processing.gbfr@novartis.com (contact only by ICTU) 
 
 


 
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9.5  
Post-treatment SAEs & Follow-Up 
The reporting requirement for SAEs affecting subjects applies for all events occurring up to the 
patients last study visit.  
All unresolved adverse events (serious and non-serious) should be followed up by the Investigator 
until the events are resolved, the subject is lost to follow-up, or the adverse event is otherwise 
explained.  At the last scheduled visit, the Investigator should document any ongoing AEs/SAEs, and 
these should be managed as per local practice.   
The Investigator should notify the ICTU of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this 
study.   
 
9.6  
Pregnancy 
If a subject or his partner becomes pregnant whilst taking part in the trial or during a stage where the 
foetus could have been exposed to an IMP, the Investigator must ensure that the subject and the 
-up information is required on the outcome of 
the pregnancy.  If the subject leaves the area, their new healthcare professional should also be 
informed. Each pregnancy occurring while the patient is on study treatment must be reported to ICTU 
within 24 hours of learning of its occurrence. Any SAE experienced during the pregnancy and 
unrelated to the pregnancy must be reported on a SAE form. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the investigational treatment. 
 
Study treatment for pregnant participants must be discontinued immediately. 
 
Contraception 
The following methods of contraception are accepted: 
(i) 
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 
(ii) 
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) 
or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow up 
hormone level assessment. 
(iii) 
Male sterilization (at least 6 months prior to screening). For female subjects on the study, the 
vasectomized male partner should be the sole partner for that subject. 
(iv) 
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/ vaginal suppository. 
(v) 
Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal 
ring or transdermal hormone contraception. In case of use of oral contraception women 
should have been stable on the same pill for a minimum of 3 months before taking study 
treatment.  
Reliable contraception should be maintained throughout the study.  


 
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9.7  
Evaluation of SAEs 
The Principal Investigator should ensure that each SAE is identified and assessed for the likelihood of 
the event being a response to an IMP.  Once reported to the ICTU, the event will also undergo a 
review of the evaluation of seriousness, expectedness and causality. Investigator reports of suspected 
SARs will be reviewed and those that are SUSARs, identified and reported to the UK regulatory 
authority (MHRA).  
In the event of a possible SUSAR, the Clinical Reviewer may contact the local PI to discuss the causality 
assessment. 
 
9.7.1 Causality of AEs 
The relationship of an AE to the IMP should be graded by the investigator responsible for the care of 
the participant as follows: 
 
Definitely related: 
 
Starts a reasonable time after the study drug administration; 
 
Stops/improves when the study drug has been stopped; 
 
Can reasonably be explained by known characteristics of the study drug. 
 
Probably related: 
 
Starts a reasonable time after the study drug administration; 
 
Stops/improves when the study drug has been stopped; 
 
 
 
Possibly related: 
 
Starts a reasonable time after the study drug administration but could have been produced by 
 
 
Unlikely to be related: 
 
ug is not likely to have 
had an association with the observed effect. 
 
Unrelated: 
 
The AE is definitely not associated with the study drug administered. 
 
If any doubt about the causality exists the local investigator should inform the study coordination 
centre who will notify the Chief Investigator.  The pharmaceutical companies and/or other clinicians 
may be asked to advise in some cases. 
In the case of discrepant views on causality between the investigator and others, all parties will 
discuss the case.  In the event that no agreement is made, the MHRA will be informed of both points 
of view. 
 
9.8  
Expedited Reporting 
The ICTU will report SUSARs to the regulatory authorities (MHRA and the relevant ethics committees) 
as follows: 


 
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SUSARs which are fatal or life-threatening will be reported within 7 calendar days of the CTU first 
becoming aware of the reaction. Any additional relevant information must be reported within a 
further 8 days ( i.e. by day 15). 
 
SUSARs that are not fatal or life-threatening will be reported within 15 days of the CTU first 
becoming aware of the reaction. 
 
