Clinical trial NCT03452540
Conditions: Severe Acute Decompensated Alcoholic Hepatitis
Sponsor: Afimmune
Start date: 2018-11-28; Completion date: 2020-03-31
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this randomised, double-blind, placebo-controlled, phase II study is to assess the efficacy and safety of orally administered DS102 in adult patients with acute decompensated alcoholic hepatitis

Detailed description:

Arms: arm 1: Participants assigned to the open label pilot phase received 1000mg DS102 (BID)for 28 days.
Interventions: intervention 1: 1000mg DS102 (BID)
Intervention descriptions: intervention 1: Participants assigned to the open label pilot phase received 1000mg DS102 (BID)for 28 days.

Protocol documents:
Prot_000.pdf: 
Confidential/Clinical Study Protocol No. DS102A-05-AH1 Version 6.0 
                          
Page 1 of 75 
 
 
 
 
 
 
 
 
A Randomised, Double-Blind, Placebo-Controlled, Phase II Study to 
Assess the Efficacy and Safety of Orally Administered DS102 in 
Patients with Severe Acute Decompensated Alcoholic Hepatitis. 
 
 
 
 
 
 
Protocol Number # DS102A-05-AH1 
Version 6.0 
14 November 2018 
EudraCT No. 2018-000819-25 
Sponsor: 
Afimmune, 
Trintech Building, 
South County Business Park, 
Leopardstown, 
Dublin 18, 
Republic of Ireland. 


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CONTACT INFORMATION 
 
 
Chief Investigator: 
Prof. Mark Thursz 
Imperial College London Kensington, 
London SW7 2AZ, United Kingdom 
Sponsor Medical Expert: 
Dr. Markus Weissbach, Medical Director, 
Afimmune, 
Trintech Building, 
South County Business Park, Leopardstown, 
Dublin 18, 
Republic of Ireland.  
Tel: +353 1 293 3590 
Pharmacovigilance/Medical Monitor: 
 
 
spm2 – safety projects & more GmbH, 
Goldbeckstraße 5, 
69493 Hirschberg a.d. Bergstraße, 
Germany 
 
        Telephone: +49 (6201) 84640 - 0 
        Email: Afimmune-PhV@spm2-safety.com 
        24 hour contact details - Europe: +49 6201 84640 600 
        24 hour contact details – USA: +1 978 513 8255        


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TABLE OF CONTENTS 
Contents 
CONTACT INFORMATION ......................................................................................................................................................................... 2 
TABLE OF CONTENTS .............................................................................................................................................................................. 3 
LIST OF TABLES ....................................................................................................................................................................................... 5 
PROTOCOL SYNOPSIS ............................................................................................................................................................................ 8 
LIST OF ABBREVIATIONS ........................................................................................................................................................................14 
1 INTRODUCTION .................................................................................................................................................. 16 
1.1 
Therapeutic Area and Disease Background ................................................................................... 16 
1.2 
Standard Treatment .......................................................................................................................... 16 
1.3 
Drug Class ......................................................................................................................................... 16 
1.4 
Preclinical Pharmacology ................................................................................................................ 17 
A subcutaneous injection of streptozotocin was administered to newborn mice followed by a high fat diet from four weeks of age. Results 
presented below represent overall outcomes from four studies performed. NAS score (NAFLD Activity Score) is separated into 
three components: steatosis, lobular inflammation and hepatocyte ballooning. Light arrows signify a decrease. Dark arrows 
signify a statistically significant difference in the extent of decrease. ............................................................................................19 
1.5 
Toxicology ......................................................................................................................................... 20 
1.6 
Previous Clinical Safety Studies with 15(S)-HEPE ........................................................................ 20 
2 
RISK BENEFIT ASSESSMENT ..................................................................................................................... 20 
3 
RATIONALE FOR THE STUDY ...................................................................................................................... 21 
4 
STUDY OBJECTIVES..................................................................................................................................... 22 
5 
STUDY ENDPOINTS ...................................................................................................................................... 23 
5.1 
Primary Endpoint .............................................................................................................................. 23 
5.2 
Secondary Endpoints ....................................................................................................................... 23 
5.3 
Exploratory Endpoints ...................................................................................................................... 23 
5.4 
Safety Endpoints ............................................................................................................................... 23 
6 
STUDY DESIGN .............................................................................................................................................. 24 
6.1 
General ............................................................................................................................................... 24 
6.2 
Rationale for Study Design and Dose Selection ............................................................................ 25 
7 
PATIENTS AND SCREENING ........................................................................................................................ 26 
7.1 
Source of Patients ............................................................................................................................. 26 
7.2 
Inclusion Criteria ............................................................................................................................... 26 
7.3 
Exclusion Criteria .............................................................................................................................. 26 
7.4 
Screening and Consent .................................................................................................................... 27 
7.5 
Withdrawal of Patients ...................................................................................................................... 28 
7.5.1 
Complete Withdrawal ...................................................................................................................................................................28 
7.5.2 
Withdrawals from Investigational Product .....................................................................................................................................28 
7.6 
Patient Replacement ......................................................................................................................... 29 
7.7 
Protocol Deviations........................................................................................................................... 29 
7.8 
Stopping Criteria ............................................................................................................................... 29 
8 
STUDY CONDUCT ......................................................................................................................................... 30 
8.1 
Study Schedule ................................................................................................................................. 30 
8.2 
Clinic Visits ........................................................................................................................................ 30 
8.2.1 
Screening Visit (Visit 1) ................................................................................................................................................................30 
8.2.2 
Treatment Period .........................................................................................................................................................................31 
8.2.3 
Baseline (Visit 2) ..........................................................................................................................................................................31 
8.2.4 
Visit 3/Day 3 .................................................................................................................................................................................32 
8.2.5 
Visit 4/Day 5 .................................................................................................................................................................................33 
8.2.6 
Visit 5/Day 7 .................................................................................................................................................................................35 
8.2.7 
Visit 6/Day 14 ...............................................................................................................................................................................35 
8.2.8 
Visit 7/Day 21 ...............................................................................................................................................................................36 
8.2.9 
Visit 8/Day 28/Early Termination ..................................................................................................................................................37 
8.2.10 
Visit 9/Day 90/Follow Up ..............................................................................................................................................................38 
9 
ASSESSMENTS ............................................................................................................................................. 40 
9.1 
Efficacy Assessments ...................................................................................................................... 40 
9.1.1 
Model for End-Stage Liver Disease ..............................................................................................................................................40 
9.1.2 
Total Bilirubin ...............................................................................................................................................................................40 


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9.1.3 
ALT, AST, AST:ALT Ratio ............................................................................................................................................................40 
9.1.4 
Gamma Glutamyl Transferase .....................................................................................................................................................40 
9.1.5 
Child-Pugh Score .........................................................................................................................................................................40 
9.1.6 
Cytokeratin-18 M30/M65 ..............................................................................................................................................................41 
9.1.7 
Maddrey Discriminant Function ....................................................................................................................................................41 
9.1.8 
Modified Sequential Organ Failure Assessment ...........................................................................................................................41 
9.1.9 
Acute Physiologic and Chronic Health Evaluation II .....................................................................................................................42 
9.1.10 
Lille Score ....................................................................................................................................................................................42 
9.1.11 
West Haven Criteria .....................................................................................................................................................................42 
9.2 
Safety Assessments ......................................................................................................................... 43 
9.2.1 
Medical History ............................................................................................................................................................................43 
9.2.2 
Physical Examination ...................................................................................................................................................................43 
9.2.3 
Electrocardiogram ........................................................................................................................................................................44 
9.2.4 
Vital Signs ....................................................................................................................................................................................44 
9.2.5 
Clinical Laboratory Safety Tests: Haematology, Serum Biochemistry, and Coagulation ...............................................................44 
9.2.6 
Virology ........................................................................................................................................................................................45 
9.2.7 
Pregnancy Test ............................................................................................................................................................................45 
9.2.8 
Exploratory Blood Sampling .........................................................................................................................................................45 
9.2.9 
Adverse Event Assessment .........................................................................................................................................................46 
9.2.10 
Concomitant Medication ...............................................................................................................................................................46 
9.2.11 
Liver Ultrasound ...........................................................................................................................................................................46 
9.2.12 
Bioanalysis...................................................................................................................................................................................46 
9.2.13 
Sample Storage, Handling and Shipping ......................................................................................................................................46 
9.2.14 
Liver Histopathology ....................................................................................................................................................................46 
9.2.15 
Urinalysis .....................................................................................................................................................................................46 
10 
INVESTIGATIONAL PRODUCT/INVESTIGATIONAL DRUG ......................................................................... 47 
DS102 Capsule:.........................................................................................................................................................................................47 
DS102 Placebo (Paraffin Oil): ....................................................................................................................................................................47 
10.1 
Supply, Packaging, Labelling, Handling and Storage ................................................................... 47 
10.2 
Dosage and Administration ............................................................................................................. 47 
10.3 
Duration of Treatment ....................................................................................................................... 48 
10.4 
Drug Accountability .......................................................................................................................... 48 
11 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................................... 50 
11.1 
Definitions of Adverse Events ......................................................................................................... 50 
11.1.1 
Seriousness .................................................................................................................................................................................50 
11.1.2 
Severity ........................................................................................................................................................................................51 
11.1.3 
Relationship to IMP ......................................................................................................................................................................51 
11.1.4 
Reporting of AEs and SAEs .........................................................................................................................................................51 
As soon as the Investigator is aware of a potential SAE, he/she should contact the pharmacovigilance (PV) contract research organisation 
(CRO) monitor by phone, fax or e-mail, and, in any case, no later than 24 hours after the knowledge of such a case. The contact 
information is provided in the ISF. ................................................................................................................................................51 
11.2 
Serious Adverse Reactions and Unexpected Adverse Reactions ............................................... 52 
11.2.1 
Definitions ....................................................................................................................................................................................52 
11.2.2 
Reporting of suspected unexpected serious adverse reactions ....................................................................................................52 
11.3 
Drug Induced Liver Injury (DILI) ...................................................................................................... 53 
11.3.1 
Severe drug-induced liver injury ...................................................................................................................................................53 
11.3.2 
Monitoring of patients with impaired liver biochemistry .................................................................................................................53 
11.4 
Pregnancy Reporting ........................................................................................................................ 53 
12 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT ...................................................................... 55 
12.1 
Study Design ..................................................................................................................................... 55 
12.2 
Randomisation .................................................................................................................................. 55 
12.3 
Estimation of Sample Size ............................................................................................................... 56 
12.4 
Blinding and Code Breaking Instructions ...................................................................................... 56 
12.5 
Data Analysis ..................................................................................................................................... 56 
12.6 
Analysis Populations ........................................................................................................................ 57 
12.7 
Safety Analysis .................................................................................................................................. 57 
12.8 
Statistical Analysis Plan ................................................................................................................... 58 
12.8.1 
Pharmacokinetic Analysis ............................................................................................................................................................58 
12.8.2 
Primary Variables .........................................................................................................................................................................59 
12.8.3 
Secondary variables ....................................................................................................................................................................59 
12.9 
Data Collection/Electronic Case Report Forms ............................................................................. 60 
12.10 
Data Management.............................................................................................................................. 60 
12.11 
Protocol Deviations........................................................................................................................... 60 
13 
REGULATORY AND ADMINISTRATIVE PROCEDURES .............................................................................. 61 
13.1 
Institutional Review........................................................................................................................... 61 
13.2 
Informed Consent and Inclusion of Subjects Incapable of Providing Informed Consent ......... 61 


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13.3 
Data and Safety Monitoring Board .................................................................................................. 62 
13.4 
Good Clinical Practice ...................................................................................................................... 62 
13.5 
Essential Documents ........................................................................................................................ 63 
13.6 
Record Retention .............................................................................................................................. 64 
13.7 
Monitoring/Quality Control ............................................................................................................... 64 
13.8 
Quality Assurance ............................................................................................................................. 64 
13.9 
Insurance and Liability ..................................................................................................................... 64 
13.10 
End of Trial ......................................................................................................................................... 64 
13.11 
Confidentiality ................................................................................................................................... 65 
13.12 
Report and Publication ..................................................................................................................... 65 
14 
REFERENCES ................................................................................................................................................ 66 
15 
APPENDICES ................................................................................................................................................. 66 
15.1 
Appendix 1: Flow Chart – Pilot Phase ............................................................................................. 70 
15. 2  
Appendix 2: Study Flowchart – Double-Blind Phase .................................................................... 72 
15.2 
Appendix 3: Acute Physiologic and Chronic Health Evaluation II ............................................... 70 
 
 
 
 
LIST OF FIGURES 
Figure 1. Structure of 15(S)-HEPE EE (DS102) ........................................................................................ 16 
Figure 2: Schematic summarising the results of four in vivo studies performed using the 
STAM™ Model (DS-PC-26, DS-PC-27, DS-PC-28, and DS-PC-29). ................................... 17 
Figure 3: Study Outline .......................................................................................................................... 23 
 
LIST OF TABLES 
Table 1: DS102 Mechanism of Action Summary .................................................................................... 16 








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PRINCIPAL SITE INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
 
 
Investigator name: 
Signature: 
Date: 
Institution Name: 
By my signature, I agree to personally supervise the conduct of this study at my study site 
and to ensure its conduct is in compliance with the protocol, informed consent, 
Independent Ethics Committee (IEC) procedures, instructions from Afimmune 
representatives, the Declaration of Helsinki, International Conference on Harmonisation 
(ICH) Good Clinical Practices Guidelines (GCP), and national/local regulations governing 
the conduct of clinical studies. 
The signature also confirms that the Investigator agrees that the results of this study may 
be used for submission to national and/or international registration and supervising 
authorities. The authorities will be notified of the Investigators name, address, 
qualifications and extent of involvement. 


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PROTOCOL SYNOPSIS 
 
STUDY TITLE: 
A Randomised, Double-Blind, Placebo-Controlled, Phase II Study to 
Assess the Efficacy and Safety of Orally Administered DS102 in 
Patients with Severe Acute Decompensated Alcoholic Hepatitis. 
SHORT TITLE: 
Efficacy and Safety of Orally Administered DS102 in Patients with 
Severe Acute Decompensated Alcoholic Hepatitis. 
PHASE: 
II 
STUDY DURATION: 
90 days (treatment duration: 28 days) 
INVESTIGATIONAL 
PRODUCT: 
DS102 Capsule 
Placebo (paraffin oil) 
OBJECTIVES: 
Efficacy Objective: 
• To compare the efficacy of orally administered DS102 capsules 
versus placebo, in the treatment of adult patients with severe acute 
decompensated Alcoholic Hepatitis (AH). 
Safety Objective: 
• To compare the safety of orally administered DS102 capsules 
versus placebo, in the treatment of adult patients with severe acute 
decompensated AH. 
Pharmacokinetic Objective: 
• To evaluate the pharmacokinetics (PK) of 15(S)-HEPE following 
orally administered DS102 capsules, in six adult patients with AH in 
the initial pilot phase of the study, followed by trough level 
assessment of 15(S)-HEPE in all study participants. 
ENDPOINTS: 
Primary Endpoint 
• 
% Change in MELD score from baseline to Day 28 
Secondary Endpoints 
• 
Change in total bilirubin from baseline to Day 7, 14, 21 and 28 
• 
Proportion of patients showing a 25% reduction of bilirubin at 
day 7, 14, 21, and 28. 
• 
Change in serum cytokeratin 18-M30/M65 from baseline to Day 
7, 14, 21 and 28 
• 
Change in AST levels from Baseline to Day 7, 14, 21 and 28 
• 
Change in AST:ALT ratio from Baseline to Day 7, 14, 21, 28 
• 
Change in MDF score from baseline to Day 7, 14, 21 and 28. 
• 
Proportion of patients showing a 25% reduction in MELD score 
from baseline to Day 7, 14, 21 and 28 
• 
Change in MELD score from baseline to Day 7, 14 and 21 
• 
Change in modified Sequential Organ Failure Assessment (m- 
SOFA) from baseline to Day 7, 14, 21 and 28 
• 
Proportion of patients with a 2-point worsening of m-SOFA 


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from baseline to Day 7, 14, 21 and 28. 
• 
Change in hepatic encephalopathy as assessed by West Haven 
criteria, from baseline at Day 7, 14, 21 and 28 
• Incidence of acute kidney injury over 28 days (defined by 
requiring medicinal or mechanical support) 
• Incidence of variceal haemorrhage, ascites or 
hepatic encephalopathy over 28 days 
Exploratory Endpoints 
• 
Survival at day 7, 14, 21, 28 and 90 using Kaplan-Meier Plot 
• 
Change in Gamma Glutamyl Transferase (GT) from Baseline to 
Day 7, 14, 21 and 28 
• 
Change in ALT from Baseline to Day 7, 14, 21 and 28. 
• 
Change in Child Pugh score from baseline to Day 7, 14, 21 and 
28 
• 
Change in APACHE-II score from baseline to Day 7, 14 and 28 
• 
Change in Lille score from baseline to Day 7, 14 and 28 
Safety Endpoints 
• 
Treatment emergent (S)AE and SUSARs 
STUDY DESIGN: 
This is a multicentre, double blind, placebo controlled, 2-arm 
parallel group comparison (Phase 2) study, preceded by an open 
label pilot phase, in which six patients will receive open label 
treatment with DS102 1000mg twice daily within 30 minutes after a 
meal for 28 days. After the pilot phase, all patients will either 
receive 2000mg DS102 (1000mg BD) or placebo (BD), in addition to 
standard of care therapy, within 30 minutes after a meal for 28 
days in the two treatment groups of 60 patients each. Before 
randomisation each patient will undergo a screening period of up to 
five days after signing informed consent. 
TOTAL 
NUMBER 
OF 
RANDOMISED PATIENTS: 
Approximately 126 male or female patients, aged 18 years or older, 
with evident severe acute decompensated AH will be included in 
this study. 
STUDY POPULATION: 
INCLUSION CRITERIA: 
1. Male or female patients aged 18 years and older 
2. Total bilirubin of ≥ 5 mg/dl (85μmol/l) 
3. Patients with definite or probable AH 
4. MELD ≥18 at baseline visit 
5. Maddrey DF ≥32 at baseline visit 
6. Aspartate aminotransferase (AST) >50 U/L 
7. Aspartate aminotransferase/alanine aminotransferase 
(AST:ALT) ratio > 1.5 


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8. Female patients, or female partners of male patients, of child 
bearing potential must use highly effective birth control 
methods or have a sterilised partner for the duration of the 
study. Highly effective birth control methods are defined as 
methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly. Such methods 
include intrauterine device or sexual abstinence. 
 
Note: A woman is considered of child bearing potential 
(WOCBP), i.e. fertile, following menarche and until becoming 
post-menopausal unless permanently sterile. Permanent 
sterilisation methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. 
 
Note: Hormonal contraceptives are contraindicated in 
patients with severe hepatic diseases and are not acceptable 
as a birth control method in this study. 
 
Note: Sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with 
the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the 
subject 
 
9. Patient and/or legally authorised representative must provide 
Informed consent 
10. Able to swallow the provided study medication 
11. Not eligible for liver transplant during this hospitalisation 


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EXCLUSION CRITERIA: 
1. Pregnant or lactating females. 
2. Spontaneous liver function improvement defined by decrease 
of bilirubin level and MDF of >10% within 5 days of hospital 
admission 
3. Grade 4 hepatic encephalopathy (West Haven Criteria) 
4. Type 1 hepatorenal syndrome (HRS) or a serum creatinine >2 x 
ULN or requirement for haemodialysis 
5. History of hypersensitivity to any substance in DS102 capsules 
or placebo capsules. 
6. Alcohol abstinence of >6 weeks prior to screening 
7. Duration of clinically apparent jaundice >3 months prior to 
baseline 
8. Other causes of liver disease including: 
a. Evidence of chronic viral hepatitis (Hepatitis B DNA 
positive or HCV RNA positive) 
b. Biliary obstruction 
c. Hepatocellular carcinoma 
d. Wilsons disease 
e. Budd Chiari Syndrome 
f. 
Non-alcoholic fatty liver disease 
9. History of or active non-liver malignancies other than curatively 
treated skin cancer (basal cell or squamous cell carcinomas). 
10. Previous entry into the study 
11. AST >400 U/L or ALT >270 U/L 
12. Treatment with any experimental drug within 30 days prior to 
Day 0 visit (Baseline), or 5 half-lives (whichever is longer). 
13. Patients who have used dietary supplements rich in omega-3 or 
omega-6 fatty acids in the four weeks prior to baseline 
14. Patients dependent on inotropic support (adrenaline or 
noradrenaline), including Terlipressin 
15. Active variceal haemorrhage on this admission requiring more 
than 2 units of blood to maintain hemoglobin level within 48 h 
16. Untreated or unresolved sepsis 
17. Presence of refractory ascites 
18. Patients with known cerebral haemorrhage, extensive retinal 
haemorrhage, acute myocardial infarction (within last 6 
weeks) 


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or severe cardiac arrhythmias (not including atrial fibrillation) 
19. Known infection with HIV at screening 
20. Significant systemic or major illnesses other than liver disease 
that, in the opinion of the investigator, would preclude or 
interfere with treatment with DS102 and/or adequate follow up 
21. Previous liver transplantation 
CONCOMITANT 
MEDICATION 
Patients requiring the need for treatment due to a comorbidity 
during the trial will be treated using the standards of care for that 
indication e.g. diabetes, cholesterol, infection management, etc. 
TEST PRODUCT, DOSE, 
AND MODE OF 
ADMINISTRATION: 
DS102 will be provided in a capsule, containing 500mg of 15(S)- 
HEPE EE with 5% w/w of colloidal silicon dioxide as viscosity 
modifier. 
Placebo (liquid paraffin) will be provided in a capsule containing 
equivalent fill weight of liquid paraffin. In the open label pilot phase 
2000mg (1000mg BD) will be orally administered within 30 minutes 
after a meal for 28 days. 
In the double-blind phase of the study either 2000mg (1000mg BD) 
or placebo (BD) will be orally administered, in addition to standard 
of care therapy, within 30 minutes after a meal for 28 days. 
SAFETY 
A Data and Safety Monitoring Board (DSMB) will be established and 
will meet regularly to monitor on-going safety. 
EVALUATION CRITERIA: 
Efficacy: 
 
Total bilirubin 
 
MELD 
 
MDF 
 
Cytokeratin (CK) 18-M30/M65 
 
m-SOFA 
 
APACHE-II 
 
ALT 
 
AST 
 
AST:ALT ratio 
 
Gamma GT 
 
Child Pugh Score 
 
West Haven score (hepatic encephalopathy) 
 
Lille score 
Safety: 
 
Physical examination, including height and weight 
 
ECG (6-lead or 12-lead) 
 
Vital signs, including blood pressure (BP), pulse and 
temperature 
 
Clinical laboratory tests (haematology, coagulation, 
biochemistry, plasma caeruloplasmin and virology)  


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 
Pregnancy test for females of child bearing potential 
 
Adverse events (AEs) 
 
Concomitant medications 
Pharmacokinetic: 
Pilot Phase: 
 
Cmax – maximum observed concentration 
 
Tmax - time of maximum observed concentration 
 
AUCt – Area under the concentration-time curve to time t 
 
AUCtau - Area under the concentration-time curve to the end of 
the dosage interval 
 
AUCinf - Area under the concentration-time curve extrapolated 
to infinite time 
 
%Extrap – Percentage of AUCinf obtained by extrapolation 
 
Kel – Apparent first-order terminal elimination rate constant 
 
T1/2 – Apparent first-order terminal elimination half-life 
 
Flucp – Fluctuation at pharmacokinetic steady-state 
 
Rac – Accumulation ratio at pharmacokinetic steady-state 
 
Tss – Time to achieve pharmacokinetic steady-state 
Double-Blind Phase: 
 
Rac – Accumulation ratio at pharmacokinetic steady-state 
 
Tss – Time to achieve pharmacokinetic steady-state 
EXPLORATORY 
Blood samples will be collected at Baseline/Visit 2, Day 14/Visit 
6 and Day 28/Visit 8 for the potential analysis of Severe 
Alcoholic Hepatitis biomarkers 
STATISTICS 
See Chapter 12 
SPONSOR: 
Afimmune Ltd 


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LIST OF ABBREVIATIONS 
 
15(S)-HEPE EE 
15(S)-Hydroxy-Eicosapentaenoic Acid Ethyl Ester 
AH 
Alcoholic Hepatitis 
ASH 
Alcoholic Steatohepatitis 
AE 
ALT 
AST 
Adverse Event 
Alanine Aminotransferase 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BP 
BUN 
Blood Pressure 
Blood Urea Nitrogen 
CAP 
Controlled Attenuation Parameter 
CK 
Cytokeratin 
COPD 
Chronic Obstructive Pulmonary Disease 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTA 
CTCAE 
Clinical Trial Agreement 
 Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
ECG 
eCRF 
Electrocardiogram 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ELF 
Enhanced Liver Fibrosis Score 
EPA 
Eicosapentanoic Acid 
Gamma GT 
Gamma Glutamyl Transferase 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
IL- 
IPF 
International Conference on Harmonisation 
Interleukin- 
Idiopathic Pulmonary Fibrosis 
INR 
International Normalised Ratio 
ISF 
Investigator Site File 
LC-MS/MS 
Liquid Chromatography Tandem Mass Spectrometry 
LPS 
Lipopolysaccharide 
LSLV 
Last Subject Last Visit 
MCP-1 
Monocyte Chemoattractant Protein-1 
MDF 
Maddrey's Discriminant Function 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MELD 
MHRA  
m-SOFA 
NAFLD 
NAS 
NASH 
NFS 
Model End-stage Liver Disease 
Medicines and Healthcare products Regulatory Agency  
Modified Sequential Organ Failure Assessment 
Non-Alcoholic Fatty Liver Disease 
NAFLD Activity Score 
Non-Alcoholic Steatohepatitis 
NAFLD Fibrosis Score 
NOAEL 
No Observed Adverse Effect Levels 
OTC 
PBMC 
PI 
PIS 
Over the Counter 
Peripheral Blood Mononuclear Cell 
Principal Investigator 
Patient Information Sheet 
PK 
Pharmacokinetic 
PV CRO 
Pharmacovigilance Contract Research Organisation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SIRS 
Systemic Inflammatory Response Syndrome 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
SUSAR 
TGF-β 
TNF-α 
WOCBP 
Suspected Unexpected Serious Adverse Reaction 
Transforming Growth Factor – Beta 
Tumour Necrosis Factor – Alpha 
Women of Child Bearing Potential 


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1 INTRODUCTION 
1.1 
Therapeutic Area and Disease Background 
Alcoholic hepatitis (AH) is a clinical condition characterised by jaundice accompanied by elevated 
levels of serum aspartate transaminase (AST). Excessive alcohol consumption is a precursor to the 
condition (Crabb et al. 2016). AH is a major cause of hospitalisation due to liver-related conditions 
in those with a history of heavy alcohol intake, also a condition prominently associated with 
repeated hospitalisations (Sanyal & Gao. 2015). Excessive consumption of alcohol is the third 
leading preventable cause of death in the United States. Regular alcohol consumption can lead to 
hepatic steatosis, which eventually progresses to steatohepatitis, fibrosis and cirrhosis. In up to 
40% of patients, severe acute alcoholic hepatitis has a mortality rate of six months (Lavallard et al. 
2011).  AH or alcoholic steatohepatitis (ASH) as its histological equivalent occurs in up to 35% of 
excessive alcohol consumers and is often a precursor of cirrhosis (Menachery & Duseja 2011). 
However, the severe acute form of AH - as evaluated in this study - is a rare, acute liver disease 
characterised by self-sustained inflammation of the liver, often leading to multi organ failure with 
a mortality exceeding 30% (Mark Thursz et al, STOPAH Trial, 2015) 
 
AH is diagnosed by patient history and anamnesis, observation of rapid onset of high bilirubin 
values, AST>ALT (and both <500) and may be histologically confirmed by liver biopsy (ASH). The 
condition is always accompanied by different degrees of fibrosis of the liver. Severe acute 
decompensated AH may also include such hallmarks as macrovesicular steatosis together with 
neutrophil infiltration, hepatocyte injury and Mallory-Denk bodies. The presence of 
megamitochondria, satellitosis and cholestasis is also often observed (Crabb et al. 2016). If left 
untreated, severe acute decompensated AH can progress to multiorgan failure, sepsis and death. 
 
1.2 
Standard Treatment 
The current standard-of-care treatment for AH includes prednisolone, a corticosteroid which 
works by altering the balance of cytokines, reducing pro-inflammatory cytokines, e.g. tumour 
necrosis factor-α (TNF-α), and increasing anti-inflammatory cytokines such as interleukin-10 (IL-
10) (Saberi et al. 2016). However, prednisolone is of limited efficacy and has numerous side 
effects (Crabb et al. 2016); in the presence of infection, steroids are contraindicated (Sanyal & 
Gao. 2015) and is often replaced by pentoxyphilline. This and other treatments for severe AH 
have not consistently shown a survival benefit (Crabb et al. 2016). 
 
Patients suffering with severe acute decompensated AH often present as malnourished. 
Nutritional supplementation is also provided as a primary treatment for AH and, in some studies, 
has been seen to facilitate equal, if not better, survival compared to treatment with 
corticosteroids (Morgan. 2007). 
 
There is an obvious unmet need for advanced treatment in this life threatening indication. 
 
1.3 
Drug Class 
DS102 is an endogenously occurring fatty acid 15-hydroxy-eicosapentaenoic acid ethyl ester (15- 
HEPE EE). 
 
 
 
 


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Figure 1. Structure of 15(S)-HEPE EE (DS102) 
 
 
1.4 
Preclinical Pharmacology 
A number of in vitro and in vivo mechanistic studies were performed by the company to elucidate 
the pharmacology of DS102 (DS-PC-17, DS-PC-18, DS-PC-21, DS-PC-22, DS-PC-23, DS-PC-26, DS-
PC- 27, DS-PC-28, DS-PC-29, and DS-PC-32). 
 
DS102 has been shown (Table 1) to be significantly anti-apoptotic in a staurosporin model of 
apoptosis. The anti-inflammatory effects of DS102 were illustrated in a model of 
lipopolysaccharide (LPS) induced inflammation in peripheral blood mononuclear cells (PBMCs) 
showing a significant decrease in tumour necrosis factor-α (TNF-α), IL-6, IL-8 and IL-23. Anti-
fibrotic effects of DS102 were observed in TGF-β treated fibroblasts isolated from idiopathic 
pulmonary fibrosis (IPF) patients, reducing the production of fibrotic markers collagen and α–
smooth muscle actin (α-SMA). DS102 also showed varying degrees of peroxisome proliferator-
activated receptor (PPAR) activation in human PPAR reporter cells. DS102 has therefore been 
shown to have a pleiotropic mechanism of action including key anti-inflammatory and anti-
fibrotic mechanisms involved in the pathogenesis of AH. 
 
Table 1: DS102 Mechanism of Action Summary 
 
Investigation of DS102 in the pathological progression of non-alcoholic steatohepatitis (NASH) 
was performed in an established NASH preclinical model (STAM™) sponsored by the company. As 


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it is postulated that pathophysiologically AH is in principle an accelerated form of NASH, it can be 


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assumed that results from this study can also be used to expand upon knowledge of DS102 in the 
pathological progression of AH. 
 
A subcutaneous injection of streptozotocin was administered to newborn mice followed by a 
high fat diet from four weeks of age. Results presented below represent overall outcomes from 
four studies performed. NAS score (NAFLD Activity Score) is separated into three components: 
steatosis, lobular inflammation and hepatocyte ballooning. Light arrows signify a decrease. 
Dark arrows signify a statistically significant difference in the extent of decrease. 
 
Figure 2: Schematic summarising the results of four in vivo studies performed using the STAM™ Model (DS- 
PC-26, DS-PC-27, DS-PC-28, and DS-PC-29). 
 
 
Treatment with DS102 at 500mg/kg significantly decreased plasma ALT, a liver injury marker, and 
plasma TGF-β, a marker of fibrosis progression. Histological analysis showed DS102 also 
significantly decrease NAFLD activity score (NAS). The improvement of NAS was attributable to 
the reduction in the lobular inflammation and hepatocellular ballooning scores. It also showed its 
efficacy in liver fibrosis of STAM™ mice. The treatment reduced the pathological deposition of 
collagen (perisinusoidal fibrosis) in the liver as demonstrated by Sirius red staining. 
 
The above results suggest that DS102 has potential hepatoprotective and anti-inflammatory 
effects against steatohepatitis. Recent research has linked fibrosis, as well as bilirubinostasis, with 
a poor outcome of AH (Sanyal & Gao. 2015). The reduction of fibrosis area suggests that DS102 
treatment could contribute to achieve a better prognosis in AH. 
 
The in vitro and in vivo studies performed to date illustrate the hepatoprotective, anti-
inflammatory and anti-fibrotic mechanisms of DS102 and supports its development as a 
compound to treat AH. 


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1.5 
Toxicology 
A number of good laboratory practice (GLP) toxicology studies were performed by the company to 
assess the safety of DS102 (CRL-527943, 527959, 529139, 529123). Daily administration of DS102 
up to 2000mg/kg/day for four weeks to rats and dogs was deemed well tolerated and safe. The no 
observed adverse effects levels (NOAEL) for repeated dosing over four weeks in both species was 
2000 mg/kg/day. The company recently completed a nine month dog and six month rat study; 
both studies concluded that administration of DS102 was well-tolerated with a NOAEL of 
1000mg/kg/day. 
 
1.6 
Previous Clinical Safety Studies with 15(S)-HEPE 
The company sponsored a phase I study, DS102A-01 (EudraCT 2015-001153-33), a first in man 
study conducted in healthy volunteers, to assess the safety, pharmacokinetics and effect of food 
on orally administered DS102. DS102 (15(S)-HEPE EE) was administered to healthy volunteers in 
the following regimens: a single dose of 100mg, 500mg, 1000mg, or 2000mg under fasted 
conditions; a single 500mg dose under two fed conditions (standard diet and high fat diet); and as 
multiple doses of 500mg, 1000mg or 2000mg taken once daily for 28 consecutive days in a fasted 
state. In this study, 57 subjects (male and female) aged 18 to 45 years were enrolled with eight 
subjects (at least three males and three females per cohort) in each cohort. Subjects in each 
cohort were randomised in a ratio of 3:1 to receive either DS102 or placebo. Cohorts were 
commenced in a sequential manner starting with the 100mg, 500mg and 1000mg single dose 
cohorts in parallel and progressing to higher doses and multiple doses following evaluation by a 
safety monitoring committee (SMC). 
 
This first in man study showed that DS102 overall had an excellent safety profile, a short 
elimination half-life of approximately two hours and a Tmax of approximately four to eight hours. 
Results across dose levels studied showed high variability in the single and multiple dose cohorts 
and did not show a linear correlation between increasing dose and that of systemic exposure. The 
study demonstrated that administration with food increased the bioavailability of 15(S)-HEPE, as 
mean plasma concentrations of 15(S)-HEPE were higher under fed conditions compared to fasted 
conditions. There was no difference in bioavailability between normal and high fat diet fed 
conditions. DS102 was safe and well-tolerated in healthy subjects in this study with no serious 
adverse events (SAEs) reported. 
 
The company is currently recruiting patients for two phase II studies, DS102A-02 (EudraCT 2016- 
000311-33), to assess the safety and efficacy of orally administered DS102 in NAFLD patients at 
doses of 1000mg or 2000mg per day, with placebo as a comparator and DS102A-03 (EudraCT 
2016-002853-39), to assess the safety and efficacy of orally administered DS102 in COPD patients 
at doses of 1000mg or 2000mg per day, with placebo as a comparator. To date, DS102 has been 
well-tolerated with no related SAEs reported. 
 
2 
RISK BENEFIT ASSESSMENT 
The company has shown potentially beneficial effects of DS102 in clinical endpoints relevant for 
the treatment of AH, namely reduction of ALT and fibrosis in a number of preclinical mechanistic 
studies. To date, toxicological studies demonstrate good tolerability of the drug substance in 


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doses of up to 2000mg/kg in two species. The phase I study conducted in healthy volunteers 
demonstrated DS102 to be safe and well-tolerated with no SAEs reported over a 28 day dosing 
period, as has the ongoing phase II study in which DS102 is administered for a 16 week 
treatment period (blinded data). 
 
Based on the data summarised above a favourable safety profile may be postulated which, in 
combination with the potential therapeutic effect of DS102 in a disease that currently lacks 
effective therapies, gives a positive risk-benefit ratio for the conduct of a Proof of Concept Study 
with DS102 in patients suffering from severe acute decompensated AH. 
 
 
The burden for patients in this study is minimised by ensuring standard of care is delivered to all 
patients and supportive care including nutritional support is available. 
The target population of the study are at high risk of mortality and significant morbitity. Without 
experimental treatments that offer an opportunity to improve outcomes, patients with severe 
AH have a very poor prognosis. 
 
3 
RATIONALE FOR THE STUDY 
The postulated mode of action of DS102 covering all relevant pathophysiological features of 
severe acute decompensated AH together with a preclinically and clinically clean safety profile 
of the compound makes DS102 an ideal candidate to evaluate clinically the effects of DS102 in 
this life threatening disease, for which no established treatment is available. 


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4 
STUDY OBJECTIVES 
Efficacy Objective: 
• To compare the efficacy of orally administered DS102 versus placebo, in the treatment of 
adult patients with severe acute decompensated AH. 
 
Safety Objective: 
• To compare the safety of orally administered DS102 in the treatment of adult patients with 
severe acute decompensated AH. 
 
Pharmacokinetic Objective: 
• To evaluate the PK of 15(S)-HEPE following orally administered DS102 capsules, in six adult 
patients with severe acute decompensated AH in an initial pilot phase of the study, followed by 
trough level assessment of 15(S)-HEPE in all study participants. 


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5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
 
• 
Percentage change in MELD score from baseline to Day 28 
 
5.2 
Secondary Endpoints 
 
• 
Change in total bilirubin from baseline to Day 7, 14, 21 and 28 
• 
Proportion of patients showing a 25% reduction of bilirubin at day 7, 14, 21, and 28. 
• 
Change in serum Cytokeratin18-M30/M65 from baseline to Day 7, 14, 21 and 28 
• 
Change in AST levels from Baseline to Day 7, 14, 21 and 28 
• 
Change in AST:ALT ratio from Baseline to Day 7, 14, 21, 28 
• 
Change in MDF score from baseline to Day 7, 14, 21 and 28. 
• 
Proportion of patients showing a 25% reduction in MELD score from baseline to Day 7, 14 
and 21 
• 
Change in m-SOFA from baseline to Day 7, 14, 21 and 28 
• 
Proportion of patients with a 2-point worsening of m-SOFA from baseline at Day 7, 14, 21 
and 28 
• 
Change in hepatic encephalopathy as assessed by West Haven criteria, from baseline at Day 
7, 14, 21 and 28 from baseline to Day 28 
• Incidence of acute kidney injury over 28 days (defined by requiring medicinal or mechanical 
support) 
• Incidence of variceal haemorrhage, ascites or hepatic encephalopathy over 28 days 
 
5.3 
Exploratory Endpoints 
 
• 
Survival at day 7, 14, 21, 28 and 90 using Kaplan-Meier Plot 
• 
Change in GT from baseline to Day 7, 14, 21 and 28 
• 
Change in ALT from baseline to Day 7, 14, 21 and 28. 
• 
Change in Child Pugh score from baseline to Day 7, 14, 21 and 28 
• 
Change in APACHE-II score from baseline to Day 7, 14 and 28 
• 
Change in Lille score from baseline to Day 7, 14 and 28 
 
5.4 
Safety Endpoints 
• 
Treatment emergent (S)AEs and SUSARs 


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6 
STUDY DESIGN 
 
6.1 
General 
This is a randomised, placebo-controlled, double-blind, parallel group, multicentre, exploratory 
phase II study preceded by an open label pilot phase to investigate the efficacy and safety of 
orally administered DS102 capsules in patients with acute decompensated AH aged over 18 
years. 
 
After the completion of the open-label phase of the study the DSMB will evaluate the safety and 
pharmacokinetic data and might recommend a dose adjustment for the double blind 
randomised phase of the study 
 
After the open-label pilot phase of the study during which six patients will be enrolled, two 
parallel groups of patients will be enrolled into the randomised double-blind phase of the study 
to compare one dose of DS102 with placebo over a 28 day treatment period. Patients will 
receive standard of care therapy in addition to their assigned IMP throughout the treatment 
period of the study. It is planned that 120 evaluable patients, 60 per treatment group, will be 
randomised. 
 
Both parts of the study, the open label phase and the double blind phase of the study consist of 
a screening period of up to five days (at the discretion of the investigator), a 28 day treatment 
period and a follow up period until day 90 after start of treatment. Screening is to commence 
upon admission to hospital; at the screening visit, after giving informed consent to participate, 
patients will be assessed using the screening examinations. 
 
A schematic diagram of the overall timeframe of the study is given in Figure 3. 
 
Figure 3: Study Outline 
 


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Any medication or therapeutic intervention deemed necessary for the patient, and which, in the 
opinion of the Investigator, do not interfere with the safety and efficacy evaluations, may be 
continued. 
 
Before the comparative treatment period can commence, patients will complete a baseline 
assessment of their disease and eligible patients will be randomly allocated to one of the two 
parallel group treatment regimens in a 1:1 randomisation ratio: 
 
 
Treatment group A: 2 x placebo 500mg capsules orally administered twice a day (BD) 
(four capsules daily) for 28 days 
 
Treatment group B: 2 x DS102 500mg capsules orally administered BD (four 
capsules daily) for 28 days 
 
To maintain the double-blind conditions, the DS102 capsule and placebo capsule will be identical 
in appearance. 
 
6.2 
Rationale for Study Design and Dose Selection 
The study is randomised, placebo-controlled, and double-blinded to minimise bias during the 
safety and efficacy assessments, preceded by an open label pilot treatment phase to gather 
pharmacokinetic information in severely impacted patients. 
 
The study consists of a treatment period of 28 days and was designed in order to assess the 
safety and efficacy of dosing of DS102 BD (total daily dose of 2000mg) in patients with acute 
decompensated AH. 
 
Studies in rats and dogs treated for up to 26 weeks and 39 weeks respectively have 
demonstrated 15-HEPE EE did not indicate any significant toxicity and resulted in a NOAEL of 
1000 mg/kg/day in both species (CRL-529123, 529139). This information along with the FDA and 
EMA guidance on first in man study dose calculation and pre-clinical studies formed the basis for 
the dose selection in the phase I trial. 
 
Doses of up to 2000mg were administered QD for 28 days in the phase I trial to healthy 
volunteers. The results from the phase I trial indicate that DS102 was safe and well tolerated. 
The pharmacokinetic profile of the DS102 seen in the phase I trial indicated that administration 
with food increased the bioavailability of 15(S)-HEPE. An ongoing phase II study includes dosing 
of up to 2000mg per day with or after food and so far, has shown DS102 to be safe and well 
tolerated with no related SAEs. The dose selection in this trial is therefore based on the phase I 
trial and ongoing phase II trial and the intention to characterise the safety and efficacy of up to 
2000mg per day given in divided doses with or after food to patients with acute decompensated 
AH. A dose adjustment may be decided based on the pharmacokinetic and safety data deriving 
from the open label phase of the study. 


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7 
PATIENTS AND SCREENING 
In order to participate in this study the patients must meet all inclusion criteria and must not 
meet any of the exclusion criteria. Inclusion in the trial starts with the informed consent 
signature. The inclusion and exclusion criteria are to be verified at the screening visit (Visit 1) 
and at the start of treatment/baseline visit (Visit 2). Patient history of alcohol abuse for at least 
six months must be documented at enrolment. 
 
7.1 
Source of Patients 
The study population will consist of male and female patients diagnosed with severe acute 
decompensated AH aged 18 years and over. 
 
7.2 
Inclusion Criteria 
1. Male or female patients aged 18 years and older 
2. Total bilirubin of ≥ 5 mg/dl (85μmol/l) 
3. Patients with definite or probable AH 
4. MELD ≥18 at baseline visit 
5. MDF ≥32 at baseline visit 
6. AST >50 U/L 
7. AST`:ALT ratio > 1.5 
8. Female patients, or female partners of male patients, of child bearing potential must use 
highly effective birth control methods or have a sterilised partner for the duration of the 
study. Highly effective birth control methods are defined as methods that can achieve a 
failure rate of less than 1% per year when used consistently and correctly. Such methods 
include intrauterine device or sexual abstinence. 
Note: A woman is considered of child bearing potential (WOCBP), i.e. fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent 
sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy  
Note: Hormonal contraceptives are contraindicated in patients with severe hepatic diseases 
and are not acceptable as a birth control method in this study 
Note: Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject 
9. Patient and/or legally authorised representative must provide informed consent 
10. Able to swallow the provided study medication 
11. Not eligible for liver transplant during this hospitalisation 
 
 
7.3 
Exclusion Criteria 


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1. Pregnant or lactating females. 
2. Spontaneous liver function improvement defined by decrease of bilirubin level and MDF of 
>10% within 5 days of hospital admission 
3. Grade 4 hepatic encephalopathy (West Haven Criteria) 
4. Type 1 hepatorenal syndrome (HRS) or a serum creatinine >2 x ULN or the requirement for 
haemodialysis 
5. History of hypersensitivity to any substance in DS102 capsules or placebo capsules. 
6. Alcohol abstinence of >6 weeks prior to screening 
7. Duration of clinically apparent jaundice >3 months prior to baseline 
8. Other causes of liver disease including: 
a. Evidence of chronic viral hepatitis (Hepatitis B DNA positive or HCV RNA positive) 
b. Biliary obstruction 
c. Hepatocellular carcinoma 
d. Wilsons disease 
e. Budd Chiari Syndrome 
f. 
Non-alcoholic fatty liver disease 
9. History of or active non-liver malignancies other than curatively treated skin cancer (basal 
cell or squamous cell carcinomas). 
10. Previous entry into the study 
11. AST >400 U/L or ALT >270 U/L 
12. Treatment with any experimental drug within 30 days prior to Day 0 visit (Baseline), or 5 
half-lives (whichever is longer). 
13. Patients who have used dietary supplements rich in omega-3 oromega-6 fatty acids in the 
four weeks prior to baseline. 
14. Patients dependent on inotropic support (adrenaline or noradrenaline), including 
Terlipressin 
15. Active variceal haemorrhage on this admission requiring more than 2 units of blood 
to maintain haemoglobin level within 48 hours 
16. Presence of refractory ascites 
17. Untreated or unresolved sepsis 
18. Patients with cerebral haemorrhage, extensive retinal haemorrhage, acute myocardial 
infarction (within last 6 weeks) or severe cardiac arrhythmias (not including atrial fibrillation) 
19. Known infection with HIV at screening. 
20. Significant systemic or major illnesses other than liver disease that, in the opinion of the 
investigator, would preclude or interfere with treatment with DS102 and/or adequate follow 
up. 
21. Previous liver transplantation 
 
7.4 
Screening and Consent 


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The Investigator will maintain a Patient Screening Log to collect information on all patients who 
sign an Informed Consent Form (ICF) regardless of whether or not they meet the study eligibility 
criteria following completion of the screening evaluations. After completion of screening, all 
patients deemed eligible to take part in this study will be entered onto an enrolment log. 
 