9.9   Annual reporting of Serious Adverse Events 
Annual Safety reports will be submitted to the Sponsor, the Ethics Committee and Regulatory 
Authority in accordance with regulatory requirements. 
Novartis Pharmaceuticals UK Limited will be responsible for submission of the Development Safety 
Update Report (DSUR).  The Sponsor (via ICTU) will provide information required by Novartis to 
include the study in the Novartis DSUR in an integrated manner.  Novartis will provide a copy of the 
submitted DSUR to ICTU for filing in the study TMF. 
 
9.10 Reporting urgent safety measures 
 
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event no later 
than 3 days from the date the measures are taken, give written notice to the relevant REC of the 
measures taken and the circumstances giving rise to those measures. 


 
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10.  Patient Loss from Study Post-Randomisation  
 
The PI will make every reasonable effort to keep each patient on study.   
 
10.1  Patients lost 
The following 3 sub-sections describe patients that will be regarded as having been lost from 
the study, i.e. no further follow-up visits will take place and no further data will be collected; 
 
10.1.1 Withdrawn 
Patients who withdraw their consent at any point in the study fall into one of two categories. 
Site staff should ascertain which category a patient wishes to be in at the point of withdrawal; 
a) Those who allow their data (collected up to the point of withdrawal) to be used 
OR 
b) Those who do not allow the use of any of their data collected prior to withdrawal.  
 
10.1.2 Lost to follow-up 
These are patients who do not attend a follow-up assessment after site staff have attempted 
to contact the patient at least twice, e.g. by telephone.  
As these patients have not withdrawn their consent, the data already collected for them may 
be used and therefore needs returning in the usual manner. 
 
10.1.3 Patients that have died 
These patients have not withdrawn their consent and therefore the data already collected for 
them may be used. 
 
10.2  Patients not lost 
Patients that fall into one or more of the following categories, which are indications for 
treatment discontinuation, are not considered as withdrawn or lost from the study. They 
should continue to attend all follow-up study assessments as per protocol, unless they 
subsequently fall into one of the categories listed in Section 10.1; 
 
 
Patients who ask to stop study treatment  
 
Pregnancy 
 
Steroid psychosis or persisting psychotic symptoms for more than 7 days, that cannot be 
explained by alcohol withdrawal 
 
Any event which in the judgement of the PI makes further study treatment inadvisable 
 
SAE requiring discontinuation of treatment. 
 
Stopping treatment or having a prolonged/numerous treatment gaps, for whatever reason, 
does not mean the patients are withdrawn or lost from the study, they should still continue 
to attend all follow-up assessments. If the screening biopsy histology is negative then the 
patient will be discontinued from the study, will not undergo any further treatment or the 
second biopsy but will be followed-up for safety assessment for 28 days, as per assessment 
schedule.  


 
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11. END OF THE CLINICAL TRIAL 
 
The recruitment period of the trial will be stopped when: 
 
 
The stated number of patients to be recruited and randomised is reached, or the trial is 
stopped for another reason, e.g. by the funding body or the regulatory authority. 
 
 
The active treatment phase will be completed: 
 
 28 days after start of treatment of the last patient randomised. 
 
 
The end of the trial is defined as: 
 
 The end of the trial will occur when the final participant has completed the last study visit 
and all study data have been captured on the study database.  
 
 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF.  All reasons for discontinuation of 
treatment must be documented.   
 
In terminating the study, the Sponsor and the Investigators will ensure that adequate 
 
 
 
 


 
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12 
REGULATORY, ETHICAL AND LEGAL ISSUES 
 
12.1 
Treatment 
 
12.1.1 Investigational Medicinal Product Details 
 
 
12.1.2 Labelling, storage and dispensing 
 
IMP (Canakinumab) is manufactured by Novartis according to Good Manufacturing Practices 
(GMP) and will be packaged/stored/transported as per requirements specified in SmPC. IMP 
(Canakinumab) will be provided by Novartis for the trial. Labelling, storage and distribution of 
drug to sites will be carried out by a company independent of the funder and Sponsor. They 
will be contracted by Imperial College to receive the study drug from Novartis, to label and 
repackage the drug for clinical trial use, for final QP release and to distribute the drugs to sites 
as requested by the trial team. 
 
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.  
 