For information on the consent process, refer to Section 13.2 
 
7.5 
Withdrawal of Patients 
Patients have the right to withdraw from the study at any time for any reason, without 
repercussion. The Investigator must explain this to the patient and that this will in no way 
prejudice their future treatment. The investigator also has the right to withdraw patients from 
the study if she/he feels it is in the best interest of the patient or if the patient is uncooperative 
or non-compliant. It is understood by all concerned that an excessive rate of withdrawal can 
render the study un-interpretable, therefore, unnecessary withdrawal of patients should be 
avoided. Should a patient decide to withdraw, all efforts will be made to complete and report 
the observations, particularly the follow-up examination, as thoroughly as possible. 
 
In the event of patient withdrawal, the Investigator or one of his or her staff members should 
talk to the patient or in case of hospital discharge contact the patient either by telephone or 
through a personal visit to determine as completely as possible the reason for the withdrawal, 
and record the reason in patient’s source document and case report form (CRF). A complete 
final early termination evaluation at the time of the patient’s withdrawal should be made with 
an explanation of why the patient is withdrawing from the study. If the reason for removal of a 
patient is an adverse event (AE) or an abnormal laboratory test result, the principal specific 
event or test will be recorded. 
Please note: the patient is allowed not to give a reason for withdrawal. If this is the case this 
must be recorded as well. 
Patients who discontinue the study before Day 28 visit and are discharged from the hospital will 
be asked to come for an early termination visit as soon as possible and have the assessments 
listed at Day 28 performed. Mortality will be assessed throughout to Day 90. 
 
There will be two main categories for withdrawals from the study: “complete withdrawal” and 
“withdrawals from investigational product”. 
 
7.5.1 
Complete Withdrawal 
Discontinuation of investigational product and all efficacy and safety evaluations. Standard 
reasons for withdrawing from further participation in the study and from the follow-up visits 
may be: 
 
 
Patient’s decision (withdrawal of consent to participate) 
 
Patient lost to follow-up 
 
7.5.2 
Withdrawals from Investigational Product 


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Discontinuation of investigational product, but continued follow-up visits, including efficacy and 
safety evaluations. Standard reasons for withdrawing from taking further investigational 
product, but continuing follow-up visits and safety evaluations may be: 
 
 
Unacceptable AEs 
 
Patient request 
 
Investigator’s discretion 
 
Intercurrent illness 
 
Pregnancy 
 
Patients who develop Grade 3 or higher National Cancer Institute Common Terminology Criteria 
or Adverse Events (NCI-CTCAE), or who experience a 2-point worsening of m-SOFA criteria, that 
is determined to be possibly or probably attributable to the study drug will be discontinued. 
 
7.6 
Patient Replacement 
Patients who are withdrawn from the study due to AE or lack of efficacy will not be replaced. 
Patients who are withdrawn for lost to follow up may be replaced. 
 
 
7.7 
Protocol Deviations 
 
All protocol deviations will be reviewed by the medical monitor as and when each violation is 
detected. Based on this review, a decision on the patient’s continuation in the trial will be 
reached and this decision will be documented as appropriate. Notification will be made to the 
relevant authorities as required. 
 
If a patient fails eligibility criteria or meets treatment withdrawal criteria then the treatment 
must be withdrawn. 
 
7.8 
Stopping Criteria 
Trial will be stopped if more than one patient has a grade 3 or higher AE on the CTCAE scale in 
any one category that is determined to be possibly or probably attributable to study drug 
(exclusion evaluation of liver function). 


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8 
STUDY CONDUCT 
 
8.1 
Study Schedule 
During the study, 8 visits to the clinic are scheduled after the screening visit (Visit 1): one at the 
start of the comparative treatment period (Baseline/Visit 2) and six in the comparative 
treatment period (Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 
8/Day 28 or Early Termination). 
 
A final safety follow-up visit (Visit 9/Day 90) will be conducted on Day 90. 
 
For patients who discontinue the study early, for whatever reason, the Early Termination visit 
(Visit 8) will be performed. Patients who discontinue the study before Day 28 and are already 
discharged from the hospital will be asked to attend the investigative site as soon as possible 
that assessments scheduled for Visit 8 can be conducted. These patients will be asked also to 
attend a final safety follow-up visit (Visit 9/Day 90). 
 
8.2 
Clinic Visits 
 
A tabulated flow chart of the study is presented in Appendix 1 and 2. 
 
8.2.1 
Screening Visit (Visit 1) 
 
The patient must sign and date the informed consent form (ICF) before any study-specific 
procedures are conducted. 
 
Once informed consent has been obtained, the Investigator will assign a patient screening 
number. The following screening assessments/sample collections will be performed: 
 
• 
Verification of inclusion/exclusion criteria (Sections 7.2 & 7.3) 
• 
Demographic data 
• 
Medical history (as detailed in Section 9.2.1) 
• 
History of alcohol abuse for at least six months documented 
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Liver ultrasound (as detailed in Section 9.2.11) 
• 
Vital signs (blood pressure, heart rate and body temperature)(as detailed in Section 
9.2.4) 
• 
Electrocardiogram (ECG) (as detailed in Section 9.2.3) 
• 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, 
coagulation tests and plasma caeruloplasmin as detailed in Section 9.2.5) 
• 
Virology (as detailed in Section 9.2.6) 
• 
Urinalysis (as detailed in Section 9.2.15) 


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• 
Pregnancy test (as detailed in Section 9.2.7) 
• 
MELD (as detailed in Section 9.1.1) 
• 
MDF (as detailed in Section 9.1.7) 
• 
West Haven criteria assessment (as detailed in Section 9.1.11) 
• 
) 
• 
Total bilirubin (as detailed in Section 9.1.2) 
• 
AST:ALT (as detailed in Section 9.1.3) 
• 
Concomitant medication assessment (as detailed in Section 9.2.10) 
All procedures that are medically necessary should be followed. 
8.2.2 
Treatment Period 
Following completion of a successful screening visit, patients will begin the comparative 
treatment period (28 days). 
 
At the start of the comparative treatment period, after confirmation of continued eligibility, 
patients will be randomly assigned to one of the two treatment regimens. 
 
Patients will take the allocated investigational medicinal product (IMP) to which he/she is 
allocated twice-daily, in the morning and in the evening, within 30 minutes after a meal, 
throughout the comparative treatment period. Each administration of IMP will be recorded in 
the eCRF/hospital records or in a patient diary card, if discharged before day 28 of the study. 
 
Patients who discontinue the study early will have all study procedures scheduled for Visit 8 (see 
Section 8.2.9) performed as soon as possible after patient withdrawal so that all study-related 
information can be recorded. 
 
Counselling on alcohol consumption should be performed during the study. In-study and post- 
discharge referral and intervention will be provided as needed. 
 
8.2.3 
Baseline (Visit 2) 
The following assessments/sample collections will be performed at Baseline/Visit 2: 
 
• 
Verification of inclusion/exclusion criteria (as detailed in Sections 7.2 & 7.3) 
• 
Medical history (as detailed in Section 9.2.1) 
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Vital signs (blood pressure, heart rate and body temperature)(as detailed in Section 
9.2.4) 
• 
ECG (as detailed in Section 9.2.3) 
• 
Pregnancy test(as detailed in Section 9.2.7) 
• 
Pharmacokinetic sampling (as detailed in Section 9.2.8.1) 
• 
Exploratory blood sampling (as detailed in Section 9.2.8.2) 


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• 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, and 
coagulation tests as detailed in Section 9.2.5) 
• 
MELD ( as detailed in Section 9.1.1) 
• 
MDF (as detailed in Section 9.1.7) 
• 
m-SOFA (as detailed in Section 9.1.8) 
• 
APACHE II score(as detailed in Section 9.1.9) 
• 
Total bilirubin (as detailed in Section 9.1.2) 
• 
CK-18 (as detailed in Section 9.1.6) 
• 
AST:ALT (as detailed in Section 9.1.3) 
• 
Child pugh score (as detailed in Section 9.1.5) 
• 
Gamma GT (as detailed in Section 9.1.4) 
• 
West Haven criteria assessment (as detailed in Section 9.1.11) 
• 
Lille score assessment (as detailed in Section 9.1.10) 
• 
Collection of acute kidney injury, ascites and variceal haemorrhage data 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.10) 
Biomarker (as detailed in Section 9.2.8.3) 
In addition, the following assessments of nutritional status will also be performed, with 
nutritional interventions provided where required: 
 
 
BMI 
 
Bedside Subjective Global Assessment (SGA) score (0, 1, 2, and 3). Patients will be 
classified into the following categories: 
 
Well nourished (0) 
 
Mild malnutrition (1) 
 
Moderate malnutrition (2) 
 
Severe malnutrition (3) 
 
If all study entry criteria are satisfied the Investigator will randomise the patient and provide the 
patient with the designated IMP or placebo from one of the patient treatment packs available at 
the site. 
 
The first dose of IMP or placebo will be administered at site once all baseline assessments have 
been completed. The patient will take their second dose of IMP or placebo in the evening of Day 
0. The capsules will then be administered twice-daily. 
 
8.2.4 
Visit 3/Day 3 
The following assessments will be performed: 
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Vital signs (blood pressure, heart rate and body temperature), as detailed in Section 
9.2.4) 


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• 
Pharmacokinetic sampling (as detailed in Section 9.2.8.1) 
• 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, and 
coagulation tests as detailed in Section 9.2.5) 
• 
MELD (as detailed in Section 9.1.1) 
• 
MDF (as detailed in Section 9.1.7) 
• 
m-SOFA (as detailed in Section 9.1.8) 
• 
APACHE II score (as detailed in Section 9.1.9) 
• 
Total bilirubin (as detailed in Section 9.1.2) 
• 
CK-18 (as detailed in Section 9.1.6) 
• 
AST:ALT (as detailed in Section 9.1.3) 
• 
Child pugh score (as detailed in Section 9.1.5) 
• 
Gamma GT (as detailed in Section 9.1.4) 
• 
Collection of acute kidney injury, ascites and variceal haemorrhage data 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.10) 
• 
Biomarker (as detailed in Section 9.2.8.3) 
• 
Lille Score (as detailed in Section 9.1.10) 
• 
West Haven criteria assessment (as detailed in Section 9.1.11) 
 
8.2.5 
Visit 4/Day 5 
The following assessments will be performed: 
 
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Vital signs (blood pressure, heart rate and body temperature), as detailed in Section 
9.2.4) 
• 
Pharmacokinetic sampling (as detailed in Section 9.2.8.1) 
• 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, and 
coagulation tests as detailed in Section 9.2.5) 
• 
MELD ( as detailed in Section 9.1.1) 
• 
MDF (as detailed in Section 9.1.7) 
• 
m-SOFA (as detailed in Section 9.1.8) 
• 
APACHE II score (as detailed in Section 9.1.9) 
• 
Total bilirubin (as detailed in Section 9.1.2) 
• 
CK-18 (as detailed in Section 9.1.6) 
• 
AST:ALT (as detailed in Section 9.1.3) 
• 
Child pugh score (as detailed in Section 9.1.5) 
• 
Gamma GT (as detailed in Section 9.1.4) 
• 
AE assessment (as detailed in Section 11) 
• 
Collection of acute kidney injury, ascites and variceal haemorrhage data 
• 
Concomitant medication assessment (as detailed in Section 9.2.10) 
• 
West Haven criteria assessment (as detailed in Section 9.1.11) 


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• 
Biomarker (as detailed in Section 9.2.8.3) 
• 
Lille Score (as detailed in Section 9.1.10)


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8.2.6 
Visit 5/Day 7 
The following assessments will be performed: 
 
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Vital signs (blood pressure, heart rate and body temperature), as detailed in Section 
9.2.4) 
• 
Pharmacokinetic sampling (as detailed in Section 9.2.8.1) 
• 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, and 
coagulation tests as detailed in Section 9.2.5) 
• 
MELD ( as detailed in Section 9.1.1) 
• 
MDF (as detailed in Section 9.1.7) 
• 
m-SOFA (as detailed in Section 9.1.8) 
• 
APACHE II score (as detailed in Section 9.1.9) 
• 
Total bilirubin (as detailed in Section 9.1.2) 
• 
CK-18 (as detailed in Section 9.1.6) 
• 
AST:ALT (as detailed in Section 9.1.3) 
• 
Child pugh score (as detailed in Section 9.1.5) 
• 
Gamma GT (as detailed in Section 9.1.4) 
• 
West Haven criteria assessment (as detailed in Section 9.1.11) 
• 
Lille score assessment (as detailed in Section 9.1.10) 
• 
Collection of acute kidney injury, ascites and variceal haemorrhage data 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.10) 
• 
Biomarker (as detailed in Section 9.2.8.3) 
 
8.2.7 
Visit 6/Day 14 
The following assessments will be performed: 
 
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Vital signs (blood pressure, heart rate and body temperature), as detailed in Section 
9.2.4) 
• 
Pharmacokinetic sampling (as detailed in Section 9.2.8.1) 
• 
Exploratory blood sampling (as detailed in Section 9.2.8.2) 
• 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, and 
coagulation tests as detailed in Section 9.2.5) 
• 
MELD ( as detailed in Section 9.1.1) 
• 
MDF (as detailed in Section 9.1.7) 
• 
m-SOFA (as detailed in Section 9.1.8) 
• 
APACHE II score(as detailed in Section 9.1.9) 
• 
Total bilirubin (as detailed in Section 9.1.2) 


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• 
CK-18 (as detailed in Section 9.1.6) 
• 
AST:ALT (as detailed in Section 9.1.3) 
• 
Child pugh score (as detailed in Section 9.1.5) 
• 
Gamma GT (as detailed in Section 9.1.4) 
• 
West Haven criteria assessment (as detailed in Section 9.1.11) 
• 
Lille score assessment (as detailed in Section 9.1.10) 
• 
Total bilirubin (as detailed in Section 9.1.2) 
Pregnancy Test (as detailed in Section 9.2.7) 
• 
Collection of acute kidney injury, ascites and variceal haemorrhage data 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.10) 
• 
Biomarker (as detailed in Section 9.2.8.3) 
 
For discharged patients, the IMP or placebo will be returned and further IMP or placebo will be 
supplied to the patient. The patient should take their next dose of IMP or placebo as soon as all 
visit assessments have been completed. The capsule will continue to be administered twice- 
daily. 
 
In addition, the following assessments of nutritional status will also be performed, with 
nutritional interventions provided where required: 
 
 
BMI 
 
Bedside Subjective Global Assessment (SGA) score (0, 1, 2, and 3). Patients will be 
classified into the following categories: 
 
Well nourished (0) 
 
Mild malnutrition (1) 
 
Moderate malnutrition (2) 
 
Severe malnutrition (3) 
 
8.2.8 
Visit 7/Day 21 
 
The following assessments will be performed: 
 
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Vital signs (blood pressure, heart rate and body temperature), as detailed in Section 
9.2.4); 
• 
Pharmacokinetic sampling (as detailed in Section 9.2.8.1) 
• 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, and 
coagulation tests as detailed in Section 9.2.5) 
• 
MELD ( as detailed in Section 9.1.1) 
• 
MDF (as detailed in Section 9.1.7) 


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• 
m-SOFA (as detailed in Section 9.1.8) 
• 
APACHE II score (as detailed in Section 9.1.9) 
• 
Total bilirubin (as detailed in Section 9.1.2) 
• 
CK-18 (as detailed in Section 9.1.6) 
• 
AST:ALT (as detailed in Section 9.1.3) 
• 
Child pugh score (as detailed in Section 9.1.5) 
• 
Gamma GT (as detailed in Section 9.1.4) 
• 
 
• 
Collection of acute kidney injury, ascites and variceal haemorrhage data 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.10) 
• 
Biomarker (as detailed in Section 9.2.8.3) 
• 
Lille score assessment (as detailed in Section 9.1.10) 
• 
West Haven criteria assessment (as detailed in Section 9.1.11) 
 
For discharged patients, the IMP or placebo will be returned and further IMP or placebo will be 
supplied to the patient. The patient should take their next dose of IMP or placebo as soon as all 
visit assessments have been completed. The capsule will continue to be administered twice- 
daily. 
 
8.2.9 
Visit 8/Day 28/Early Termination 
 
The following assessments will be performed: 
 
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Vital signs (blood pressure, heart rate and body temperature), as detailed in Section 
9.2.4); 
• 
ECG (as detailed in Section 9.2.3) 
• 
Pharmacokinetic sampling (as detailed in Section 9.2.8.1) 
• 
Exploratory blood sampling (as detailed in Section 9.2.8.2) 
• 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, and 
coagulation tests as detailed in Section 9.2.5) 
• 
Pregnancy test (as detailed in Section 9.2.7) 
• 
MELD (as detailed in Section 9.1.1) 
• 
MDF (as detailed in Section 9.1.7) 
• 
m-SOFA (as detailed in Section 9.1.8) 
• 
APACHE II score (as detailed in Section 9.1.9) 
• 
Total bilirubin (as detailed in Section 9.1.2) 
• 
CK-18 (as detailed in Section 9.1.6) 
• 
AST:ALT (as detailed in Section 9.1.3) 
• 
Child pugh score (as detailed in Section 9.1.5) 


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• 
Gamma GT (as detailed in Section 9.1.4) 
• 
Biomarker (as detailed in Section 9.2.8.3) 
• 
West Haven criteria assessment (as detailed in Section 9.1.11) 
• 
Lille score assessment (as detailed in Section 9.1.10) 
• 
Collection of acute kidney injury, ascites and variceal haemorrhage data 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.10) 
 
In addition, the following assessments of nutritional status will also be performed, with 
nutritional interventions provided where required: 
 
 
BMI 
 
Bedside Subjective Global Assessment (SGA) score (0, 1, 2, and 3). Patients will be 
classified into the following categories: 
 
Well nourished (0) 
 
Mild malnutrition (1) 
 
Moderate malnutrition (2) 
 
Severe malnutrition (3) 
 
The IMP or placebo will be returned. Further IMP or placebo will not be supplied to the patient. 
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in 62 days at Visit 9 for final assessment. 
 
8.2.10 Visit 9/Day 90/Follow Up 
 
In case of the patient’s survival the following assessments will be performed: 
 
• 
Physical examination (as detailed in Section 9.2.2) 
• 
Vital signs (blood pressure, heart rate and body temperature), as detailed in Section 
9.2.4); 
• 
Samples for clinical laboratory safety tests (haematology, serum biochemistry, and 
coagulation tests as detailed in Section 9.2.5) 
• 
MELD ( as detailed in Section 9.1.1) 
• 
MDF (as detailed in Section 9.1.7) 
• 
m-SOFA (as detailed in Section 9.1.8) 
• 
West Haven criteria assessment (as detailed in Section 9.1.11) 
• 
Lille score assessment (as detailed in Section 9.1.10) 
• 
APACHE II score (as detailed in Section 9.1.9) 
• 
Total bilirubin (as detailed in Section 9.1.2) 
• 
CK-18 (as detailed in Section 9.1.6) 


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• 
AST:ALT (as detailed in Section 9.1.3) 
• 
Child pugh score (as detailed in Section 9.1.5) 
• 
Gamma GT (as detailed in Section 9.1.4) 


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9 
ASSESSMENTS 
 
9.1 
Efficacy Assessments 
9.1.1 
Model for End-Stage Liver Disease 
The model for end-stage liver disease (MELD) is employed in the evaluation of hepatic function 
and the assessment of prognosis. MELD is calculated based on variables including the 
international normalised ratio (INR), serum creatinine, and serum bilirubin. 
 
A MELD score ≥18 (within 24 hours of presentation) is considered a good predictor of 90 day 
mortality in patients with AH. 
 
MELD will be assessed at Visit 1/Screening, Visit 2/Baseline, Visit 3/Day 3, Visit 4/Day 5, Visit 
5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 8/Day 28/Early Termination and Visit 9/Day 
90/Follow up. 
 
9.1.2 
Total Bilirubin 
Total bilirubin concentration is a marker of hepatic function. 
 
Blood samples will be taken to assess total bilirubin at Visit 1/Screening, Visit 2/Baseline, Visit 
3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 8/Day 28/Early 
Termination and Visit 9/Day 90/Follow up. 
 
9.1.3 
ALT, AST, AST:ALT Ratio 
Increased liver enzymes (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) 
are a marker of liver injury and will be assessed at all time points. 
 
Blood sample will be taken to assess ALT, AST, and AST:ALT ratio at Visit 1/Screening, Visit 
2/Baseline, Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 8/Day 
28/Early Termination and Visit 9/Day 90/Follow up. 
 
9.1.4 
Gamma Glutamyl Transferase 
Gamma glutamyl transferase (GGT) is a liver enzyme indicative of liver dysfunction and alcohol 
intake. 
 
Gamma GT levels will be assessed as part of serum biochemistry at Visit 2/Baseline, Visit 3/Day 
3, Visit 4/ Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 8/Day 28/Early Termination 
and Visit 9/Day 90/Follow up. 
 
9.1.5 
Child-Pugh Score 
The Child-Pugh score is a means of assessing the severity of chronic liver disease, including 
cirrhosis, based on five clinical parameters, each of which is allocated a score; total score 
indicates the severity and prognosis of chronic liver disease. 


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Table 1: Child-Pugh Score (Jackson & Gleeson 2010) 
 
Factor 
1 point 
2 points 
3 points 
Bilirubin (µmol litre−1) 
< 34 
34–50 
< 50 
Albumin (g litre−1) 
> 35 
28 – 35 
< 28 
INR 
< 1.7 
1.7 – 2.2 
> 2.2 
Ascites 
None 
Controlled 
Refractory 
Hepatic encephalopathy 
None 
I – II or controlled 
III – IV or refractory 
 
Blood samples will be taken to assess the Child-Pugh score at Visit 2/Baseline, Visit 3/Day 3, Visit 
4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 8/Day 28/Early Termination and Visit 
9/Day 90/Follow up. 
 
9.1.6 
Cytokeratin-18 M30/M65 
Cytokeratin(CK)-18 M30 and M65 are biomarkers of hepatocyte apoptosis and total cell death, 
respectively, and are employed in the detection of fibrosis and steatosis. 
 
Blood samples will be taken to perform this assessment at Visit 2/Baseline, Visit 3/Day 3, Visit 
4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 8/Day 28/Early Termination and Visit 
9/Day 90/Follow up. 
 
9.1.7 
Maddrey Discriminant Function 
The Maddrey discriminant function (MDF) is a measure of liver dysfunction and a method of 
assessing disease severity. 
 
MDF is calculated as follows: 
 
MDF = 4.6 (patient’s PT − control PT) + total bilirubin (mg/dl) 
 
MDF will be assessed at Visit 1/Screening, Visit 2/Baseline, Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 14, 
Visit 7/Day 21, Visit 8/Day 28/Early Termination and Visit 9/Day 90/Follow up. 
9.1.8 
Modified Sequential Organ Failure Assessment 
The m-SOFA score is used in the assessment of disease severity, as well as in predicting outcome 
and is classified as follows: 


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Organ System 
0 
1 
2 
3 
4 
Respiratory 
SpO2/FiO2 
>400 
≤400 
≤315 
≤235 
≤150 
Liver 
No scleral 
icterus or 
jaundice 
Scleral icterus or 
jaundice 
Cardiovascular, 
hypotension 
No hypo- 
tension 
MAP <70 
mm Hg 
dopamine≤5 
or 
dobutamine 
any dose 
dopamine>5 
epinephrine≤0.1 
norepinephrine≤0.1 
dopamine>15 
epinephrine>0.1 
norepinephrine>0. 
1 
CNS, Glasgow 
Coma Score 
15 
13-14 
10-12 
6-9 
<6 
Renal, 
Creatinine mg/dL 
<1.2 
1.2-1.9 
2.0-3.4 
3.5-4.9 
>5.0 
 
m-SOFA will be assessed at Visit 2/Baseline, Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 
14, Visit 7/Day 21, Visit 8/Day 28/Early Termination and Visit 9/Day 90/Follow up. 
 
 
9.1.9 
Acute Physiologic and Chronic Health Evaluation II 
The acute physiologic and chronic health evaluation (APACHE) II score (see appendix 15.3) will 
assess patients for the presence of multiple organ dysfunction and predict mortality by 
generating a point score ranging from 0 to 71 based on twelve physiologic variables, age and 
underlying health. 
 
APACHE II will be assessed at Visit 2/Baseline, Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 
6/Day 14, Visit 7/Day 21, Visit 8/Day 28/Early Termination and Visit 9/Day 90/Follow up. 
 
 
9.1.10 Lille Score 
The Lille score is a composite score which predicts mortality in patients with AH who are not 
responding to steroid therapy. It is based on age, albumin, bilirubin (initial), bilirubin (day 7), 
creatinine and PT; a score of >0.45 identifies 75% of deaths, a score of >0.45 predicts a 6-month 
survival of 25%, and a score of <0.45 predicts survival of 85%. 
 
Lille score will be assessed at Visit 2/Baseline, Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 
6/Day 14, Visit 7/Day 21, Visit 8/Day 28/Early Termination and Visit 9/Day 90/Follow up. 
 
 
9.1.11 West Haven Criteria 
The West Haven Criteria is used to classify the severity of hepatic encephalopathy with a grading 
of 1 – 4, Grade 1 being the least serious with the patient having a trivial lack of awareness to 
Grade 4 in which the patient is in a state of unconsciousness. 


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Grade 
Criteria 
1 
Trivial lack of awareness 
Euphoria or anxiety 
Shortened attention span 
Impaired performance of addition 
2 
Lethargy or apathy 
Minimal disorientation of time or place 
Subtle personality changes 
Inappropriate behaviour 
3 
Somnolence to semi-stupor but responsive to verbal stimuli 
Confusion 
Gross disorientation 
4 
Coma (unresponsive to verbal or noxious stimuli) 
(Ferenci et al. 1998) 
 
West Haven criteria will be assessed at Visit 1/Screening , Visit 2/Baseline, Visit 3/Day 3, Visit 
4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 8/Day 28/Early Termination and Visit 
9/Day 90/Follow up. 
 
 
9.2 
Safety Assessments 
 
9.2.1 
Medical History 
A complete review of the patient’s medical history will be undertaken by the Investigator or 
designee at the Visit 1/Screening and Visit 2/Baseline) to ensure that no exclusion criteria have 
been met.  
 
Any concomitant disease, whether considered relevant for the study or not by the Investigator, 
must be reported in the CRF. The date of diagnosis or duration of the condition should be noted 
where possible. A history of alcohol abuse for > 6 months is key to qualify for the study. 
 
9.2.2 
Physical Examination 
A physical examination, including height and weight, will be performed by the Investigator as 
per the Study Flow Chart (Appendix 1 and 2) at Visit 1/Screening, Visit 2/Baseline, Visit 3/Day 3, 
Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 8/Day 28/Early Termination and 
Visit 9/Day 90/Follow up, in accordance with local practices. 
 
A complete physical examination will be conducted at Visit 2/Baseline. At subsequent visits, the 
examination will be directed by patient symptoms and clinical features i.e., a standard panel of 
body systems will not be assessed unless indicated by patient. For example should the patient 
report to the investigator the presence of ‘rash’ then the skin would be evaluated. It is not 
required that additional body systems are assessed unless clinically warranted. Any abnormal 
results should be recorded in the CRF. Changes in findings of the physical examination compared 
with the baseline examination should be recorded as an AE. 


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9.2.3 
Electrocardiogram 
A 6-lead electrocardiogram (ECG) 10 mm/1 mV, 25 mm/s with a 10 second lead II rhythm strip 
will be recorded at each time point. ECGs will be recorded using the GE Mac 1200 or equivalent 
model. Patients will be rested quietly in a fully supine position for five minutes before the ECG is 
taken. Recordings will be made at Visit 1/Screening, Visit 2/Baseline and Visit 8/Day 28/Early 
Termination. 
Use of a 12-lead ECG is acceptable if no 6-lead ECG is available. 
 
9.2.4 
Vital Signs 
Vital signs measurements will be performed as per the Study Flow Chart (Appendix 1 and 2) at 
Visit 1/Screening, Visit 2/Baseline, Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 
7/Day 21, Visit 8/Day 28/Early Termination and Visit 9/Day 90/Follow up. 
 
Measurements to be taken include: 
- 
Blood pressure: will be performed as supine (after at least five minutes of rest); systolic 
and diastolic blood pressure (in mmHg) will be recorded. 
- 
Heart rate: taken at rest (in bpm). 
- 
Temperature: will be taken as per clinic practice. Temperature and route will be 
recorded in the CRF. 
 
Vital signs measurements will be performed before any blood samples are taken. All new 
findings or changes to previous findings considered clinically significant will be recorded in the 
CRF as an AE if the finding is made after the patient has signed the ICF. 
 
9.2.5 
Clinical Laboratory Safety Tests: Haematology, Serum Biochemistry, and Coagulation  
 
Blood and urine samples will be taken as per the Study Flow Chart (Appendix 1 and 2) for routine 
haematology, serum biochemistry, coagulation. All samples will be analysed in a central 
laboratory. 
 
Haematology: 
Full blood count to include red cell count, haemoglobin, haematocrit, 
white cell count, differential white cell count, platelet count and 
reticulocyte count. 
Serum biochemistry:  
Urea (blood urea nitrogen (BUN)), creatinine, uric acid, total bilirubin, 
indirect and direct bilirubin, sodium, bicarbonate potassium, 
phosphorus, calcium chloride, alkaline phosphatase (ALP), AST, ALT, 
AST:ALT ratio, gamma GT, albumin, total protein, total cholesterol, 
triglycerides, glucose, C-reactive protein (CRP), plasma caeruloplasmin 
(screening only). 
Coagulation: 
PT (prothrombin time), INR and APTT (activated partial prothrombin 
time) 
 
 


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9.2.6 
Virology 
A blood sample will be taken to perform virology tests including human immunodeficiency virus 
(HIV), Hepatitis C and Hepatitis B as detailed in Study Flow Chart (Appendix 1 and 2)  
 
9.2.7 
Pregnancy Test 
For female patients of childbearing potential only, a pregnancy test will be carried out as per the 
Study Flow Chart (Appendix 1 and 2) at Visit 1/Screening, Visit 2/Baseline, Visit 6/Day 14 and 
Visit 8/Day 28/Early Termination. 
 
9.2.8 
Exploratory Blood Sampling 
Details of the volume of blood to be taken, sample preparation and handling are contained in a 
separate laboratory procedures manual. 
 
Laboratory results will be reviewed for clinically significant values by each investigator following 
sample analysis and verification. The report must be signed and dated by the investigator before 
insertion in the eCRF. 
 
Additional blood may be required for repeats of safety laboratory test. 
 
9.2.8.1 
Pharmacokinetic sampling 
Blood samples for pharmacokinetic (PK) analysis will be collected via direct venepuncture as per 
the Study Flow Chart (Appendix 1 and 2) at Visit 2/Baseline, Visit 3/Day 3, Visit 4/Day 5, Visit 
5/Day 7, Visit 6/Day 14, Visit 7/Day 21, and Visit 8/Day 28/Early Termination. 
 
Trough plasma samples will be obtained from all patients (pilot and double blind phases) prior to 
first daily dose on the indicated days. Additional post-dose serial plasma samples will be 
obtained from the six patients on Days 0 and 7 of the preceding pilot phase for full PK 
characterisation at 0.5, 1, 2, 3, 4, 6, 7, 8, 10, and 12 (before next dose) hours post-dose. 
 
A 1 mL blood sample will be taken at each time point. Following centrifugation, plasma samples 
will be split in two and a back-up sample will be handled as specified in Section 9.2.12 and 
described in the laboratory manual. 
 
9.2.8.2 
Exploratory Blood Collection 
Blood for genomic DNA will be collected as per the Study Flow Chart (Appendix 1 and 2) at Visit 
2/Baseline and Visit 6/Day 14 and Visit 8/Day 28/Early Termination and stored for potential gene 
array analysis or additional exploratory testing at a later date. 
 
Blood for essential lipid analysis will be collected as per Study Flow Chart (Appendix 1 and 2) 
atVisit 2/Baseline, Visit 6/Day 14 and Visit 8/Day 28/Early Termination and analysed at a later 
date. 


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9.2.8.3 
Biomarker Blood Collection 
Blood for biomarkers will be collected as per the Study Flow Chart (Appendix 1 and 2) at Visit 
2/Baseline, Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 8/Day 
28/Early Termination and will be stored for later biomarker analysis. 
 
9.2.9 
Adverse Event Assessment 
See Section 11. 
 
9.2.10 Concomitant Medication 
All administered concomitant medications should be recorded throughout the study. 
 
Patients should avoid both during the study and for 4 weeks prior to baseline, ingesting food 
supplements rich in omega-3 or omega-6 fatty acids (e.g., cod liver oil capsules). 
 
9.2.11 Liver Ultrasound 
A liver ultrasound will be conducted at screening which, in conjunction with patient history and 
clinical examination, will eliminate other causes of liver disease including biliary obstruction, 
hepatocellular carcinoma and Budd Chiari syndrome. 
 
9.2.12 Bioanalysis 
Human plasma levels of 15(S)-HEPE will be determined using validated liquid chromatography 
tandem mass spectrometry (LC-MS/MS) methods and conducted at Charles River Laboratories 
Edinburgh Ltd. 
 
9.2.13 Sample Storage, Handling and Shipping 
Sample storage, handling and shipping will be done as per standard operating procedures and as 
specified in the laboratory procedures manual. 
 
9.2.14 Liver Histopathology 
For patients who have liver biopsies as part of their clinical care before and/or during the study, liver 
histopathology results will be reported in the eCRF 
 
9.2.15 Urinalysis 
pH, protein, glucose, blood, ketones, leukocytes, leukocyte esterase, bilirubin, specific gravity, urobilinogen and 
nitrate will be assessed. Reflex micro to be done locally if blood, protein, leukocyte esterase or nitrate/nitrite 
are present. 
 
Note: Urinalysis assessment will be conducted at screening only. 


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10 
INVESTIGATIONAL PRODUCT/INVESTIGATIONAL DRUG 
 
The following medication supplies will be used in the study: 
 
DS102 Capsule: 
Description: 
White, opaque hard-shelled capsule (size 0) containing 500mg of 15-HEPE EE with 5% w/w of 
colloidal silicon dioxide as viscosity modifier. 
 
DS102 Placebo (Paraffin Oil): 
Description: 
White, opaque hard-shelled capsule (size 0) containing equivalent fill weight of liquid paraffin 
with 1% w/w of colloidal silicon dioxide as viscosity modifier. 
 
10.1 Supply, Packaging, Labelling, Handling and Storage 
The study treatment is capsules of 15-HEPE EE or placebo. DS102 (15(S)-HEPE EE) will be 
provided by Afimmune. 
 
DS102 and Placebo capsules will be stored at 2 – 8°C in a secure area (e.g., a locked refrigerator 
or drug storage room), protected from unintended use. 
 
The test materials will be identified by the batch numbers and expiry date. 
 
Labelling, packaging and release will be in accordance with the Clinical Trials Directive 
2001/20/EC and GMP Directive 2003/94/EC as for Investigational Medicinal Products and Annex 
13 of the GMP Guide. Labels will be blinded to the dose and contain the randomisation number. 
In addition, DS102 (15(S)-HEPE EE) and placebo capsules will be labelled with information 
according to local regulations. 
 
10.2 Dosage and Administration 
Patients who fulfil all inclusion and no exclusion criteria may be accepted in the study. Each 
patient must read and sign an ICF prior to any screening procedures being performed. This 
study involves a comparison of DS102 with placebo, administered orally within 30 minutes after 
a meal twice daily for a total duration of 28 days. Patients will also receive standard of care 
therapy in addition to their assigned IMP throughout the treatment period of the study. The 
last study drug administration should occur on the day preceding Visit 6/Day 28/Early 
Termination. 
 
Patients will be randomised to one of the two treatment groups in a 1:1 ratio: 
 
 Treatment group A: 2 x placebo 500mg capsules orally administered BD (four capsules 
daily) for 28 days 


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 Treatment group B: 2 x DS102 500mg capsules orally administered BD (four capsules 
daily) for 28 days 
 
Patients will be required to take the capsules within 30 minutes after a meal. Medication(s) for 
other conditions that are permitted in the study can be taken as usual. 
 
Walleted blister packs will consist of seven days of four capsules. Patients will be instructed to 
take the two capsules from left to right, on the relevant day, as shown below: 
 
 
 
10.3 Duration of Treatment 
Patients will take assigned medication for 28 consecutive days. 
 
10.4 Drug Accountability 
The Investigator is responsible for maintaining accurate records of the study medication 
received initially, the study drug dispensed/used, the returned medication by patients (in the 
case of patients discharged prior to 28 days) and the medication returned to the Sponsor or 
designee for destruction. All study drug accountability forms and treatment logs must be 
retained in the ISF. These records must be available for inspection by the Sponsor, its designees 
or by regulatory agencies at any time. 
 
Used drug boxes/blister packs will be stored safely until destruction and must be accounted for 
by the Investigator. The study monitor will perform drug accountability for all study drug at the 
site and assist in returning study drug, including used and unused study drug, to the Sponsor or 
designee. After verification of the drug accountability by the Sponsor, the Investigator will 
ensure proper destruction or return of the remaining study product. 


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Any study medication accidentally or deliberately destroyed will need to be accounted for. Any 
discrepancies between amounts dispensed and returned will need to be explained. 
 
 


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11 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
11.1 Definitions of Adverse Events 
 
11.1.1 Seriousness 
Adverse Events (AE): 
An AE is defined as any undesirable experience occurring to a patient that has signed the ICF and 
who has taken their first dose of the study drug, whether or not considered related to the 
IMP(s). All AEs must be recorded in the eCRF, defining relationship to IMP and severity. AEs 
should also be recorded by the Investigator in the patient file/notes. 
 
Serious Adverse Events (SAE): 
If a patient experiences a SAE after the first dose of the study drug, the event will be recorded as 
a SAE. 
 
A SAE (experience) or reaction is any untoward medical occurrence that at any dose: 
 
 
results in death 
 
is life-threatening 
 
requires in-patient hospitalisation or prolongation of existing hospitalisation 
 
results in persistent or significant disability/incapacity, or 
 
is a congenital anomaly/birth defect 
 
Note: the term “life-threatening” in the definition of “serious” refers to an event in which the 
patient 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. 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalisation but may jeopardise the patient or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
should also usually be considered serious. 
 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or 
development of drug dependency or drug abuse. 
 
Unexpected Adverse Event (UAE): 
A UAE is defined as an experience not previously reported in the Investigator’s Brochure (IB) or 
similar product information sheet such as the Summary of Products Characteristics (SPC). 


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11.1.2 Severity 
The intensity of an AE is an estimate of the relative severity of the event made by the 
Investigator based on his or her clinical experience. The following definitions are to be used to 
rate the severity of an AE: 
 
 
Mild: the AE is transient and easily tolerated. 
 
Moderate: the AE causes the patient discomfort and interrupts the patient’s usual 
activities. 
 
Severe: the AE causes considerable interference with the patient’s usual activities, and 
may be incapacitating or life-threatening. 
 
11.1.3  Relationship to IMP 
The Investigator will establish causality of the AE to experimental treatment. The Investigator 
should take into account the patient’s history, most recent physical examination findings, and 
concomitant medications. 
 
The following definitions will be used to determine causality of an AE: 
 
 Not related: temporal relationship of the onset of the AE, relative to the experimental 
treatment is not reasonable or another cause can explain the occurrence of the AE. 
 Related: temporal relationship of the onset of the AE, relative to the experimental 
treatment is reasonable, follows a known response pattern to the treatment, and an 
alternative cause is unlikely. 
 
11.1.4 Reporting of AEs and SAEs 
All AEs must be recorded in the eCRF, defining relationship to IMP and severity. 
 
As soon as the Investigator is aware of a potential SAE, he/she should contact the 
pharmacovigilance (PV) contract research organisation (CRO) monitor by phone, fax or e-mail, 
and, in any case, no later than 24 hours after the knowledge of such a case. The contact 
information is provided in the ISF. 
 
At the time of the call, the Investigator must provide, as a minimum requirement, the patient 
number, birth date, nature of the SAE and a preliminary assessment of causality. The 
Investigator should follow-up the initial notification of the potential SAE by faxing a copy of the 
SAE reporting form to the PV CRO at the number provided in the ISF. The faxed SAE reporting 
form should be sent to the PV CRO within 24 hours of knowledge of such a case. 
 
Follow-up information on an existing SAE that is fatal or life-threatening should be reported by 
the Investigator to the PV CRO within five days after the initial report. Where appropriate, 
hospitalisation or autopsy reports should be made available. All SAEs will be followed up until 
resolution (i.e., asymptomatic, stabilization or death). 


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AEs should be reported from the first dose of study drug up to and including the follow up 
period. Following completion of the study, if the Investigator becomes aware of any AE that is 
potentially related to the IMP the Sponsor should be notified. 
 
11.2 Serious Adverse Reactions and Unexpected Adverse Reactions 
 
11.2.1 
Definitions 
Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions. 
 
The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e. the relationship cannot be 
ruled out. 
 
For marketed medicinal products, an adverse reaction is a response to a drug which is noxious 
and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for modification of physiological function. 
 
Unexpected Adverse Reaction: 
An unexpected adverse reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information (e.g. IB for an unauthorised IMP 
or similar product information sheet such as the SPC). 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR): 
A SUSAR is defined as any serious adverse reaction that might be related to the IMP and is 
unexpected according to the definition above. 
 
11.2.2 
Reporting of suspected unexpected serious adverse reactions 
SUSARs will be reported by the PV CRO according to appropriate competent authority and EC 
requirements. SUSARs will be reported to Investigators according to ICH GCP and to local 
regulations. SUSAR reporting to competent authorities and ECs will be performed according to 
local regulations in an unblinded manner. The competent authorities will be notified of all 
SUSARs through the EudraVigilance database. 
 
Fatal and life-threatening SUSARs should be reported by the PV CRO as soon as possible to the 
competent authorities and ECs according to local regulations, and, in any case, no later than 
seven calendar days after knowledge by the PV CRO of such a case. Relevant follow-up 
information on the case will be subsequently communicated within an additional eight days. All 
other SUSARs shall be reported to the competent authorities and ECs according to local 
regulations as soon as possible but within a maximum of fifteen days of first knowledge by the 
PV CRO. 


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11.3 Drug Induced Liver Injury (DILI) 
 
11.3.1 Severe drug-induced liver injury 
Irrespective of perceived causation, in the event of severe drug-induced liver injury (DILI) then 
the investigational drug should be discontinued until the episode is deemed to have resolved. In 
the event the investigational drug is deemed to be the cause of the liver injury then the patient 
should not be re-challenged with the drug. 
 
Potential severe DILI in the study population (severe acute decompensated AH patients with 
impaired baseline liver biochemistry) stipulates evidence of hepatic impairment as 
demonstrated by: 
 
• 
Total bilirubin >2x baseline and ALT and/or AST >3x baseline (confirmed by immediate 
repeat testing) 
• 
Total bilirubin >3x baseline (confirmed by immediate repeat testing) 
• 
ALT and/or AST >5x baseline (confirmed by immediate repeat testing) 
• 
ALT and/or AST >500 U/L (confirmed by immediate repeat testing) 
• 
Alkaline Phosphatase ≥5x baseline 
• 
An increase in MELD score > 10 
• 
Lille score > 0.85 
 
Prompt (within 24 hours) adjudication of events of possible DILI or treatment failure, as listed 
above, will be performed by an independent expert in AH and DILI with recommendations for or 
against drug discontinuation. 
 
Other causal factors should be considered and if found they must be discussed with the sponsor 
before investigational product is restarted. 
 
Even if patients discontinue the investigational drug they should still be encouraged to attend 
study visits for continued study data collection. 
 
 
11.3.2 Monitoring of patients with impaired liver biochemistry 
 
Abnormalities of liver biochemistry indicating evidence of hepatic impairment as listed above 
should be followed by repeat testing within 48-72 hours to confirm/determine if the 
biochemical changes are improving or worsening. AE information should be collected alongside 
a thorough physical examination. A liver aetiology screen and/or other appropriate testing 
should be undertaken. In the event of liver dysfunction then the patient should be managed as a 
severe drug-induced liver injury (see above). Pausing of drug treatment should be considered if 
any of the criteria in the previous section occur. 
 
11.4 Pregnancy Reporting 
If a patient or a patient’s partner becomes pregnant during the study, study staff must be 


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informed as soon as possible. Upon confirmation of the pregnancy, the patient must be 
withdrawn from the study drug but may continue study participation. The Investigator must 
complete a study-specific pregnancy form upon confirmation of a pregnancy and send it to the 
Sponsor within 24 hours of confirmation of the pregnancy. 
 
Post-treatment follow-up should be done to ensure patient safety. Pregnancy itself is not an AE 
or SAE, however maternal/foetal complications or abnormalities will be recorded as AEs or SAEs, 
as appropriate. The Investigator will follow the pregnancy until completion (or until pregnancy 
termination) and notify the Sponsor of the outcome as a follow up to the initial pregnancy form. 