The trial team at each site will randomise each new patient on the study eCRF/InForm 
database. This will provide a code to the trial team for that patient (that does not identify the 
treatment allocation) and the code will be used by the site pharmacy to identify if the patient 
will have active drug or placebo based on a pre specified randomisation list that pharmacy 
will be provided with. This will be double checked by a second pharmacist against the code 
on InForm and the code on the randomisation list to reduce the risk of error. The pharmacist 
will then either prepare the i.v. infusion bag at trial pharmacy or dispense the 
IMP+Placebo/Placebo-only to a designated unblinded research member who will then make 
up the i.v. infusion bag and label it with this code  this will be double checked by another 
unblinded member of the research team before administration by a blinded nurse/doctor.  
Patients with moderate to severe ascites should undergo large volume paracentesis prior to 
administration of Canakinumab.  
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. 
 
Drug Name 
Dosage 
Description 
Canakinumab 
 
3mg Canakinumab per kg.
 
Canakinumab will be made up by dilution 
in 100ml 5% dextrose and administered 
intravenously 
Placebo 
100ml 5% Dextrose 
Dextrose alone will be administered 
intravenously 


 
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Overdose of IMP should be reported immediately and recorded as a protocol deviation and 
AE on the InForm database and the patient followed up. Reported experience with overdose 
of IMP is limited. In early clinical trials, patients and healthy volunteers received doses as high 
as 10 mg/kg, administered intravenously or subcutaneously, without evidence of acute 
toxicity. 
 
12.1.3 Accountability 
 
Hospital pharmacies will be responsible for recording study drugs dispensed. Preparation of 
all drug solution for injection will be recorded on the study drug accountability logs, and drug 
administration 
. The study drug stores will include a sheet 
recording the use of each vial of active drug. Used vials will be checked for reconciliation by 
the Trial Monitor at monitoring visits before destruction. At the end of the study any 
remaining unused vials of drug will be destroyed. 
 
12.2 
Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformity with the 7th 
revision of the 1964 Declaration of Helsinki. 
 
12.3 
Good Clinical Practice  
The study will be conducted in accordance with the guidelines laid down by the International 
Conference on Harmonisation for Good Clinical Practice (ICH GCP E6 R2 guidelines).  
 
12.4 
Independent Ethics Committee Approval  
 
(vi) 
Initial Approval 
Prior to the enrolment of subjects, the REC must provide written approval of the conduct of 
the study at named sites, the protocol and any amendments, the Subject Information Sheet 
and Consent Form and any other written information that will be provided to the subjects.  
 
(vii) 
Approval of Amendments 
Proposed amendments to the protocol and aforementioned documents must be submitted 
to the REC for approval as instructed by the Sponsor. Amendments requiring REC approval 
roval letter has been obtained. 
 
Amendments that are intended to eliminate an apparent immediate hazard to subjects may 
be implemented prior to receiving Sponsor or REC approval. However, in this case, approval 
must be obtained as soon as possible after implementation. 
 
(iii) 
Annual Progress Reports 
The REC will be sent annual progress reports in accordance with national requirements. 
 
(iv) 
Annual Safety Reports and End of Trial Notification 
 


 
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The REC will be sent annual safety updates in order to facilitate their continuing review of the 
study (reference. ICH GCP E6 Section 3.1.4) and will also be informed about the end of the 
trial, within the required timelines. 
 
12.5 
Regulatory Authority Approval 
The study will be performed in compliance with UK regulatory requirements. Clinical Trial 
Authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) will 
be obtained prior to the start of the study. In addition, the MHRA will approve amendments 
prior to their implementation (as instructed by the Sponsor), receive SUSAR reports and 
annual safety updates, and be notified of the end of the trial. 
 
12.6 
HRA Approval 
Health Research Authority (HRA) approval will be obtained prior to starting the study. Each 
participating site will confirm capacity and capability prior to commencing. 
The HRA and all participating sites also need to be notified of all protocol amendments to 
assess whether the amendment affects the institutional approval for each site.  
 
12.7 
Insurance and Indemnity 
Imperial College London, the Sponsor of the trial has civil liability insurance, which covers this 
study in all participating centres. Imperial College London also holds negligent harm and non-
negligent harm insurance policies which apply to this study. 
 