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12 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT 
 
12.1 Study Design 
This clinical trial employs a randomised, double-blind, placebo-controlled 2-arm parallel group 
design preceded by an open-label pilot phase. Randomisation is used to minimise assignment 
bias and to increase the likelihood that known and unknown patient attributes (e.g. 
demographic characteristics) are evenly balanced across the treatment groups. Blinding is used 
to reduce potential bias during data collection and the evaluation of safety and efficacy. The use 
of placebo as a comparator is justified as a reasonable design to assess safety and efficacy in 
patients based on the brevity of the study duration and the absence of any real established 
standard of care for alcoholic hepatitis. A full description of the study design is presented in 
Section 6 above. 
 
12.2 Randomisation 
For the open label pharmacokinetic pilot phase, six patients will be enrolled and treated with 
study drug (2 x DS102 500mg capsules orally administered BD (four capsules daily)), for 28 days. 
Results of this pilot phase will be assessed by a DSMB for safety and if dose adjustments for the 
main study are needed. 
 
For the main, double-blind phase, approximately 120 patients will be randomised into double- 
blind treatment groups in a 1:1 ratio as follows: 
 
 Treatment group A: 2 x placebo 500mg capsules orally administered BD (four 
capsules daily) for 28 days 
 Treatment group B: 2 x DS102 500mg capsules orally administered BD (four capsules 
daily) for 28 days 
 
At the investigational site, each patient will be assigned a patient screening number during 
screening that will be used on all patient documentation. The patient screening number will 
contain the site number and the patient number assigned in numerical order at the screening 
visit (e.g.: 02-010 for the tenth patient screened at the site #02). Numbers will be assigned in 
ascending order starting with 001. 
 
A randomisation list, permuted blocks and stratified by site, will be generated by Afimmune or 
its designee. The randomisation schedule with study drug assignments will be generated prior to 
the start of the study and will be known only to the individuals responsible for labelling the 
study drug, the statisticians generating the schedule and the interactive web response system 
(IWRS) team responsible for implementing the schedule. The IWRS will assign medication kit 
numbers to each patient, as required, at visits and the contents will be based on the 
randomisation code. 


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12.3 Estimation of Sample Size 
Two-Sample T-Tests using Effect Size 
Numeric Results for Two-Sample T-Test 
Alternative Hypothesis: H1: d ≠ 0 
 
Effect 
Target 
Power 
Actual 
Power 
N1 
N2 
N 
Size 
d 
Alpha 
0.80 
0.8036 
100 
100 
200 
0.40 
0.050 
0.80 
0.8002 
90 
90 
180 
0.42 
0.050 
0.80 
0.8045 
83 
83 
166 
0.44 
0.050 
0.80 
0.8044 
76 
76 
152 
0.46 
0.050 
0.80 
0.8051 
70 
70 
140 
0.48 
0.050 
0.80 
0.8015 
64 
64 
128 
0.50 
0.050 
0.80 
0.8065 
60 
60 
120 
0.52 
0.050 
0.80 
0.8014 
55 
55 
110 
0.54 
0.050 
0.80 
0.8074 
52 
52 
104 
0.56 
0.050 
0.80 
0.8030 
48 
48 
96 
0.58 
0.050 
0.80 
0.8037 
45 
45 
90 
0.60 
0.050 
 
 
To discover an effect size of 0.54 (=Difference in means/standard deviation) in MELD change 
from baseline with 80% power, 55 patients per group are necessary under ideal assumptions 
using the t-test for independent samples (alpha=0.05, two-sided). 
 
To take deviations from ideal parametric conditions and drop-outs into account randomisation 
of 60 patients per group is recommended. 
 
12.4 Blinding and Code Breaking Instructions 
All study site personnel, as well as the personnel involved in the monitoring or conduct of the 
study, will be blinded to the individual patient treatment assignments. Randomisation details 
will be kept strictly confidential, accessible only in an emergency to authorised persons, until the 
time of formal unblinding. The blinded code for the trial will be broken only after all patient data 
has been recorded and verified and the database locked. 
 
Emergency unblinding will be performed via the IWRS, with relevant site personnel and PV 
monitors provided with the required system access to carry out unblinding. 
 
12.5 Data Analysis 
Data analysis will be performed at the CRO. All computations will be completed using SAS® 
version 9.1.3 or later. Graphical summaries will be produced using SAS®. A detailed description 
of the analyses to be performed will be provided in the Statistical Analysis Plan (SAP). 
 
 
 


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12.6 Analysis Populations 
Full Analysis Set (FAS): 
Patients will be included in the FAS for analysis of efficacy if they are randomised to the study 
and received at least one dose of study medication. The specific criteria for the FAS will be 
detailed in a separate SAP. Analysis will be done according to treatment as randomised. 
 
Safety Analysis Set (SAS) 
The SAS consists of all patients who received at least one dose of the medication. SAS is the 
analysis population for all safety endpoints. Analysis will be done according to the actual 
treatment patients received. 
 
Pharmacokinetic Population 
The PK population consists of all patients who received at least one dose of study medication. 
 
Per Protocol Set: 
In order to qualify for the Per Protocol Set (PPS), the patients must have followed the study 
protocol without any major protocol deviation. Protocol violations will be assessed for each 
patient in a blinded fashion prior to database lock at a Blind Data Review Meeting (BDRM), and 
the PPS will also be finalised during this meeting. PPS is a supportive analysis population for the 
primary efficacy endpoint. Analysis will be done according to the treatment that patients were 
randomised to. 
 
Total population: 
Any patient who withdraws from the randomised phase of the study will be included in the 
safety analysis (AEs and laboratory parameters). Data for all patients will be listed, and a list of 
withdrawn patients, with all reasons for withdrawal, will be given. 
 
Total population also includes data for those patients who, after having consented to 
participate, underwent screening examinations required for inclusion into the study but who, 
because a criterion for exclusion was met or for other reasons, were not included in the study. 
 
12.7 Safety Analysis 
Demographic information, medical history and physical examination data will be listed for each 
patient and summarised descriptively. 
 
All AEs recorded during the study will be coded to system organ class and preferred terms using 
the current version of the Medical Dictionary for Regulatory Activities (MedDRA). Treatment- 


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emergent AEs will be tabulated and summarised by treatment, relationship to treatment, 
seriousness and severity. Non-treatment emergent AEs will be listed separately. 
 
Clinical laboratory values (haematology, biochemistry, and coagulation) will be listed for each 
patient by treatment and day. Values outside the laboratory normal ranges will be listed 
separately with associated comments as to their clinical significance, with potentially clinically 
significant abnormalities highlighted and summarised by treatment. Clinical laboratory values 
obtained prior to dosing will be defined as baseline values. 
 
Individual values of vital signs will be listed and summarised descriptively for each treatment 
and day. 
 
ECG assessments will be listed for each patient with all associated comments and summarised 
by treatment and day. 
 
Concomitant medications (if any), categorised by medication group and subgroup according to 
the latest version of the World Health Organisation drug dictionary (WHODD), will be listed and 
summarised by treatment. 
 
In general, appropriate descriptive statistics, according to the nature of the variable, will be 
applied. Categorical variables will be presented using counts and percentage, whilst continuous 
variables will be presented using mean, standard deviation, median, minimum, maximum, 
coefficient of variation and number of patients. 
 
 
12.8 Statistical Analysis Plan 
In addition to the summarised analysis outlined below, a separate document, SAP for DS102A- 
05-AH1, will detail all analysis to be performed. 
 
 
12.8.1 Pharmacokinetic Analysis 
PK will be analysed using the following parameters: 
 
Pilot Phase: 
 
Cmax – maximum observed concentration 
 
Tmax - time of maximum observed concentration 
 
AUCt – Area under the concentration-time curve to time t 
 
AUCtau - Area under the concentration-time curve to the end of the dosage interval 
 
AUCinf - Area under the concentration-time curve extrapolated to infinite time 
 
%Extrap – Percentage of AUCinf obtained by extrapolation 
 
Kel – Apparent first-order terminal elimination rate constant 
 
T1/2 – Apparent first-order terminal elimination half-life 


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 
Flucp – Fluctuation at pharmacokinetic steady-state 
 
Rac – Accumulation ratio at pharmacokinetic steady-state 
 
Tss – Time to achieve pharmacokinetic steady-state 
 
Double-Blind Phase: 
 
Rac – Accumulation ratio at pharmacokinetic steady-state 
 
Tss – Time to achieve pharmacokinetic steady-state 
 
12.8.2 Primary Variables 
The primary efficacy variable will be change in MELD score from baseline to Day 28. This change 
in MELD score and its difference between treatment groups will be estimated using a General 
Linear Repeated Measures Model with treatment arm, baseline MELD value, visit and treatment 
arm by visit interaction as factors. The primary analysis will be based on the FAS and repeated 
for the PPS as a supportive analysis. 
 
12.8.3 Secondary variables 
The secondary and exploratory efficacy variables will be summarised with descriptive statistics 
per treatment group and visit. The change from baseline to Day 28 (and other visits) for the 
active treatment group will be compared against placebo either via logistic regression or analysis 
of covariance taking the baseline level as covariate into account. Survival time will be analysed 
using the Cox Proportional Hazards model including treatment group and MELD score at 
baseline as covariate. The 5% level of significance will be used for all treatment comparisons of 
secondary and exploratory endpoints without adjustment for multiplicity. 
 
A new secondary efficacy variable will be a 5-level ordinal variable combining change of MELD 
score from baseline, premature treatment terminations and mortality as follows; each patient 
will be allocated to the first level that occurs 
 
level 1: death within 28 days, 
 
level 2: death within 90 days, 
 
level 3: early treatment termination because of safety issues or lack of efficacy, 
 
level 4: no improvement in Meld Score at day 28 compared to baseline, 
 
level 5: improvement in Meld Score at day 28 compared to baseline 
 
Patients with lost to follow up within 28 days will be allocated to level 4 or 5 according to their 
imputed result at day 28 based on the model in 12.9.2 as for these patients the MAR assumption 
seems appropriate. 
 
This ordinal variable will be analysed using ordinal logistic regression with MELD score as 
baseline covariate (alpha=0.05 two-sided). An odds ratio including 95%-confidence limits will be 
calculated as measure of effect size for this variable. 


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12.9 Data Collection/Electronic Case Report Forms 
Data will be collected using a validated electronic data capture (EDC) solution. eCRFs will be 
utilised for recording data from each patient meeting the eligibility criteria and being 
randomised in the study, and a limited amount of data will be completed for patients who fail to 
meet eligibility criteria (i.e. screen failures). Electronic access to the eCRF will be available to all 
investigator sites. All study staff responsible for entering data into the eCRF system will be 
trained prior to the start-up of the study. A personal log-in will be provided for all responsible 
personnel to allow for an audit trail relating to the study data to be maintained. 
 
All evaluations performed shall be entered in a timely manner into the eCRF by a member of the 
site staff delegated responsibility for this specific task by the Principal Investigator of the clinical 
site. It is the responsibility of the Investigator to ensure that the eCRFs are properly completed. 
The data in the eCRFs should be consistent with the relevant source documents. The 
Investigator will sign the designated signature fields of the eCRF to confirm that the information 
on each screen is accurate and complete. All data must be stored in an unidentifiable form 
treated with strict confidentiality in accordance with applicable data-protection regulations. 
 
Captured data will be monitored electronically and source data verification (SDV) will take place 
at the site where all information will be verified against the individual patient records. Any 
inconsistencies will be presented as queries, either as automatically generated queries if raised 
by the logical data checks of the eCRF system, or by manually generated queries if raised by the 
data validation checks or the SDV performed by the data manager (DM) or the clinical research 
associate (CRA), respectively. Queries shall be resolved in a timely manner by a trained member 
of the site staff. 
 
12.10 Data Management 
Data will be transmitted electronically into the web based EDC system. Data will be coded 
according to pre-specified dictionaries and in accordance with CRO SOPs. The handling of data, 
including data quality control, will comply with all applicable regulatory guidelines. 
 
12.11 Protocol Deviations 
Protocol deviations will be captured through site self-reporting, CRA SDV and data management 
edit checks, and will be recorded by the CRA throughout the study in both monitoring visit 
reports and in a centralised log. 


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13 
REGULATORY AND ADMINISTRATIVE PROCEDURES 
 
13.1 Institutional Review 
Investigators will agree that the study will be conducted according to the principles of the ICH E6 
Guideline on GCP and the ethical principles that have their origins in the World Medical 
Association Declaration of Helsinki. The Investigator will conduct all aspects of this study in 
accordance with all national, state and local laws or regulations. 
 
The protocol and the PIS/ICF will be approved by the relevant competent authorities and ECs, 
and possibly other public bodies according to local requirements, before commencement of the 
study. If a protocol amendment is necessary, this will be prepared with the agreement of the 
national co-ordinating Investigator and signed by the relevant parties. If the amendment is 
considered to be substantial, it will be submitted to the competent authorities and ECs, and 
possibly other public bodies according to local requirements, for review and approval. The 
protocol amendment will not be implemented before such approvals are obtained, if required. 
Minor amendments which do not affect the safety or physical or mental integrity of the clinical 
trial participants or the scientific value of the trial (i.e. non-substantial amendments) do not 
need to be submitted to competent authorities 
 
SUSAR reports and periodic safety reports will be sent to competent authorities and ECs, 
according to local regulations. 
 
13.2 Informed Consent and Inclusion of Subjects Incapable of Providing 
Informed Consent 
It is the responsibility of the Investigator, or a person designated by the Investigator (if 
acceptable to local regulation), to obtain written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives and 
potential hazards of the study. If the patient is incapacitated, e.g. in the case of Grade II or Grade 
III hepatic encephalopathy, a relative (with the exception of certain countries) or legal 
representative will be responsible for giving informed consent on behalf of the patient in 
accordance with the Declaration of Helsinki.  
Additional requirements for representatives giving informed consent for an incapacitated 
patient may apply in certain countries. Investigators in these countries will be notified 
accordingly in a protocol clarification memo and the patient information sheet and informed 
consent will be  adapted.  
Clinical trials are essential to improve the outcomes of subjects with critical illness, such as the 
target population of this study. However, individuals with Severe Acute Alcoholic Hepatitis 
comprise a critically ill patient population in which it may be difficult to obtain robust informed 
consent. The value and generalisability of study results is contingent upon recruitment of a 
representative sample of patients, ensuring that consenting participants and non-consenting 
participants are not systematically different. As a result, it may be necessary that persons who 
are incapable of giving informed consent are included in this study.  
Robust measures are in place to ensure that in such situations informed consent is obtained 


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from an appropriate relative or legal representative. A separate ICF will be used in such cases. 
When a potential research subject who is deemed incapable of giving informed consent is able 
to give assent to decisions about participation in research, the recruiting physician must seek 
that assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent must be respected. 
The patient, or a relative/legal representative, if applicable, will be given the opportunity to ask 
questions to the investigational team. It must also be explained that they are completely free to 
refuse permission to enter the study or to withdraw from it at any time for any reason. Sufficient 
time will be given to consider participation in the study. If, after this, permission is given to enter 
the study, the patient, or relative/legal representative, if applicable, will be asked to sign and 
date one original copy of the written informed consent form (ICF). The patient, or relative/legal 
representative, if applicable, will then receive a copy of the signed and dated patient 
information sheet (PIS)/ICF. The original signed ICF will be filed in the Investigator Site File (ISF). 
The PIS will contain site contact information in case of any questions or medical emergency. 
If, at a later stage, a previously incapacitated patient becomes able to give consent to the study, 
the Investigator, or delegate, must obtain informed consent from the patient for them to 
continue in the study. 
The investigator will constantly assess the level of burden to the patients, and if new safety 
information results in significant changes in the risk/benefit assessment or any new information 
presents that may affect willingness to continue to participate, the consent form should be 
updated and approved, if necessary, by the Research Ethics Committee (REC)/Institutional 
Review Board (IRB). All patients (including those already being treated) should be informed of 
the new information, given a copy of the revised form and asked to give their consent to 
continue in the study. In the case of patients who remain unable to give consent, a relative/legal 
representative will receive the updated information and be asked to give consent for the patient 
to continue in the study. Any written information given to potential patients or relatives/legal 
representatives will be submitted to, and approved by, the respective Ethics Committee(s) (EC) 
prior to implementation. 
 
 
13.3 Data and Safety Monitoring Board 
A data and safety monitoring board (DSMB) will be in place, composed of independent experts, 
to monitor the safety and scientific integrity of the study. The DSMB will periodically review 
accumulated patient data for safety, study conduct and progress and efficacy, and assess the 
potential benefits and risks to the patient. The DSMB also can provide recommendations to the 
sponsor related to the continuation, modification or termination of the study. Details of the 
roles and responsibilities of the DSMB members are regulated in the DSMB charter. 
 
13.4 Good Clinical Practice 
The study will be managed and conducted according to the latest ICH GCP and applicable 
regulatory requirement(s) (specifically the principles of GCP in ICH topic E6, as laid down by the 
Commission Directive 2005/28/EC and in accordance with applicable local laws and guidelines). 
A copy of the ICH guidelines can be found in the ISF. 


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13.5 Essential Documents 
The ICH guideline for GCP lists a number of essential GCP documents required prior to, during, 
and after the conduct of the study. It is the responsibility of the monitor to ensure that the 
Investigator is always provided with a copy of such documents prepared by the study 
management, and it is likewise the responsibility of the Investigator to provide the monitor with 
essential documents prepared by the Investigator or the local EC. A complete list of essential 
GCP documents can be found in the ISF. 


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13.6 Record Retention 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These records 
include, but are not limited to, the identity of all participating patients, all original signed 
informed consent documents, copies of all eCRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition and adequate documentation of relevant 
correspondence. 
 
The records should be retained by the Investigator according to ICH, local regulations, or as 
specified in the clinical trial agreement (CTA), whichever is longest. 
 
13.7 Monitoring/Quality Control 
Monitoring visits will be conducted during the study at regular intervals. Monitoring visits will be 
conducted to ensure protocol adherence, quality of data, accuracy of entries in the eCRF, drug 
accountability, compliance with regulatory requirements and continued adequacy of the 
investigational site and its facilities. 
 
Incorrect or missing entries in the eCRFs will be queried and will be corrected appropriately. 
 
All clinical data will undergo quality control checks prior to clinical database lock. Edit checks will 
then be performed for appropriate databases as a validation routine using SAS® to check for 
missing data, data inconsistencies, data ranges, etc. Each eCRF will be reviewed and signed by 
the PI. 
 
13.8 Quality Assurance 
Investigational sites may be audited during or after the study is completed by Sponsor 
representatives, or regulatory authorities may conduct an inspection. The Investigator(s) will be 
expected to cooperate with such a visit and to provide assistance and documentation (including 
all study documentation, and patient source data), as requested. 
 
13.9 Insurance and Liability 
Insurance and liability for the study is the responsibility of the sponsor, Afimmune. Patient 
insurance is taken out for study participants in accordance with legal requirements. 
 
13.10 End of Trial 
The end of trial is defined as ‘last patient last visit (LPLV)’. LPLV is defined as the date the 
Investigator reviews the last subject’s safety data and determines that no further evaluation is 
required for the subject to complete the trial. 
 
The study will be prematurely terminated should more than one patient experience a Grade 3 or 
higher AE on the CTCAE scale in any one category that is determined to be possibly or probably 
attributable to study drug (excluding evaluation of liver function), or a 2-point worsening of 
modified m-SOFA score if possibly or probably attributable to study drug. 


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13.11 Confidentiality 
All information obtained during the conduct of the study with respect to the patients’ state of 
health will be regarded as confidential. This is detailed in the written information provided to 
the patient. An agreement for disclosure of any such information will be obtained in writing and 
is included in the ICF signed by the patient. The study data shall not be disclosed to a third party 
without the written consent of the Sponsor. 
 
13.12 Report and Publication 
Production of a clinical study report (CSR) in accordance with the ICH guidelines will be the 
responsibility of the CRO. No information from the study will be published without the prior 
written consent of the Sponsor. 


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14 
REFERENCES 
 
Adams et al. 2005. The natural history of nonalcoholic fatty liver disease: a population- 
based cohort study. Gastroenterology. 129:113-121 
 
 
Bays et al. 2011. Eicosapentaenoic acid ethyl ester (AMR101) therapy in patients with 
very high triglyceride levels (from the Multi-center, plAcebo-controlled, Randomized, 
double-blINd, 12-week study with an open-label Extension [MARINE] trial). Am J Cardiol; 
108(5):682-90 
 
 
Braeckman et al. 2013. Icosapent ethyl, a pure EPA omega-3 fatty acid: Effects on 
plasma and red blood cell fatty acids in patients with very high triglyceride levels (results 
from the MARINE study). Prostaglandins Leukot Essent Fatty Acids; 89(4):195-201 
 
 
Brunt EM et al. 1999. Nonalcoholic steatohepatitis: a proposal for grading and staging 
the histological lesions. Am J Gastroenterol; 94:2467 
 
 
Brunt EM et al. 2005. Pathological features of NASH. Frontiers in Bioscience;10:1475 
 
 
Bullock et al. 2004. Association of non-alcoholic steatohepatitis without significant 
fibrosis with hepatocellular carcinoma. J hepatol. 41:685-686 
 
 
Calder 2006. N-3 Polyunsaturated fatty acids, inflammation, and inflammatory diseases. 
Am J Clin Nutr 2006;83(suppl):1505S-19S 
 
 
Crabb DW et al. 2016. Standard Definitions and Common Data Elements for Clinical 
Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic 
Hepatitis Consortia. Gastroenterology. 150(4):785-90 
 
 
CRL-527943. A 4 week study of 15(S)-HEPE EE by oral (gavage) in rats with a 2 week 
recovery period. 
 
 
CRL-527959. A 4 week study of 15(S)-HEPE EE by oral (gavage) in dogs with a 2 week 
recovery period. 
 
 
CRL-529139. A 39 week study of 15(S)-HEPE EE by oral (gavage) in dogs with a 4 week 
recovery period. 
 
 
CRL-529123. A 26 week study of 15(S)-HEPE EE by oral (gavage) in rats with a 4 week 
recovery period. 
 
 
Desbois and Lawlor 2013. Antibacterial activity of longchain polyunsaturated fatty acids 
against Propionibacterium acnes and Staphylococcus aureus. Mar Drugs; 11(11):4544-57 
 
 
Dobo KL, Greene N, Fred C, Glowienke S, Harvey JS, Hasselgren C, Jolly R, Kenyon MO, 
Munzner JB, Muster W, Neft R, Reddy MV, White AT, Weiner S. (2012). In silico methods 


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combined with expert knowledge rule out mutagenic potential of pharmaceutical 
impurities: an industry survey. Regul Toxicol Pharmacol. 62(3):449-55. 
 
 
FDA. 2012. 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202057_vascepa_toc.cfm 
 
 
FDA: Center for Drug Evaluation and Research (CDER): Guidance for Industry: Estimating 
the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers (2005) 
 
 
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic 
encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of 
the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. 
Hepatology. 2002;35:716-21 
 
 
Hillebrecht A, Muster W, Brigo A, Kansy M, Weiser T and Singer T (2011). Comparative 
evaluation of in silico systems for Ames test mutagenicity prediction: scope and 
limitations. Chemical Research in Toxicology 24, 843-54. 
 