12.8 
Trial Registration 
The study will be registered on a trial database (clinicaltrials.gov and/or ISRCTN) in 
accordance with requirements of the International Committee of Medical Journal Editors 
(ICMJE) regulations. 
 
12.9 
Informed Consent 
Informed consent will be obtained from all participants or their legal representative. Further 
details are given in Section 4. 
The right of the participant to refuse to participate without giving reasons must be respected. 
All participants are free to withdraw at any time from the protocol treatment without giving 
reasons and without prejudicing further treatment. 
 
12.10 
Non-compliance and serious breaches 
 
All protocol deviations and protocol violations will be reported via the eCRF/CRF and reviewed 
by the Chief Investigator and reported to the ICTU QA manager on a monthly basis. Protocol 
violations will be reported to the Sponsor. 
An assessment of whether the protocol deviation/violation constitutes a serious breach will 
be made.  
A serious breach is defined as: 


 
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A breach of the conditions and principles of GCP in connection with a trial or the trial 
protocol, which is likely to affect to a significant degree:  
 The safety or physical or mental integrity of the UK trial subjects; or 
 The overall scientific value of the trial 
 
The Sponsor will be notified within 24 hours of identifying a likely Serious Breach. If a decision 
is made that the incident constitutes a Serious Breach, this will be reported to the MHRA and 
REC within 7 days of becoming aware of the serious breach. 
 
12.11 
Contact with General Practitioner  
the subject is taking part in the study provided the subject agrees to this, and information to 
this effect is included in the Patient Information Sheet and Informed Consent. A copy of the 
letter should be filed in research record for the patient at sites. 
 
12.12 
Subject Confidentiality 
other documents submitted to the Sponsors, subjects will be identified by a subject ID 
number only. Documents that are not submitted to the Sponsor (e.g., signed informed 
consent form) should be kept in a strictly confidential file by the investigator. 
 
for the 
purposes of monitoring, auditing, or inspection by the Sponsor, authorised representatives of 
the Sponsor, Regulatory Authorities and RECs. 
 
12.13 
Data Protection 
 
All personnel involved in the study will observe or work within the confines of the local data 
protection guidelines. 
 
12.14 
End of Trial 
The end of the trial is defined in Section 11. 
 
12.15 
Study Documentation and Data Storage 
The investigator will retain essential documents until notified by the Sponsor, and for at least 
ten years after study completion. Patient files and other source data (including copies of 
protocols, CRFs, original reports of test results, IMP dispensing logs, correspondence, records 
of informed consent, and other documents pertaining to the conduct of the study) will be 
retained. Documents will be stored in such a way that they can be accessed/data retrieved at 
a later date.  
 
No study document will be destroyed without prior written agreement between the Sponsor 
and the investigator. Should the investigator wish to assign the study records to another party 
or move them to another location, written agreement must be obtained from the Sponsor. 
 


 
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13 
STUDY MANAGEMENT STRUCTURE  
 
13.1 
Trial Steering Committee  
A Trial Steering Committee (TSC) will be convened including as a minimum an independent 
Chair, 2 independent clinicians, a lay representative (also independent), the Chief Investigator 
and Trial Manager. The role of the TSC is to provide overall supervision of trial conduct and 
progress. A TSC Charter will be devised to list the roles and responsibilities of the TSC 
members. Frequency of meetings will be defined in the Charter. The first TSC meeting to take 
place following the start of recruitment will be after the first 10 patients have been 
randomised to the study and thereafter frequency of meetings will be determined by the 
DMEC and TSC based on this initial data. 
 