 
Jackson, P and Gleeson, D. 2010. Alcoholic liver disease. Continuing Education in 
Anaesthesia Critical Care & Pain; 10(3) 66–71 
 
 
Lavallard VJ, Bonnafous S, Patouraux S, Saint-Paul M-C, Rousseau D, Anty R, et al. (2011) 
Serum Markers of Hepatocyte Death and Apoptosis Are Non Invasive Biomarkers of 
Severe Fibrosis in Patients with Alcoholic Liver Disease. PLoS ONE 6(3): e17599. 
https://doi.org/10.1371/journal.pone.0017599 
 
 
Lee et al. 1991. Effects of dietary fish oil lipids on allergic and inflammatory diseases. 
Allergy Proc; 12(5):299-303 
 
 
Malhotra N, Beaton MD. 2015. Management of non-alcoholic fatty liver disease in 2015. 
World J Hepatol 2015; 7(30): 2962-2967 
 
 
Menachery, J & Duseja, A (2011). Treatment of Decompensated Alcoholic Liver Disease. 
Int J Hepatol. Published online 2011 Jul 12. doi: 10.4061/2011/219238 
 
 
Morgan, TR. 2007. Management of Alcoholic Hepatitis. Gastroenterology & Hepatology. 
3(2):97–99. 
 
 
Nemoto et al. 2009. Ethyl-eicosapentaenoic acid reduces liver lipids and lowers plasma 
levels of lipids in mice fed a high-fat diet. In vivo; 23(5):685-9. 
 
Saberi B, Dadabhai AS, Jang Y-Y, Gurakar A, Mezey E. 2016. Current Management of Alcoholic Hepatitis and 
Future Therapies. J Clin Transl Hepatol. 28; 4(2): 113–122. 
 
Sanyal et al. 2011. Endpoints and clinical trial design for nonalcoholic steatohepatitis. 


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Hepatology. 4(1):344-53 
 
 
Sanyal et al. 2014 No Signiﬁcant Effects of Ethyl-Eicosapentanoic Acid on Histologic 
Features of Nonalcoholic Steatohepatitis in a Phase II Trial. Gastroenterology 
2014;147:377-384 
 
 
Sanyal AJ & Gao B. 2015. Gaps in Knowledge and Research Priorities for Alcoholic 
Hepatitis. Gastroenterology. 149(1):4–9 
 
 
Tsunomori et al. 1995. 15-hydroperoxyeicosapentaenoic acid inhibits arachidonic acid 
metabolism in rabbit platelets more potently than eicosapentaenoic acid. Biochimica et 
Biophysica Acta; 1300(3):171-6. 
 
 
Ziboh et al. 2000. Metabolism of polyunsaturated fatty acids by skin epidermal enzymes: 
generation of anti-inflammatory and anti-proliferative metabolites. Am J Clin Nutr; 71(1 
Suppl):361S-6S. 
 
 
ICH Harmonised Tripartite Guideline: Assessment and Control of DNA Reactive 
(Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk: M7. June 
2014 
 
 
DS-PC-17 (2015). In vivo study to examine the nuclear receptor targets affected by 
administration of 15(S)-HEPE-EE to sprague dawley rats. 
 
 
DS-PC-18 (2015). Activation of human and rat ppar-alpha, delta, gamma nuclear 
receptor activity in vitro by 15(S)-HEPE-EE and EPA-EE. 
 
 
DS-PC-21 (2015). Evaluation of the inhibitory effect of 5 compounds on staurosporine- 
induced caspase 3/7 activity in normal dermal fibroblasts. 
 
 
DS-PC-22 (2015). Effects of 15(S)-HEPE on LPS induced Inflammation. 
 
 
DS-PC-23(2015). Effects of 15(S)-HEPE on TGF-beta induced fibrosis markers. 
 
 
DS-PC-26 (2013). In vivo efficacy study of 15-HETRE, 15-OH EPA and EPA in STAM model 
of non-alcoholic steatohepatitis. 
 
 
DS-PC-27 (2013). In vivo efficacy study of 15-HETRE, 15-OH EPA and EPA in STAM model 
of non-alcoholic steatohepatitis. 
 
 
DS-PC-28 (2014). In vivo efficacy study of 15(S)-HETRE and 15(S)-HEPE in STAM model of 
non-alcoholic steatohepatitis. 


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 
DS-PC-29 (2015). In vivo efficacy study of 15(S)-HETRE and 15(S)-HEPE in STAM model of 
non-alcoholic steatohepatitis. 
 
 
DS-PC-32 (2015). Determination of 15(S) HEPE in Rat Lung, Plasma, Heart, Spleen,  
Kidney 
and 
Liver 
Samples 
From 
ARG 
Study 
No. 
OXI5263. 
 
 
 
 
 
 
 


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15 
APPENDICES 
15.1 Appendix 1: Flow Chart – Pilot Phase 
 
Visit 
Screening/ 
Visit 1 
Baseline/ 
Visit 2 
Day 3/ 
Visit 3 
Day 5/ 
Visit 4 
Day 7/ 
Visit 5 
Day 14/ 
Visit 6 
Day 21/ 
Visit 7 
Day 28/Visit 8/ Early 
Termination 
Day 90/Visit 9/ 
Follow Up 
Day 
0 
3 
5 
7 
14 
21 
28 
90 
Visit Window 
N/A 
±0 day 
±0 day 
±0 day 
±2 day 
±2 day 
±2 day 
±1 day 
±10 days 
Informed Consent3 
X 
Inclusion/Exclusion 
X 
X 
Demographics 
X 
Patient Randomisation 
X 
Medical History 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (6-lead or 12-lead) 
X 
X 
X 
Pharmacokinetic Sampling4 
X 
X 
X 
X 
X 
X 
X 
Exploratory Blood Sample 
X 
X 
X 
Clinical Laboratory Tests1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Virology 
X 
Urinalysis 
X 
Liver ultrasound 
X 
Pregnancy Test2 
X 
X 
X 
 
X 
MELD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
m-SOFA 
 
X 
X 
X 
X 
X 
X 
X 
X 
West Haven Criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
APACHE II 
 
X 
X 
X 
X 
X 
X 
X 
X 
Lille score 
 
X 
X 
X 
X 
X 
X 
X 
X 
Total Bilirubin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CK-18 
X 
X 
X 
X 
X 
X 
X 
X 
ALT, AST 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Child Pugh Score 
X 
X 
X 
X 
X 
X 
X 
X 
Gamma GT 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of nutritional status 
X 
X 
X 
Collection of acute kidney injury, 
ascites and variceal haemorrhage 
data 
X 
X 
X 
X 
X 
X 
X 
Biomarker 
x 
x 
x 
x 
x 
x 
x 


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Visit 
Screening/ 
Visit 1 
Baseline/ 
Visit 2 
Day 3/ 
Visit 3 
Day 5/ 
Visit 4 
Day 7/ 
Visit 5 
Day 14/ 
Visit 6 
Day 21/ 
Visit 7 
Day 28/Visit 8/ Early 
Termination 
Day 90/Visit 9/ 
Follow Up 
Mortality 
X 
X 
X 
X 
X 
X 
X 
IMP/Placebo Administration 
X -------------------------------------------------------------------------------------------------------------------------------------------- X 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
¹ Includes biochemistry, haematology,and coagulation tests. Caeruloplasmin will be collected at screening only 
² Female Patients of child bearing potential only. 
3 Patient may be required to reconsent after Visit 1 if new information is made available. 
4PK sampling for pilot phase will be conducted at the following timepoints on Day 0 and Day 7: 0.5hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 7 hours, 8 hours, 10 hours and 12 hours (before 
next dose). Trough plasma samples will also be obtained prior to the first daily dose on the indicated days. 


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15. 2 Appendix 2: Study Flowchart – Double-Blind Phase 
Visit 
Screening/ 
Visit 1 
Baseline/ 
Visit 2 
Day 3/ 
Visit 3 
Day 5/ 
Visit 4 
Day 7/ 
Visit 5 
Day 14/ 
Visit 6 
Day 21/ 
Visit 7 
Day 28/Visit 8/ Early 
Termination 
Day 90/Visit 9/ 
Follow Up 
Day 
0 
3 
5 
7 
14 
21 
28 
90 
Visit Window 
N/A 
±0 day 
±0 day 
±0 day 
±2 day 
±2 day 
±2 day 
±1 day 
±10 days 
Informed Consent3 
X 
Inclusion/Exclusion 
X 
X 
Demographics 
X 
Patient Randomisation 
X 
Medical History 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (6-lead or 12-lead) 
X 
X 
X 
Pharmacokinetic Sampling 4 
X 
X 
X 
X 
X 
X 
X 
Exploratory Blood Sample 
X 
X 
X 
Clinical Laboratory Tests1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Virology 
X 
Urinalysis 
x 
Liver ultrasound 
X 
Pregnancy Test2 
X 
X 
X 
X 
MELD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MDF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
m-SOFA 
 
X 
X 
X 
X 
X 
X 
X 
X 
West Haven Criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
APACHE II 
 
X 
X 
X 
X 
X 
X 
X 
X 
Lille score 
 
X 
X 
X 
X 
X 
X 
X 
X 
Total Bilirubin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CK-18 
X 
X 
X 
X 
X 
X 
X 
X 
ALT, AST 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Child Pugh Score 
X 
X 
X 
X 
X 
X 
X 
X 
Gamma GT 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of nutritional status 
X 
X 
X 
Collection of acute kidney injury, 
ascites and variceal haemorrhage 
data 
X 
X 
X 
X 
X 
X 
X 
Biomarker 
x 
x 
x 
x 
x 
x 
x 


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Visit 
Screening/ 
Visit 1 
Baseline/ 
Visit 2 
Day 3/ 
Visit 3 
Day 5/ 
Visit 4 
Day 7/ 
Visit 5 
Day 14/ 
Visit 6 
Day 21/ 
Visit 7 
Day 28/Visit 8/ Early 
Termination 
Day 90/Visit 9/ 
Follow Up 
Mortality 
X 
X 
X 
X 
X 
X 
X 
IMP/Placebo Administration 
X -------------------------------------------------------------------------------------------------------------------------------------------- X 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
¹ Includes biochemistry, haematology, and coagulation tests. Caeruloplasmin will be collected at screening only 
² Female Patients of child bearing potential only. 
3 Patient may be required to reconsent after Visit 1 if new information is made available. 
4 Trough plasma PK samples will also be obtained prior to the first daily dose on the indicated days. 


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15.2 Appendix 3: Acute Physiologic and Chronic Health Evaluation II 
 
Physiologic Variable 
High Abnormal Range 
Low Abnormal Range 
+4 
+3 
+2 
+1 
0 
+1 
+2 
+3 
+4 
Points 
Temperature - rectal (°C) 
>41° 
39 to 40.9° 
38.5 to 38.9° 
36 to 38.4° 
34 to 35.9° 
32 to 33.9° 
30 to 31.9° 
<29.9° 
Mean Arterial Pressure - mm Hg 
>160 
130 to 159 
110 to 129 
70 to 109 
50 to 69 
<49 
Heart Rate (ventricular response) 
>180 
140 to 179 
110 to 139 
70 to 109 
55 to 69 
40 to 54 
<39 
Respiratory Rate 
(non-ventilated or ventilated) 
>50 
35 to 49 
25 to 34 
12 to 24 
10 to 11 
6 to 9 
<5 
Oxygenation: A-aDO2 orPaO2 (mm Hg) 
a. FIO2 >0.5 record A-aDO2 
b. FIO2 <0.5 record PaO2 
>500 
350 to 499 
200 to 349 
<200 
PO2>70 
PO2 61 to 70 
PO2 55 to 60 
PO2<55 
Arterial pH (preferred) 
Serum HCO3 (venous mEq/l) 
(not preferred, but may use if no ABGs) 
>7.7 
>52 
7.6 to 7.69 
41 to 51.9 
7.5 to 7.59 
32 to 40.9 
7.33 to 7.49 
22 to 31.9 
7.25 to 7.32 
18 to 21.9 
7.15 to 7.24 
15 to 17.9 
<7.15 
<15 
Serum Sodium (mEq/l) 
>180 
160 to 179 
155 to 159 
150 to 154 
130 to 149 
120 to 129 
111 to 119 
<110 
Serum Potassium (mEq/l) 
>7 
6 to 6.9 
5.5 to 5.9 
3.5 to 5.4 
3 to 3.4 
2.5 to 2.9 
<2.5 
Serum Creatinine (mg/dl) 
Double point score for acute renal failure 
>3.5 
2 to 3.4 
1.5 to 1.9 
0.6 to 1.4 
<0.6 
Hematocrit (%) 
>60 
50 to 59.9 
46 to 49.9 
30 to 45.9 
20 to 29.9 
<20 
White Blood Count (total/mm3) 
(in 1000s) 
>40 
20 to 39.9 
15 to 19.9 
3 to 14.9 
1 to 2.9 
<1 
Glasgow Coma Score (GCS) 
Score = 15 minus actual GCS 
A. Total Acute Physiology Score (sum of 12 above points) 
B. Age points (years) <44=0; 45 to 54=2; 55 to 64=3; 65 to 74=5; >75=6 
C. Chronic Health Points (see below) 
Total APACHE II Score (add together the points from A+B+C) 
Chronic Health Points: If the patient has a history of severe organ system insufficiency or is immunocompromised as defined below, assign points as follows: 
5 points for nonoperative or emergency postoperative patients 
2 points for elective postoperative patients 


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Definitions: organ insufficiency or immunocompromised state must have been evident prior to this hospital admission and conform to the following criteria: 
 
 
Liver – biopsy proven cirrhosis and documented portal hypertension; episodes of past upper GI bleeding attributed to portal hypertension; or prior episodes of hepatic failure/encephalopathy/coma. 
 
Cardiovascular – New York Heart Association Class IV. 
 
Respiratory – Chronic restrictive, obstructive, or vascular disease resulting in severe exercise restriction (i.e., unable to climb stairs or perform household duties; or documented chronic hypoxia, hypercapnia, 
secondary polycythemia, severe pulmonary hypertension (>40 mmHg), or respirator dependency. 
 
Renal – receiving chronic dialysis. 
 
Immunocompromised – the patient has received therapy that suppresses resistance to infection (e.g., immunosuppression, chemotherapy, radiation, long term or recent high dose steroids, or has a disease that 
is sufficiently advanced to suppress resistance to infection, e.g., leukaemia, lymphoma, AIDS). 

SAP_001.pdf: 
Syne qua non study no: ANE18001
Afimmune study no: DS102A-05-AH1
Date: 25JAN2019 
Page 1 of 26
Version: Final 1.0
ST/form/010/11
A Randomised, Double-Blind, Placebo-Controlled, Phase II 
Study to Assess the Efficacy and Safety of Orally 
Administered DS102 in Patients with Severe Acute 
Decompensated Alcoholic Hepatitis
Afimmune Study No: DS102A-05-AH1
Syne qua non Ltd Study No:  ANE18001
Statistical Analysis Plan 
Version: Final 1.0
Date: 25th January 2019
For Syne qua non Ltd 
Lead Statistician
Sig1sig
For Afimmune
Sig2sig
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Syne qua non study no: ANE18001 
 
Afimmune study no: DS102A-05-AH1 
 
Date: 25JAN2019 
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Contents 
 
1 
Introduction...................................................................................................................................... 6 
2 
Study Objectives and Design .......................................................................................................... 6 
2.1 
Study Objectives ......................................................................................................................... 6 
2.2 
Study Endpoints .......................................................................................................................... 6 
2.3 
Study Design ............................................................................................................................... 7 
2.4 
Visit Structure .............................................................................................................................. 8 
3 
Sample Size .................................................................................................................................... 8 
4 
Randomisation ................................................................................................................................ 8 
5 
Interim analysis ............................................................................................................................... 8 
6 
Analysis Plan ................................................................................................................................... 9 
6.1 
General ....................................................................................................................................... 9 
6.2 
Blinded Data Review Meeting ..................................................................................................... 9 
6.3 
General Derivations .................................................................................................................... 9 
6.4 
Analysis Sets ............................................................................................................................ 10 
6.5 
Data presentations .................................................................................................................... 11 
6.6 
Disposition of patients ............................................................................................................... 12 
6.7 
Protocol Deviations ................................................................................................................... 12 
6.8 
Background and Demographic Characteristics ........................................................................ 12 
6.8.1 
Demography .......................................................................................................................... 12 
6.8.2
Medical History ......................................................................................................................13
6.8.3 
HIV, Hepatitis B and Hepatitis C screening ........................................................................... 13 
6.8.4 
Liver Ultrasound ..................................................................................................................... 13 
6.9 
Prior and Concomitant Medications .......................................................................................... 13 
6.10 
Administration of Study Treatment and Compliance ................................................................ 13 
6.11 
Primary Endpoint ...................................................................................................................... 14 
6.11.1 
Primary Analysis .................................................................................................................... 14 
6.11.2 
Sensitivity Analysis ................................................................................................................ 15 
6.11.3 
Descriptive summaries and listing ......................................................................................... 15 
6.12 
Secondary Endpoints ................................................................................................................ 15 
6.12.1 
Change in total bilirubin from baseline to Day 7, 14, 21 and 28 ............................................ 15 
6.12.2 
Proportion of patients showing a 25% reduction of bilirubin at Day 7, 14, 21 and 28 ........... 15 
6.12.3 
Change in serum Cytokeratin-18 M30/M65 from baseline to Day 7, 14, 21 and 28 ............. 16 
6.12.4 
Change in AST levels from baseline to Day 7, 14, 21 and 28 ............................................... 16 
6.12.5 
Change in AST:ALT ratio from baseline to Day 7, 14, 21 and 28 ......................................... 16 
6.12.6 
Change in MDF score from baseline to Day 7, 14, 21 and 28 .............................................. 16 
6.12.7 
Proportion of patients showing a 25% reduction in MELD score from baseline to Day 7, 14, 
21 and 28 ............................................................................................................................... 17 
6.12.8 
Change in MELD score from baseline to Day 7, 14 and 21 .................................................. 17 
6.12.9 
Change in m-SOFA total score from baseline to Day 7, 14, 21 and 28 ................................ 17 
6.12.10 Proportion of patients with a 2-point worsening of m-SOFA from baseline to Day 7, 14, 21 
and 28 .................................................................................................................................... 18 
6.12.11 Change in hepatic encephalopathy as assessed by West Haven Criteria, from baseline to 
Day 7, 14, 21 and 28 ............................................................................................................. 18 
6.12.12 Incidence of acute kidney injury over 28 days ....................................................................... 19 
6.12.13 Incidence of variceal haemorrhage, ascites or hepatic encephalopathy over 28 days ......... 19 
6.13 
Exploratory Endpoints ............................................................................................................... 19 
6.13.1 
Survival at day 7, 14, 21, 28 and 90 ...................................................................................... 19 
6.13.2 
Change in GT from baseline to day 7, 14, 21 and 28 ............................................................ 20 
6.13.3 
Change in ALT from baseline to day 7, 14, 21 and 28 .......................................................... 20 
6.13.4 
Change in Child-Pugh score from baseline to day 7, 14, 21 and 28 ..................................... 20 
6.13.5 
Change in APACHE-II score from baseline to day 7, 14 , 21 and 28 .................................... 21 
6.13.6 
Change in Lille score from baseline to day 7, 14, 21 and 28 ................................................ 21 
6.13.7 
Combination of change of MELD score from baseline, premature treatment terminations and 
mortality ................................................................................................................................. 22 
6.14 
Multiplicity ................................................................................................................................. 22 
6.15 
Pharmacokinetics...................................................................................................................... 22 
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6.16 
Safety Evaluation ...................................................................................................................... 23 
6.16.1 
Adverse Events ...................................................................................................................... 23 
6.17 
Clinical Laboratory Evaluation .................................................................................................. 24 
6.18 
Vital Signs ................................................................................................................................. 24 
6.19 
Electrocardiography .................................................................................................................. 25 
6.20 
Physical Examination ................................................................................................................ 25 
6.21 
Pregnancy test .......................................................................................................................... 25 
6.22 
Exploratory Blood Collection ..................................................................................................... 25 
6.23 
Liver Histopathology ................................................................................................................. 25 
6.24 
Nutritional Status Assessment .................................................................................................. 25 
6.25 
Changes from the Protocol Planned Analysis .......................................................................... 25 
7 
Appendix 1  Pharmocokinetic Data Analysis Plan ...................................................................... 26 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AH 
Alcoholic Hepatitis 
AIC 
 
ALT 
Alanine Transaminase 
APACHE II Acute Physiologic and Chronic Health Evaluation II 
AST 
Aspartate Transaminase 
AUCinf 
Area under the concentration-time curve extrapolated to infinite time 
AUCt 
Area under the concentration-time curve to time t 
AUCtau 
Area under the concentration-time curve to the end of the dosage 
interval 
BD 
Twice a day 
BDRM 
Blinded Data Review Meeting 
BMI 
Body Mass Index 
BP 
Blood Pressure 
Cmax 
Maximum Observed Concentration 
CNS 
Central Nervous System 
CI 
Confidence Interval 
CS 
Clinically Significant 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
Flucp 
Fluctuation at pharmacokinetic steady-state 
GT 
Gamma Glutamyl Transferase 
HIV 
Human Immunodeficiency Virus 
IMP 
Investigational Medicinal Product 
INR 
International normalised ratio 
Kel 
Apparent first-order terminal elimination rate constant 
z 
Terminal Elimination Rate Constant 
LLOQ 
Lower Limit of Quantification 
LS 
Least Squares 
MAR 
Missing at Random 
MDF 
Maddrey Discriminant Function 
MedDRA 
Medical Dictionary for Regulatory Activities 
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MELD 
Model End-stage Liver Disease 
MMRM 
Mixed-Model Repeated Measures 
m-SOFA 
Modified Sequential Organ Failure Assessment 
NASH 
Non-Alcoholic Steatohepatitis 
NCS 
Not Clinically Significant 
%Extrap 
Percentage of AUCinf obtained by extrapolation 
PK 
Pharmacokinetic 
PKAP 
Pharmacokinetic data analysis plan 
PPS 
Per Protocol Set 
PT 
Preferred Term 
Q1 
25th percentile 
Q3 
75th percentile 
Rac 
Accumulation ratio at pharmacokinetic steady-state 
RAN 
All Randomised Patients 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Terminal Elimination Half-Life 
TEAE 
Treatment Emergent Adverse Event 
tmax 
Time of the Maximum Observed Plasma Concentration 
Tss 
Time to achieve pharmacokinetic steady-state 
WHO Drug World Health Organization Drug Dictionary 
 