13.2 
Trial Management Group 
A Trial Management Group (TMG) will be convened including the Chief Investigator, co-
investigators and key collaborators, trial statistician and trial manager. The TMG will be 
responsible for day-to-day conduct of the trial and operational issues including recruitment 
and other practical aspects of the trial. 
The day-to-day management of the trial will be co-ordinated through the Imperial Clinical 
Trials Unit and the Chief Investigator. 
13.3 
Data Monitoring Committee 
 
An independent Data Monitoring and Ethical Committee (DMEC) will be set up to monitor 
progress, patient safety and any ethical issues involved in this trial. They will review trial 
progress, recruitment rates, event rates and safety data. A separate charter will be drawn up 
defining their exact remit and criteria for reporting to the trial steering committee. Frequency 
of meetings will be defined in the Charter. The first DMEC meeting to take place following the 
start of recruitment will be after the first 10 patients have been randomised to the study and 
thereafter frequency of meetings will be determined by the DMEC and TSC based on this 
initial data. 
13.4 
Early Discontinuation of the Study 
If, in the opinion of the Chief Investigator, clinical events indicate that it is not justifiable to 
continue the trial, the Trial Steering Committee may terminate the trial following consultation 
with the Sponsor. 
13.5 
Risk Assessment 
A study-specific risk assessment will be performed prior to the start of the study to assign a 
the ICTU QA Manager in collaboration with the Study Manager/Operations Manager and the 
result will be used to guide the monitoring plan. The risk assessment will consider all aspects 
of the study and will be updated as required during the course of the study. The risk 
assessment will also provide guidance for risk reduction activities so where risks are identified 
prior to the start of the study they can be managed and identified early on and measures put 
in place to reduce the risk. 
 


 
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13.6  
Monitoring  
The study will be monitored periodically by a trial monitor to assess the progress of the study, 
verify adherence to the protocol, ICH GCP E6 guidelines and other national/international 
requirements and to review the completeness, accuracy and consistency of the data. 
A monitoring plan will be devised based on risk analysis and described in detail in the 
monitoring manual. A Trial Monitor will visit all sites and facilities where the trial will take 
place to ensure compliance with the protocol, GCP and local regulatory compliance.  
Initiation visits will be completed at all trial sites prior to the recruitment of participants, and 
will consist of review of protocol and trial documents, training with respect to trial procedures 
(informed consent, SAE reporting, inclusion and exclusion criteria), review of recruitment 
strategy, review of site facilities and equipment, essential document receipt, collection and 
filing, and archiving and inspection.   
The investigators will allow the monitors to:  
 inspect the site, the facilities, IMP management and materials used for the trial 
 meet all members of the team involved in the trial, and ensure all staff working on the 
trial are experienced and appropriately trained, and have access to review all of the 
documents relevant to the trial  
 have access to the electronic case record forms and source data  
 discuss with the investigator and site staff trial progress and any issues on a regular 
basis  
The monitor will ensure that; 
 all participant records will be inspected for confirmation of existence, eligibility and 
informed consent 
 there is adherence to the protocol, including consistency with inclusion/exclusion 
criteria 
 there is GCP and regulatory compliance   
 Trial Documentation is complete and up to date (e.g. correct versions of documents 
being used, source data captured) and relevant documents are collected for the Trial 
Master File (TMF)  
 The eCRFs have been completed correctly and accurately, and all entries correspond 
to data captured in source documents  
At the end of the trial, close out visits will be performed by the monitor after the final 
participant visit has been completed.  
Each investigator will also be notified that an audit or inspection may be carried out - by the 
sponsor, sponsor's representatives or the host institution, or regulatory authorities - at any 
time, before, during or after the end of the trial.  The investigator must allow the 
representatives of the audit or inspection team:  
 to inspect the site, facilities and material used for the trial,  
 to meet all members of his/her team involved in the trial, 
to have direct access to trial data and source documents, to consult all of the documents 
relevant to the trial. If an Investigator is informed of an impending audit or inspection, the 
trial coordination centre should be notified immediately. 
 


 
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13.7 
Quality Control and Quality Assurance 
Quality Control will be performed according to Imperial Clinical Trials Unit internal 
procedures. The study may be audited by a Quality Assurance representative of the Sponsor 
and/or ICTU. All necessary data and documents will be made available for inspection. 
 
The study may be subject to inspection and audit by Imperial College London under their 
remit as Sponsor, the Study Coordination Centre and other regulatory bodies to ensure 
adherence to GCP. 
 
13.8  
Disclosure of Data and Publication 
 
Verbal or written discussion of results prior to study completion and full reporting should only 
be undertaken with written consent from the Sponsor. 
 
Therefore all information obtained as a result of the study will be regarded as CONFIDENTIAL, 
at least until appropriate analysis and review by the investigator(s) are completed.  
 
The results may be published or presented by the investigator(s), but the Sponsor will be given 
the opportunity to review and comment on any such results before any presentations or 
publications are produced. 
All publications and presentations relating to the study will be authorised by the Trial 
Management Group.  Authorship will be determined according to the internationally agreed 
criteria for authorship (www.icmje.org). Authorship of parallel studies initiated outside of the 
Trial Management Group will be according to the individuals involved in the project but must 
acknowledge the contribution of the Trial Management Group and the Study Coordination 
Centre. 
Novartis, as study funder, will be informed of study publications as per the contract between 
Novartis and Imperial College. 
13.9 
Patient and Public Involvement (PPI) 
At least one PPI representative will sit on the Trial Steering Committee and will provide input 
from a patient perspective at trial meetings. Representatives have reviewed and provided 
feedback on all of the project documents prior to the ethics and regulatory submissions and 
their comments have been incorporated. 
 
13.10 
Peer review 
The trial has undergone peer review as part of the funding application to Novartis. The trial 
has also been reviewed by senior members of ICTU as part of the Collaborations process. 
 
 
 
 


 
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14 
References 
 
1. 
Altamirano J, Miquel R, Katoonizadeh A, Abraldes JG, Duarte-Rojo A, Louvet A, et al. A 
histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology. 
2014;146(5):1231-9.e1-6. doi: 10.053/j.gastro.2014.01.018. Epub  Jan 15. 
2. 
Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. NEnglJMed. 2009;360(26):2758-69. 
3. 
EASL clinical practical guidelines: management of alcoholic liver disease. JHepatol. 
2012;57(2):399-420. 
4. 
Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, et al. Prednisolone or 
pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015;372(17):1619-28. doi: 
10.056/NEJMoa1412278. 
5. 
Singh S, Murad MH, Chandar AK, Bongiorno CM, Singal AK, Atkinson SR, et al. Comparative 
Effectiveness of Pharmacological Interventions for Severe Alcoholic Hepatitis: A Systematic Review 
and Network Meta-analysis. Gastroenterology. 2015;149(4):958-70.e12. doi: 
10.1053/j.gastro.2015.06.006. Epub  Jun 16. 
6. 
Vergis N, Atkinson SR, Knapp S, Maurice J, Allison M, Austin A, et al. Patients With Severe 
Alcoholic Hepatitis Given Prednisolone Therapy Who Have High Circulating Levels Of Bacterial DNA 
are at Increased Risk for Developing Infections. Gastroenterology. 2016:019. 
7. 
Tilg H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G, et al. Serum levels of cytokines 
in chronic liver diseases. Gastroenterology. 1992;103(1):264-74. 
8. 
Tilg H, Moschen AR, Szabo G. Interleukin-1 and inflammasomes in alcoholic liver 
disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. 
Hepatology. 2016;64(3):955-65. doi: 10.1002/hep.28456. Epub 2016 Mar 9. 
9. 
Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, et al. IL-1 receptor antagonist 
ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest. 
2012;122(10):3476-89. doi: 10.1172/JCI60777. Epub 2012 Sep 4. 
10. 
Mathews S, Gao B. Therapeutic potential of interleukin 1 inhibitors in the treatment of 
alcoholic liver disease. Hepatology. 2013;57(5):2078-80. doi: 10.1002/hep.26336. 
11. 
Boetticher NC, Peine CJ, Kwo P, Abrams GA, Patel T, Aqel B, et al. A randomized, double-
blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. 
Gastroenterology. 2008;135(6):1953-60. doi: 10.053/j.gastro.2008.08.057. Epub  Sep 13. 
12. 
Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, et al. A double-
blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic 
hepatitis. Hepatology. 2004;39(5):1390-7. 
13. 
Vergis N, Atkinson SR, Knapp S, Maurice J, Allison M, Austin A, et al. In Patients With Severe 
Alcoholic Hepatitis, Prednisolone Increases Susceptibility to Infection and Infection-Related 
Mortality, and Is Associated With High Circulating Levels of Bacterial DNA. Gastroenterology. 
2017;152(5):1068-77.e4. doi: 10.53/j.gastro.2016.12.019. Epub  Dec 30. 
14. 
Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, et al. The Lille model: a 
new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. 
Hepatology. 2007;45(6):1348-54. 
15. 
Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring 
system for nonalcoholic fatty liver disease. Hepatology 2005;41: 1313 1321. 
16. 
Bedossa P. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) 
algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic 
fatty liver disease. Hepatology 2014;60: 565 575 
 