 
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1 INTRODUCTION 
This document details the statistical analysis of the data that will be performed for the 
Afimmune study: A Randomised, Double-Blind, Placebo-Controlled, Phase II Study to 
Assess the Efficacy and Safety of Orally Administered DS102 in Patients with Severe 
Acute Decompensated Alcoholic Hepatitis.  
The proposed analysis is based on the contents of Version 4.0 of the protocol (dated 
01-AUG-2018). In the event of future amendments to the protocol, this statistical 
analysis plan (SAP) may be modified to account for changes relevant to the statistical 
analysis.  
The table, listing and figure shells are supplied in a separate document. 
2 STUDY OBJECTIVES AND DESIGN 
2.1 Study Objectives 
Efficacy Objective: 
treatment of adult patients with severe acute decompensated Alcoholic Hepatitis (AH). 
Safety Objective: 
versus placebo, in the treatment 
of adult patients with severe acute decompensated AH. 
Pharmacokinetic Objective: 
 pharmacokinetics (PK) of 15(S)-HEPE following orally administered 
DS102 capsules, in six adult patients with AH in an initial pilot phase of the study, 
followed by trough level assessment of 15(S)-HEPE in all study participants. 
2.2 Study Endpoints 
The primary endpoint of the study is: 
 Percentage change in Model End-stage Liver Disease (MELD) score from 
baseline to Day 28. 
The secondary endpoints are: 
 Change in total bilirubin from baseline to Day 7, 14, 21 and 28 
 Proportion of patients showing a 25% reduction of bilirubin at day 7, 14, 21, 
and 28 
 Change in serum Cytokeratin 18-M30/M65 from baseline to Day 7, 14, 21 and 
28 
 Change in Aspartate Transaminase (AST) levels from Baseline to Day 7, 14, 
21 and 28 
 Change in AST: Alanine Transaminase (ALT) ratio from Baseline to Day 7, 14, 
21, 28 
 Change in Maddrey Discriminant Function (MDF) score from baseline to Day 
7, 14, 21 and 28 
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 Proportion of patients showing a 25% reduction in MELD score from baseline 
to Day 7, 14 and 21 
 Change in MELD score from baseline to Day 7, 14 and 21 
 Change in modified sequential organ failure assessment (m-SOFA) from 
baseline to Day 7, 14, 21 and 28 
 Proportion of patients with a 2-point worsening of m-SOFA from baseline at 
Day 7, 14, 21 and 28 
 Change in hepatic encephalopathy as assessed by West Haven criteria, from 
baseline at Day 7, 14, 21 and 28 
 Incidence of acute kidney injury over 28 days (defined by requiring medicinal 
or mechanical support) 
 Incidence of variceal haemorrhage, ascites or hepatic encephalopathy over 28 
days 
The exploratory endpoints are: 
 Survival at day 7, 14, 21, 28 and 90 using Kaplan-Meier Plot 
 Change in Gamma Glutamyl Transferase (GT) from baseline to Day 7, 14, 21 
and 28 
 Change in ALT from baseline to Day 7, 14, 21 and 28. 
 Change in Child-Pugh score from baseline to Day 7, 14, 21 and 28 
 Change in Acute Physiologic and Chronic Health Evaluation (APACHE) II 
score from baseline to Day 7, 14, 21 and 28 
 Change in Lille score from baseline to Day 7, 14, 21 and 28 
The safety endpoints are: 
 Treatment emergent serious adverse events (SAEs), adverse events (AEs) and 
suspected unexpected serious adverse reactions (SUSARs) 
2.3 Study Design 
This is a randomised, placebo-controlled, double-blind, parallel group, multicentre, 
exploratory phase II study preceded by an open label pilot phase to investigate the 
efficacy and safety of orally administered DS102 capsules in patients with acute 
decompensated AH aged over 18 years.  Patients will be recruited from 50 sites across 
9 countries.  
The open label pilot phase is a single arm study, all 6 patients will receive study drug 
(2 x DS102 500mg capsules orally administered twice a day (BD) (four capsules 
daily)), for 28 days. Results of the pilot phase will be assessed by a data and safety 
monitoring board (DSMB) for safety and if dose adjustments for the main study are 
needed. 
After the open-label pilot phase of the study, two parallel groups of patients will be 
enrolled into the randomised double-blind phase of the study to compare one dose of 
DS102 with placebo over a 28-day treatment period. Patients will receive standard of 
care therapy in addition to their assigned investigational medicinal product (IMP) 
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throughout the treatment period of the study. It is planned that 120 evaluable patients, 
60 per treatment group, will be randomised. 
 
The study population will consist of male and female patients diagnosed with severe 
acute decompensated AH aged 18 years and over. 
2.4 Visit Structure 
During the study, 8 visits to the clinic are scheduled after the screening visit (Visit 1): 
one at the start of the comparative treatment period (Baseline/Visit 2) and six in the 
comparative treatment period (Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 
14, Visit 7/Day 21, Visit 8/Day 28 or Early Termination). 
A final safety follow-up visit (Visit 9/Day 90) will be conducted on Day 90. 
Both the pilot and main, double-blind, phase will follow the same structure. 
Full details of the visit structure and scheduled assessments are detailed in the study 
protocol section 8 Study Conduct and Appendices 1 and 2. 
3 SAMPLE SIZE 
To discover an effect size of 0.54 (=Difference in means/standard deviation) in MELD 
change from baseline with 80% power, 55 patients per group are necessary under 
ideal assumptions using the t-test for independent samples (alpha=0.05, two-sided). 
To take deviations from ideal parametric conditions and drop-outs into account, 60 
patients per group will be randomised. 
4 RANDOMISATION  
For the main, double-blind phase, approximately 120 patients will be randomised into 
double blind treatment groups in a 1:1 ratio as follows: 
 Treatment group A: 2 x placebo 500mg capsules orally administered BD (four 
capsules daily) for 28 days 
 
 Treatment group B: 2 x DS102 500mg capsules orally administered BD (four 
capsules daily) for 28 days 
5 INTERIM ANALYSIS 
An interim analysis may be conducted in the main, double-blind phase once 50% of 
planned patients have completed their Day 28 assessments. Details of this will be 
covered in a detailed Interim Analysis Plan in accordance with Sponsor standard 
 and is not covered by 
this SAP. 
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6 ANALYSIS PLAN 
6.1 General 
The decision to proceed to the double-blind phase of this study will be determined by 
the DSMB following review of the safety and pharmacokinetic data from the pilot phase 
as detailed in the DSMB charter. No statistical outputs will be produced for the DSMB 
review as part of this SAP, details of the PK analysis for the pilot study are included in 
Appendix 1. Patients from the pilot phase will be included in the same listings for the 
double-blind phase as a separate group. Should the study be discontinued after the 
pilot phase, the listings described in the sections below will be produced for the pilot 
phase only. 
The summary tables and figures described in the following sections relate to the main, 
double-blind, study only unless specifically mentioned otherwise. 
Summary statistics for continuous variables will consist of number of non-missing 
observations (n), mean, standard deviation (SD), minimum, 25th percentile (Q1), 
median, 75th percentile (Q3), and maximum, unless specified otherwise.  The precision 
of these variables is defined in the table, figure and listing shells document. 
For categorical variables the number and percentage of patients in each category will 
be presented, based on the number of non-missing observations apart from 
disposition of patients, protocol deviations, background and demographic 
characteristics, prior and concomitant medications/procedures and adverse events 
where the percentage will be based on the number of patients in the analysis set. 
All statistical tests will be performed using a two-tailed 5% overall significance level, 
unless otherwise stated.  The null hypothesis at all times will be that the treatments 
are equivalent.  All comparisons between the treatments will be reported with 95% 
confidence intervals for the difference.  
6.2 Blinded Data Review Meeting  
The Sponsor will convene a blinded data review meeting (BDRM) after the data has 
been cleaned and before the study is unblinded.  
The BDRM will make decisions that will include, but will not be limited to: 
 the determination of whether protocol violations are 'major' or 'minor', or not a 
protocol violation at all; 
 the allocation of patients to analysis sets; 
 changes required to the SAP. 
After the BDRM and prior to database lock a SAP amendment will be issued if 
necessary. 
6.3 General Derivations 
 Definition of baseline 
Baseline is defined as the last non-missing value (including scheduled and 
unscheduled assessments) prior to the patient receiving study treatment. 
 
 
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 Incomplete dates 
For calculation purposes, incomplete dates will be completed using worst case. 
Further details are detailed in the relevant sections as required.   
 
 Non-numeric values recorded in a numeric field 
 in a numeric field, 
then for analysis purposes a value of x will be taken. Where a range of values is quoted 
the midpoint of the range will be taken. For example, if a laboratory safety parameter 
is reported as being below the limit of quantification or < x, the value of the limit will be 
used in the calculation of summary statistics.  The recorded value will be reported in 
listings. 
 Methods for handling withdrawals and missing data 
Imputation of any data will be detailed in the relevant sections. 
6.4 Analysis Sets 
The Enrolled Set includes all patients who provided informed consent irrespective of 
whether they received the study treatment. 
All Randomised Patients 
 consists of all patients who were assigned a 
randomisation number, irrespective of the treatment they received, if any.  If this 
analysis set coincides with the full analysis set, it will be omitted from the tables and 
listings. 
The Full Analysis Set (FAS) includes all randomised patients who receive at least 
one administration of study treatment. Patients will be analysed according to the 
treatment they are assigned to at randomisation, irrespective of what treatment they 
actually received. 
The Per-Protocol Set (PPS) will be a subset of the Full Analysis Set consisting of 
those patients who: 
1. Complete 80% of the study treatment from baseline to day 28 or early termination 
visit and do not miss more than 3 consecutive days of dosing (or 6 consecutive 
doses) 
2. Have complete MELD score data at baseline and day 28/early termination visit. 
3. Do not have major protocol deviations considered having a serious impact on the 
efficacy results. 
All protocol deviations will be assessed and documented on a case-by-case basis prior 
to the database lock, and major deviations considered having a serious impact on the 
efficacy results will lead to the relevant patient being excluded from the set.  Major 
protocol deviations considered having a serious impact on the efficacy results include 
but are not limited to: 
 
Patients failing any eligibility criteria. 
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Patients with treatment deviation. 
Protocol deviations other than those specified above may be identified.  These will be 
identified using programmatic data checking where possible, supported by visual 
review of the data.  These deviations will be categorised as either minor or major prior 
to database lock, at the BDRM prior to unblinding. 
The Safety Analysis Set (SAF) consists of all patients who take at least one 
administration of study treatment.  Patients will be analysed according to the treatment 
actually taken.   
Pharmacokinetic (PK) Set (pilot phase) will consist of those patients who have at 
least one quantifiable post-dose plasma 15(S)-HEPE concentration. Patients will be 
analysed according to the treatment actually taken.  An evaluable profile allows the 
determination of one or more PK parameters and will be determined at the discretion 
of the pharmacokineticist. The Pharmacokinetic set will be used for the summaries of 
all PK data. 
The Pharmacokinetic (PK) Set (double-blind phase) will consist of those patients 
who have at least one quantifiable post-dose plasma 15(S)-HEPE concentration. 
Patients will be analysed according to the treatment actually taken. 
The treatment actually taken will assumed to be the treatment randomised to unless 
otherwise notified by the sponsor at the time of unblinding. 
The list of patients included in the SAF, FAS, PPS and PK (pilot phase) and PK 
(double-blind phase) set will be agreed prior to breaking the blind for blinded studies, 
once all study data is available. The definitions for the SAF, FAS and PK (pilot phase) 
and PK (double-blind phase) set are sufficient to determine the patients included within 
these analysis sets and so do not require listing and agreeing prior to breaking the 
blind for blinded studies. 
6.5 Data presentations 
The data will be summarised in tabular form by treatment group apart from disposition 
of patients, protocol deviations, background and demographic  data and adverse 
events which will be summarised by treatment group and overall patients.  Treatment 
labels will be 
 (where 
applicable).  
Only scheduled post-baseline laboratory, electrocardiogram (ECG), nutritional status 
assessment, cytokeratin18-M30/M65 and vital signs values will be tabulated, post-
baseline repeat/unscheduled assessments will be disregarded, although they will be 
listed and in particular all clinically significant values will be noted (where applicable). 
Analysis sets will be summarised using the enrolled set. Study completion/withdrawal 
and protocol deviations will be summarised using the RAN set. Background and 
demographic characteristics will be summarised using the FAS. The primary efficacy 
endpoint will be summarised using the FAS and the PPS. Secondary endpoints will be 
based on the FAS only. Prior/concomitant medications, administration of study 
treatment and exposure and safety will be summarised using the SAF.  PK (double-
blind phase) will be summarised using the PK (double-blind phase) set. 
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PK (pilot phase) will be based on the PK (pilot phase) set, PK (double-blind phase) will 
be based on the PK (double-blind phase), safety listings will be based on the SAF set, 
and all other listings will be based on the enrolled set.  
Listings will be sorted by phase, treatment group, patient number and date/time of 
assessment.   
Treatment groups will be presented in the following order 
phase: 1000 mg 
DS102 (BD)
-blind phase: 1000 mg DS102 (BD)  and Placebo (BD)  
Graphical presentations of the data will also be provided where appropriate. 
6.6 Disposition of patients 
The number and percentage of all patients enrolled, included in the RAN, FAS, PPS, 
SAF and PK (double-blind phase) analysis sets, who completed the study and 
prematurely discontinued the study, study duration and treatment duration, will be 
summarised.  The number and percentage of patients will be summarised by their 
reasons for withdrawal from the study and study treatment. Study duration for each 
patient will be derived as the number of days between date of randomisation and the 
date of study completion or the date of early study withdrawal. Treatment duration will 
be derived as the number of days between 1st administration of study drug and the 
date of the last administration of study drug. 
Eligibility for each of the analysis sets along with reasons for exclusion will be listed. 
Study completion/withdrawal data will be listed. Consent and visit dates will be listed.  
Randomisation details will be listed. 
Analysis sets presented will be the ones defined in this SAP. 
6.7 Protocol Deviations 
Prior to database lock, Afimmune will review the individual deviations and classify 
them as major (which includes those described in section 6.3 above) or minor during 
a BDRM. 
Details of all protocol deviations (date, deviation category, specific details and 
classification of major or minor) and patient eligibility will be listed.   
The number and percentage of patients with at least one major protocol deviation will 
be summarised. Major protocol deviations will be summarised for each major deviation 
category.  
6.8 Background and Demographic Characteristics 
6.8.1 
Demography 
Demographic characteristics (age, sex, ethnic origin and race), body measurements 
(height, weight, body mass index (BMI)), alcoholic hepatitis duration, average weekly 
consumption of alcohol (units per week) and the presence of a history of alcohol abuse 
for > 6 months (Yes/No) will be summarised by treatment group and overall. 
Age at informed consent is captured on the electronic case report form (eCRF).  
BMI is calculated as (weight (kg)/height (m)2).  
Date of alcoholic hepatitis diagnosis will be recorded. Alcoholic hepatitis duration will 
be calculated in years as [date of informed consent -  date of alcoholic hepatitis 
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diagnosis+1]/365. Dates will be imputed according to this rule: if the day is missing, 
day will be imputed as 1st day of the month, if the month is missing, month will be 
imputed as 1st month of the year.  
All patient demographic data including informed consent, AH diagnosis and substance 
use data will be listed. 
6.8.2 
Medical History 
Medical history events will be coded using the latest Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary version.  The version used will be indicated in the data 
summaries and listings.  The number and percentage of patients will be presented for 
ongoing conditions and previous conditions separately by system organ class (SOC), 
and preferred term (PT), where SOC and PT will be presented in decreasing frequency 
of the total number of patients with medical history events. All events will be listed. 
6.8.3 
HIV, Hepatitis B and Hepatitis C screening 
Details of the screen for human immunodeficiency virus (HIV), hepatitis B and hepatitis 
C will be listed. 
6.8.4 
Liver Ultrasound 
Liver ultrasound data will be summarized and listed. 
6.9 Prior and Concomitant Medications 
Medications will be coded using the latest World Health Organization Drug dictionary 
(WHO Drug) version.  The version used will be indicated in the data summaries and 
listings.  
Prior medications are defined as those that started and ended prior to the first 
administration of study treatment. Medications that are ongoing at the first 
administration of study treatment or started after time of first administration will be 
deemed to be concomitant medications. If medication dates are incomplete and it is 
not clear whether the medication was concomitant, it will be assumed to be 
concomitant. 
The number and percentage of patients taking prior and separately concomitant 
medications will be summarised by medication class and standardised medication 
name, where medication class and standardised medication name will be presented 
in decreasing frequency of the total number of patients with medications.  In summary 
tables, patients taking multiple medications in the same medication class or having the 
same standardised medication recorded multiple times in the study will be counted 
only once for that specific medication class and standardised medication name.  
Medication data will be listed, and concomitant medications will be flagged. 
6.10 Administration of Study Treatment and Compliance 
The number of doses of study treatment administered will be derived as the (total 
number of study drug capsules dispensed  total number of study drug capsules 
returned) over all visits. 
Patients compliance with treatment will be measured by the information captured on 
the patient diary card.  
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Overall treatment compliance will be derived as a percentage as the (number of doses 
of study treatment recorded as being administered/N) *100.  
Where N= the number of times the patient should have received study treatment= 
(Date of treatment withdrawal or day 28/early termination visit  date of baseline visit 
+ 1) x 2 
Number of doses of study treatment administered and overall treatment compliance 
will be summarised. 
Study drug dispensing, study drug return and diary card data will be listed. 
6.11 Primary Endpoint 
The model for end-stage liver disease is employed in the evaluation of hepatic function 
and the assessment of prognosis. MELD is calculated based on variables including 
the international normalised ratio (INR), serum creatinine and serum bilirubin. 
A MELD score  18 (within 24 hours of presentation) is considered a good predictor 
of 90-day mortality in patients with AH. 
The efficacy primary endpoint of the study is the change in MELD score from baseline 
to day 28.  
For the primary endpoint primary analysis; the null hypothesis (Ho: µ1 = µ2) of no 
difference in change from baseline to day 28 between those patients treated with 
1000mg DS102 (BD) and placebo will be rejected in favour of the alternative 
hypothesis (H1: µ1  µ2) should the probability of the test statistic from observed data 
occurring if the null hypothesis were 
 