 
 


 
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APPENDIX 1 
Summary of treatment plan for the Isaiah study  
 
 
 
 
 


 
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APPENDIX 2 
Protocol Exempt Adverse Events  
 
Neurological 
 
Fits or seizures 
 
Confusion 
 
 
 
 
 
Coma 
 
Peripheral neuropathy 
 
Proximal myopathy 
 
Delirium tremens 
 
Tremor 
Cardiac 
 
Arrhythmias 
 
Hypotension 
 
Hypertension 
 
Cardiac failure 
 
Tachycardia 
 
Peripheral Oedema 
Respiratory 
 
Hydrothorax 
 
ARDS 
Renal 
 
Acute renal failure 
 
Hypomagnesaemia 
 
Hypophosphataemia 
 
Hyponatraemia 
 
Hypokalaemia 
 
Hypoglycaemia 
Gastrointestinal 
 
Vomiting 
 
Haematemesis 
 
Melaena 
 
Chronic pancreatitis 
Dermatological 
 
Bruising 
 
Psoriasis 
Haematological 
 
Anaemia 
 
Acanthocytosis 
 
Coagulopathy 
Gynaecological 
 
Menstrual irregularity 
 
Amenorrhea 
 
Menorrhagia 
 
 


 
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SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
 
The signature below constitutes approval of this protocol by the signatory and provides 
the necessary assurances that this study will be conducted according to all stipulations 
of the protocol including all statements regarding confidentiality. 
 
 
Study Title:  
 
IL-1 Signal Inhibition in Alcoholic Hepatitis 
(Isaiah) 
 
 
Protocol Number:  
Protocol number: 17SM4152 
 
                                     
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Mark Thursz 
 
 
 
Professor of Hepatology 
 
 
 
Imperial College, London. 
 
 
 
9th September 2020 
 
Date:  
 
_____________________ 
  
 
 


 
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SIGNATURE PAGE 2 (SPONSOR) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title:  
 
IL-1 Signal Inhibition in Alcoholic Hepatitis 
(Isaiah) 
 
 
 
Protocol Number:  
Protocol number: 17SM4152 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
 
 
 
 
____________________________ 
 
 
 
Joint Research Compliance Office 
 
 
 
Imperial College, London 
 
 
 
 
 
 
Date:  
 
_____________________ 
 
 


 
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SIGNATURE PAGE 3 (STATISTICIAN) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title:  
 
IL-1 Signal Inhibition in Alcoholic Hepatitis 
(Isaiah) 
 
 
Protocol Number:  
Protocol number: 17SM4152 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Dr Francesca Fiorentino 
 
 
 
Senior Statistician 
 
 
 
Imperial College, London 
 
 
Date:  
 
_____________________ 
 
 


 
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SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
 
The signature of the below constitutes agreement of this protocol by the signatory and 
provides the necessary assurance that this study will be conducted at his/her 
investigational site according to all stipulations of the protocol including all statements 
regarding confidentiality. 
 
 
Study Title:  
 
IL-1 Signal Inhibition in Alcoholic Hepatitis 
(Isaiah) 
 
 
Protocol Number:  
Protocol number: 17SM4152 
 
 
Address of Institution:  
____________________________________________ 
 
 
 
 
 
 
 
 
 
 
____________________________________________ 
 
 
 
 
 
 
____________________________________________ 
 
 
 
Signed: 
 
 
____________________________________________ 
 
 
Print Name and Title: 
____________________________________________ 
 
 
Date:  
 
 
_____________________