6.11.1 Primary Analysis 
Percentage change in MELD score from baseline up to and including day 28 will be 
assessed by modelling change from baseline with a mixed-model repeated measures 
(MMRM) analysis, using the FAS, including terms for treatment group, visit, treatment-
by-visit interaction as fixed effects and the baseline MELD value as a covariate. The 
adjusted treatment least squares (LS) means and adjusted mean LS difference 
between the active dose and placebo will be presented along with 95% confidence 
intervals (CI) and p-value for the day 28 timepoint. Early termination data will be 
entered into the model at the next scheduled visit following the date of termination, not 
at day 28. 
F-tests from PROC MIXED will be based on Kenward-
freedom.  The following variance/covariance matrix structures for the repeated visits 
within a patient will be assessed: Compound symmetry, 1st order autoregressive, 
Toeplitz and unstructured. The variance/covariance matrix structure that results in the 
smallest 
 information criterion (AIC), indicating the best model fit will be 
selected. 
Assumptions of normality will be assessed visually using diagnostic plots.  Should 
assumptions of normality not hold the model will be fitted to the change from baseline 
of log-transformed data.  Should the assumptions behind the model still not hold an 
alternative approach to the analysis will be decided following the BDRM and will be 
detailed in a SAP amendment. 
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6.11.2 Sensitivity Analysis 
The primary analysis will be repeated for the PPS. 
Missing MELD data will be imputed using a last observation carried forward approach 
and the primary analysis will be repeated with the imputed data included. 
6.11.3 Descriptive summaries and listing 
MELD score observed values, absolute change from baseline and percentage change 
from baseline will be summarised and listed by treatment group and visit. 
6.12 Secondary Endpoints 
6.12.1 Change in total bilirubin from baseline to Day 7, 14, 21 and 28 
Total bilirubin concentration is a marker of hepatic function. 
6.12.1.1 
Analysis 
Change in total bilirubin from baseline up to and including day 28 will be assessed with 
an MMRM analysis, using the FAS, including terms for treatment group, visit, 
treatment-by-visit interaction as fixed effects and the baseline total bilirubin value as a 
covariate. The adjusted treatment means and adjusted mean difference between the 
active dose and placebo will be presented along with 95% CI and p-value at days 7, 
14, 21 and 28. 
The modelling process described in section 6.11.1 will be followed. 
6.12.1.2 
Descriptive summaries and listing 
Covered under section 16.7. 
6.12.2 Proportion of patients showing a 25% reduction of bilirubin at Day 7, 
14, 21 and 28 
The proportion of patients showing a 25% reduction of total bilirubin at days 7, 14, 21 
and 28 will be compared between treatment groups using a MMRM logistic regression 
model. 
At each visit, patients with >=25% reduction in total bilirubin from baseline will be 
assigned a value of 1 (indicating 25% reduction achieved) while patients with a <25% 
reduction will be assigned a value of 0 (indicating 25% reduction not achieved). 
The model will include treatment, visit, treatment-by-visit as fixed effects and baseline 
bilirubin as a covariate. 
The variance/covariance matrix structure that results in best model fit will be selected 
using the process described in section 6.11.1. The adjusted LS estimate for the 
treatment odds of achieving the endpoint and treatment odds ratio (DS102:Placebo) 
and corresponding 95% CIs and p-value corresponding to the treatment odds ratio will 
be presented.  
6.12.2.1 
Descriptive summaries and listing 
The number and percentage of patients showing and patients not showing a 25% 
reduction of bilirubin at days 7, 14, 21 and 28 will be presented by treatment group. 
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6.12.3 Change in serum Cytokeratin-18 M30/M65 from baseline to Day 7, 14, 
21 and 28 
Change in serum cytokeratin18-M30/M65 from baseline up to and including day 28 
will be assessed with an MMRM analysis, using the FAS, including terms for treatment 
group, visit and treatment-by-visit interaction as fixed effects and the baseline serum 
cytokeratin18-M30/M65 value as a covariate. The adjusted treatment means and 
adjusted mean difference between the active dose and placebo will be presented 
along with 95% CIs and p-value at days 7, 14, 21 and 28.  
The modelling process described in section 6.11.1 will be followed. 
6.12.3.1 
Descriptive summaries and listing 
Serum cytokeratin18-M30/M65 observed values, absolute change from baseline and 
percentage change from baseline will be listed and summarised by treatment group 
and visit. 
6.12.4 Change in AST levels from baseline to Day 7, 14, 21 and 28 
Aspartate aminotransferase is liver enzyme and a marker of liver injury. 
6.12.4.1 
Analysis 
Change in AST from baseline up to and including day 28 will be assessed with an 
MMRM analysis, using the FAS, including terms for treatment group, visit and 
treatment-by-visit interaction as fixed effects and the baseline AST value as a 
covariate. The adjusted treatment means and adjusted mean difference between the 
active dose and placebo will be presented along with 95% CI and p-value at days 7, 
14, 21 and 28. 
The modelling process described in section 6.11.1 will be followed. 
6.12.4.2 
Descriptive summaries and listing 
Covered under section 16.7. 
6.12.5 Change in AST:ALT ratio from baseline to Day 7, 14, 21 and 28 
Change in AST:ALT from baseline up to and including day 28 will be assessed with 
an MMRM analysis, using the FAS, including terms for treatment group, visit and 
treatment-by-visit interaction as fixed effects and the baseline AST:ALT value as a 
covariate. The adjusted treatment means and adjusted mean difference between the 
active dose and placebo will be presented along with 95% CI and p-value at days 7, 
14, 21 and 28. 
The modelling process described in section 6.11.1 will be followed. 
6.12.5.1 
Descriptive summaries and listing 
Covered under section 16.7. 
6.12.6 Change in MDF score from baseline to Day 7, 14, 21 and 28 
The Maddrey discriminant function (MDF) is a measure of liver dysfunction and a 
method of assessing disease severity. 
6.12.6.1 
Analysis 
Change in MDF score from baseline up to and including day 28 will be assessed with 
an MMRM analysis, using the FAS, including terms for treatment group, visit and 
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treatment-by-visit interaction as fixed effects and the baseline MDF value as a 
covariate. The adjusted treatment means and adjusted mean difference between the 
active dose and placebo will be presented along with 95% CI and p-value at days 7, 
14, 21 and 28.  
The modelling process described in section 6.11.1 will be followed. 
6.12.6.2 
Descriptive summaries and listing 
MDF score observed values, absolute change from baseline and percentage change 
from baseline will be listed and summarised by treatment group and visit. 
6.12.7 Proportion of patients showing a 25% reduction in MELD score from 
baseline to Day 7, 14, 21 and 28 
The proportion of patients showing at least a 25% reduction in MELD score at days 7, 
14, 21 and 28 will be compared between treatment groups using a MMRM logistic 
regression model. 
At each visit, patients with >=25% reduction from baseline will be assigned a value of 
1 (indicating 25% reduction achieved) while patients with a <25% reduction will be 
assigned a value of 0 (indicating 25% reduction not achieved). 
The model will include treatment, visit, treatment-by-visit interaction as fixed effects 
and baseline MELD score as a covariate. 
The variance/covariance matrix structure that results in best model fit will be selected 
using the process described in section 6.11.1. 
The adjusted LS estimate for the treatment odds of achieving the endpoint and 
treatment odds ratio (DS102:Placebo) along with corresponding 95% CIs and p-value 
(corresponding to the treatment odds ratio) will be presented at days 7, 14, 21 and 28.  
6.12.7.1 
Descriptive summaries and listing 
The number and percentage of patients showing and patients not showing a 25% 
reduction in MELD score at days 7, 14, 21 and 28 will be presented by treatment group. 
6.12.8 Change in MELD score from baseline to Day 7, 14 and 21 
Estimates for the adjusted treatment LS means and adjusted mean LS difference 
between the active dose and placebo will be presented along with 95% confidence 
intervals (CI) and p-value for days 7, 14 and 21 will be obtained from the model fitted 
in section 6.11.1 and presented in the same table as the primary endpoint. 
6.12.8.1 
Descriptive summaries and listing 
Covered under section 6.11.3. 
6.12.9 Change in m-SOFA total score from baseline to Day 7, 14, 21 and 28 
The m-SOFA score is used in the assessment of disease severity, as well as in 
predicting mortality.  
A score between 0 - 4 will be assigned to the following organ systems parameters: 
Respiratory, liver, cardiovascular, central nervous system (CNS) and renal. 
Respiratory function will be measured by SpO2/FiO2, liver function will be classified 
as scleral icterus or jaundice or no scleral icterus or jaundice, cardiovascular function 
will check for hypotension, CNS function will be measured using the Glasgow coma 
score and renal function will be measured by creatinine (mg/dL) levels. A total score 
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m-SOFA score is derived from the individual scores. For this study, the m-SOFA score 
is recorded in the eCRF. 
6.12.9.1 
Analysis 
Change in m-SOFA score from baseline up to and including day 28 will be assessed 
with an MMRM analysis, using the FAS, including terms for treatment group, visit, 
treatment-by-visit interaction as fixed effects and the baseline m-SOFA value as a 
covariate. The adjusted treatment means and adjusted mean difference between the 
active dose and placebo will be presented along with 95% CI and p-value at days 7, 
14, 21 and 28.  
The modelling process described in section 6.11.1 will be followed. 
6.12.9.2 
Descriptive summaries and listing 
m-SOFA score observed values, absolute change from baseline and percentage 
change from baseline will be listed and summarised by treatment group and visit. 
6.12.10 Proportion of patients with a 2-point worsening of m-SOFA from 
baseline to Day 7, 14, 21 and 28 
6.12.10.1 
Analysis 
The proportion of patients showing a 2-point worsening/increase in m-SOFA score at 
days 7, 14, 21 and 28 will be compared between treatment groups using a MMRM 
logistic regression model. 
At each visit, patients achieving a >=2-point increase in m-SOFA score from baseline 
will be assigned a value of 1 (indicating a 2-point worsening) while patients achieving 
<2-point increase in MELD score will be assigned a value of 0 (indicating not a 2-point 
worsening). 
The model will include treatment, visit, treatment-by-visit interaction and baseline 
m-SOFA score as a covariate. 
The variance/covariance matrix structure that results in best model fit will be selected 
using the process described in section 6.11.1. 
The adjusted LS Means for the treatment odds of achieving the endpoint and treatment 
odds ratio (DS102:Placebo) along with corresponding 95% CIs and p-value 
(corresponding to the treatment odds ratio) will be presented at days 7, 14, 21 and 28. 
6.12.10.2 
Descriptive summaries and listing 
The number and percentage of patients showing and patients not showing a two-point 
worsening in m-SOFA at days 7, 14, 21 and 28 will be presented by treatment group. 
6.12.11 Change in hepatic encephalopathy as assessed by West Haven 
Criteria, from baseline to Day 7, 14, 21 and 28 
The West Haven Criteria is used to classify the severity of hepatic encephalopathy 
with a grading of 1  4, grade 1 being the least serious with the patient having a trivial 
lack of awareness to grade 4 in which the patient is in a state of unconsciousness. 
6.12.11.1 
Analysis 
West Haven Criteria data will be analysed using an MMRM ordinal logistic regression 
model. The model will include treatment, visit and treatment-by-visit interaction as 
fixed effects and baseline west haven criteria as a covariate. 
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The variance/covariance matrix structure that results in best model fit will be selected 
using the process described in section 6.11.1. 
Assumptions about the proportionality of odds will also be assessed. Should 
assumptions not hold an alternative approach to the analysis will be decided following 
the BDRM and will be detailed in a SAP amendment. 
The LS estimate for the treatment odds of achieving the endpoint and treatment odds 
ratio (DS102:Placebo) along with corresponding 95% CIs and p-value (corresponding 
to the treatment odds ratio) will be presented at days 7, 14, 21 and 28.  
6.12.11.2 
Descriptive summaries and listing 
West Haven Criteria observed values and absolute change from baseline will be listed 
and summarised by treatment group and visit. 
6.12.12 Incidence of acute kidney injury over 28 days  
The number and percentage of patients who experienced an acute kidney injury 
between baseline and day 28 will be summarised by treatment group. The associated 
95% Clopper-Pearson exact confidence intervals will also be presented. 
Details of treatment measures undertaken for the acute kidney injury will also be 
summarised. 
All acute kidney injury data will be listed. 
6.12.13 Incidence of variceal haemorrhage, ascites or hepatic encephalopathy 
over 28 days  
The number and percentage of patients who experience a variceal haemorrhage 
between Baseline and Day 28 will be summarised by treatment group. The associated 
95% Clopper-Pearson exact confidence intervals will also be presented. 
The number and percentage of patients who have ascites between baseline and day 
28 will be summarised by treatment group. The associated 95% Clopper-Pearson 
exact confidence intervals will also be presented. 
Patients who have a hepatic encephalopathy score of 2 or 3 in the data collected for 
the Child-Pugh score will be classed as having hepatic encephalopathy (Yes). Any 
patient with a score of 1 will be classed as not having hepatic encephalopathy (No). 
the number and percentages of patients who have hepatic encephalopathy between 
baseline and day 28 will be summarised by treatment group. The associated 95% 
Clopper-Pearson exact confidence intervals will also be presented. 
All variceal haemorrhage and ascites data will be listed.  Hepatic encephalopathy will 
be included into the Child-Pugh listing. 
6.13 Exploratory Endpoints 
6.13.1 Survival at day 7, 14, 21, 28 and 90  
Survival time will be derived as: 
(Death date/last date patient known to be alive  date of randomisation + 1). 
Survival time will be analysed with a Cox proportional hazards model including 
covariates for treatment group and baseline MELD score. Tied observations will be 
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handled using the Breslow-Henshaw method.  The assumption of proportional hazards 
will be assessed visually using the log-log plot. 
Estimates for the hazard ratio (DS102:Placebo), associated 95% CI and p-values will 
be presented. 
Estimates of survival rate and associated 95% CI at days 7, 14, 21, 28 and 90 will be 
presented for each treatment group. 
Kaplan-Meier plot of the probability of survival against time (days) will be presented 
for each treatment group.  
6.13.2 Change in GT from baseline to day 7, 14, 21 and 28 
Gamma glutamyl transferase is a liver enzyme indicative of liver dysfunction and 
alcohol intake. 
6.13.2.1 
Analysis 
Change in GT from baseline up to and including day 28 will be assessed with an 
MMRM analysis, using the FAS, including terms for treatment group, visit, treatment-
by-visit as fixed effects and the baseline GT value as a covariate. The adjusted 
treatment means and adjusted mean difference between the active dose and placebo 
will be presented along with 95% CI and p-value for the day 7, 14, 21 and 28 timepoint.  
The modelling process described in section 6.11.1 will be followed. 
6.13.2.2 
Descriptive summaries and listing 
Covered under section 16.7. 
6.13.3 Change in ALT from baseline to day 7, 14, 21 and 28 
Alanine aminotransferase is liver enzyme and a marker of liver injury. 
6.13.3.1 
Analysis 
Change in ALT from baseline up to and including day 28 will be assessed with an 
MMRM analysis, using the FAS, including terms for treatment group, visit, treatment-
by-visit as fixed effects and the baseline ALT value as a covariate. The adjusted 
treatment means and adjusted mean difference between the active dose and placebo 
will be presented along with 95% CI and p-value for the day 7, 14, 21 and 28 timepoint.  
The modelling process described in section 6.11.1 will be followed. 
6.13.3.2 
Descriptive summaries and listing 
Covered under section 16.7. 
6.13.4 Change in Child-Pugh score from baseline to day 7, 14, 21 and 28 
The Child-Pugh score is a means of assessing the severity of chronic liver disease, 
including cirrhosis, based on five clinical parameters (bilirubin, albumin, INR, ascites 
and hepatic encephalopathy) scored on a scale of 1 to 3. A total score is which 
indicates the severity and prognosis of chronic liver disease is then derived. 
6.13.4.1 
Analysis 
Change in Child-Pugh score from baseline up to and including day 28 will be assessed 
with an MMRM analysis, using the FAS, including terms for treatment group, visit, 
treatment-by-visit as fixed effects and the baseline Child-Pugh score as a covariate. 
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The adjusted treatment means and adjusted mean difference between the active dose 
and placebo will be presented along with 95% CI and p-value for the day 7, 14, 21 and 
28 timepoint.  
The modelling process described in section 6.11.1 will be followed. 
6.13.4.2 
Descriptive summaries and listing 
Child-Pugh score observed values, absolute change from baseline and percentage 
change from baseline will be listed and summarised by treatment group and visit. 
6.13.5 Change in APACHE-II score from baseline to day 7, 14 , 21 and 28 
The acute physiologic and chronic health evaluation II score will assess patients for 
the presence of multiple organ dysfunction and predict mortality by generating a point 
score ranging from 0 to 71 based on twelve physiologic variables, age and underlying 
health. 
6.13.5.1 
Analysis 
Change in APACHE-II score from baseline up to and including day 28 will be assessed 
with an MMRM analysis, using the FAS, including terms for treatment group, visit, 
treatment-by-visit as fixed effects and the baseline APACHE-II value as a covariate. 
The adjusted treatment means and adjusted mean difference between the active dose 
and placebo will be presented along with 95% CI and p-value for the day 7, 14, 21 and 
28 timepoints.  
The modelling process described in section 6.11.1 will be followed. 
6.13.5.2 
Descriptive summaries and listing 
APACHE-II score observed values, absolute change from baseline and percentage 
change from baseline will be listed and summarised by treatment group and visit. 
6.13.6 Change in Lille score from baseline to day 7, 14, 21 and 28 
The Lille score is a composite score which predicts mortality in patients with AH who 
are not responding to steroid therapy. It is based on age, albumin, bilirubin (initial), 
bilirubin (day 7), creatinine and prothrombin time. A score of > 0.45 identifies 75% of 
deaths, a score of > 0.45 predicts a 6-month survival of 25% and a score of < 0.45 
predicts survival of 85%. 
6.13.6.1 
Analysis 
Change in Lille score from baseline up to and including day 28 will be assessed with 
an MMRM analysis, using the FAS, including terms for treatment group, visit, 
treatment-by-visit as fixed effects and the baseline Lille score as a covariate. The 
adjusted treatment means and adjusted mean difference between the active dose and 
placebo will be presented along with 95% CI and p-value for the day 7, 14, 21 and 28 
timepoints.  
The modelling process described in section 6.11.1 will be followed. 
6.13.6.2 
Descriptive summaries and listing 
Lille score observed values, absolute change from baseline and percentage change 
from baseline will be listed and summarised by treatment group and visit. 
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6.13.7 Combination of change of MELD score from baseline, premature 
treatment terminations and mortality 
A 5-level ordinal variable combining change of MELD score from baseline, premature 
treatment terminations and mortality will be derived. 
Each patient will be allocated to the lowest/worst level that occurred. 
Level 1: death within 28 days using survival time derived in section 6.13.1 
Level 2: death within 90 days using survival time derived in section 6.13.1 
Level 3: early termination because of safety issues or lack of efficacy 
Level 4: no improvement in MELD score at day 28 compared to baseline (classed as 
less than 25% reduction in MELD score from baseline to day 28). 
Level 5: improvement in MELD score at day 28 compared to baseline (classed as 
greater than or equal to a 25% reduction in MELD score baseline to day 28). 
Patients who are lost to follow up within 28 days and therefore do not have a day 28 
MELD score will be allocated to level 4 or 5 depending on their imputed result at day 
28 based on the model in section 6.11.1 under a missing at random (MAR) 
assumption.  
6.13.7.1 
Analysis 
The 5-level ordinal variable will be analysed using an ordinal logistic regression model. 
The model will include treatment as a fixed effect and baseline MELD score as a 
covariate. 
Assumptions about the proportionality of odds will also be assessed. Should 
assumptions not hold, then the treatment odds ratios for the individual cumulative 
levels of the variable will be presented.. 
The adjusted LS estimate for the treatment odds and treatment odds ratio 
(DS102:Placebo) along with corresponding 95% CI and p-value (corresponding to the 
treatment odds ratio) will be presented.  
6.13.7.2 
Descriptive summaries and listing 
The 5-level ordinal variable be listed and summarised by treatment group and visit. 
6.14 Multiplicity 
All secondary endpoints and the supportive analyses will be considered as descriptive 
evidence of efficacy and will be analysed without any procedures to account for 
multiple comparisons. 
6.15  Pharmacokinetics 
Pharmacokinetics analyses for the pilot and double-blind phases of the study will be 
conducted as detailed in Appendix 1 Pharmacokinetic Data Analysis Plan (PKAP).  
Only outputs relating to the double-blind phase will be produced as part of this SAP.  
Note the double-blind phase is referred to as treatment phase in the PKAP. 
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6.16  Safety Evaluation 
6.16.1 Adverse Events 
Adverse events (AEs) will be coded using the latest MedDRA dictionary version.  The 
version used will be indicated in the data summaries and listings.  
A treatment-emergent adverse event (TEAE) is defined as an AE that started on or 
after the start of the administration study treatment. If adverse event dates are 
incomplete and it is not clear whether the adverse event was treatment-emergent, it 
will be assumed to be treatment-emergent. 
Any AE commencing after the last administration of study treatment may be 
considered treatment emergent. 
A summary table by treatment and overall will present the following:  
 TEAEs (events and patients).  
 Serious TEAEs (events and patients).  
 Serious study treatment related TEAEs (events and patients). 
 TEAEs by pattern (intermittent/continuous/single event) (events and patients). 
 TEAEs by severity (mild/moderate/severe) (events and patients). 
 TEAEs by relationship to study treatment (events and patients). 
 TEAEs leading to withdrawal from study (patients only).  
 TEAEs leading to discontinuation of study treatment (patients only). 
 Study treatment related TEAEs leading to discontinuation of study treatment 
(patients only). 
 TEAEs leading to death (patients only). 
In the above summaries, if a patient experienced more than one TEAE, the patient will 
study 
treatment  and related to study treatment
 and at the worst severity for the 
 If a patient experienced more than one TEAE, the patient will 
be counted once for each pattern recorded.  For summaries at the patient level, the 
number and percent of patients will be presented. 
The above summary table will be presented for the pilot and double-blind phases. 
The following tables will be presented: 
 TEAEs by System Organ Class (SOC) and Preferred Term (PT). 
 TEAEs by PT. 
 TEAEs by SOC, PT and severity. 
 TEAEs by SOC, PT and relationship to study treatment (related/ not related). 
 Serious TEAEs by SOC and PT 
 TEAEs leading to withdrawal by SOC and PT 
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For all of the above, SOC and PT will be presented in decreasing frequency of the 
total number of patients with TEAEs.  Number of events and number and percentage 
of patients will be presented. 
Further details of the above four tables are given below: 
1. If a patient experienced more than one TEAE the patient will be counted once 
for each SOC and once for each PT. 
2. If a patient experienced more than one TEAE, the patient will be counted once 
for each PT. 
3. If a patient experienced more than one TEAE, the patient will be counted once 
for each SOC and once for each PT at the worst severity. 
4. If a patient experienced more than one TEAE, the patient will be counted once 
for each SOC and once for each PT using the most related event. 
Adverse event data will be listed in full and this will also include a treatment emergent 
flag, the time of onset and cessation of event percentage to first dosing of study 
treatment and duration of AE.   
6.17 Clinical Laboratory Evaluation 
Observed values and change from baseline in haematology, biochemistry, urinalysis, 
and coagulation assessments will be summarised over time. If the test results are 
reported in categorical format, the results will be summarised by patient counts and 
percentage for each category.  Percentage change will be included on the 
biochemistry summary table. 
Ratio of AST to ALT will be derived and presented along with the other assessments. 
Each haematology, biochemistry, urinalysis and coagulation parameter will be classed 
as low, normal, high, missing based on the reference ranges. Shift tables in relation to 
the normal range from baseline over time will be presented.  
Haematology, biochemistry, urinalysis and coagulation data will be listed separately 
including change from baseline, reference ranges flagging all out of range values and 
their clinical significance. 
Listings of clinically significant haematology, biochemistry, urinalysis and coagulation 
laboratory measurements recorded throughout the study will be provided. 
6.18 Vital Signs 
Vital sign observed values and change from baseline by parameter (unit) will be 
summarised over time. 
from baseline in systolic/diastolic blood pressure (systolic BP [<-40 mmHg, 
>+40 mmHg], diastolic BP [<-20 mmHg, >+20 mmHg]) and heart rate [<-30 bpm, 
>+30 bpm]). The number and percentage of patients with changes from baseline as 
categorised above will be summarised separately for positive and negative changes 
over time and at any post-baseline time point.    
All vital sign data will be listed including change from baseline and flags for substantial 
changes from baseline, reference ranges flagging all out of range values and their 
clinical significance. 
DocuSign Envelope ID: 48CDB6F0-2DB3-4F28-BA09-C054F65F86FE


Syne qua non study no: ANE18001 
 
Afimmune study no: DS102A-05-AH1 
 
Date: 25JAN2019 
Page 25 of 26 
Version: Final 1.0 
ST/form/010/11 
 
A listing of clinically significant vital signs recorded throughout the study will be 
provided. 
6.19 Electrocardiography 
The overall interpretation of the ECG (Normal, Abnormal Not Clinically Significant 
(NCS), and Abnormal Clinically Significant (CS)) will be summarised over time. 
All ECG data will be listed. 
6.20 Physical Examination 
Details of timings of physical examinations will be listed.  
6.21 Pregnancy test 
Pregnancy test details will be listed. 
6.22 Exploratory Blood Collection 
Exploratory blood collection data will be listed. 
6.23 Liver Histopathology 
Liver Biopsy History and Liver histopathology data including Non-Alcoholic 
Steatohepatitis (NASH) activity grading and fibrosis staging will be summarised and 
listed. 
6.24 Nutritional Status Assessment  
Bedside subjective global assessment will be scored as (0,1,2 and 3). Patients will be 
classified into the following categories: well nourished (0), mild malnutrition (1), 
moderate malnutrition (2) and severe malnutrition (3). 
 
BMI will be recorded on the eCRF.  
 
Nutritional status assessment data will be summarised and listed. 
6.25 Changes from the Protocol Planned Analysis 
The study protocol refers to a total population set however no analyses will be 
performed using this set because screen failures will not be databased. 
The study protocol section 5.3 states that exploratory endpoints for APACHE-II and 
Lille scores will be change from baseline to Day 7, 14 and 28, this SAP is also including 
change from baseline to Day 21 as an exploratory outcome to be in-line with other 
outcome measures. 
The study protocol section 5.4 states that SUSARs will be one of the safety endpoints, 
reporting of these is not covered by this SAP. 
The study protocol section 12.9.1 refers to calculation and reporting of PK parameters 
for the double-blind phase.  These will not be carried out as part of the PKAP and will 
not be reported as part of this SAP. 
 
 
DocuSign Envelope ID: 48CDB6F0-2DB3-4F28-BA09-C054F65F86FE


Syne qua non study no: ANE18001
Afimmune study no: DS102A-05-AH1
Date: 25JAN2019 
Page 26 of 26
Version: Final 1.0
ST/form/010/11
7
APPENDIX 1 
PHARMOCOKINETIC DATA ANALYSIS PLAN
Afm091318_PK 
DAP_V01.docx
Afm091318_PK DAP 
TABLES_V01.xlsx
Afm091318_PK DAP 
FIGURES_V01.xlsx
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$475ae068c3a8$8D3D76A8324E45D39E9101282A36DB6F.Docx
15 Sep 2018
Study DS102A-05-AH1:  A Randomised, Double-Blind, Placebo-Controlled, Phase II Study 
to Assess the Efficacy and Safety of Orally Administered DS102 in Patients with 
Severe Acute Decompensated Alcoholic Hepatitis
Document Stage:  DRAFT
Prepared 15 September 2018
Roger D. Toothaker, PhD
Principal Consultant,
PKPD Strategies, LLC
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15 Sep 2018 
 
Signature Page 
 
 
PKPD Strategies Author/Reviewer/Approver: 
 
 
 
____________________________________                                  ___________________ 
Roger D. Toothaker, PhD 
 
 
 
 
 
Date 
Principal Consultant 
PKPD Strategies, LLC 
 
 
 
Sponsor Reviewer/Approver: 
 
 
____________________________________                                  __________________ 
Moayed Hamza 
 
 
 
 
 
 
Date 
Associate Medical Director 
Afimmune 
 
 
 
 
DocuSign Envelope ID: 48CDB6F0-2DB3-4F28-BA09-C054F65F86FE


 
 
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15 Sep 2018 
Table of Contents 
 
Signature Page ............................................................................................................................. 2 
Abbreviations ................................................................................................................................ 4 
Objectives and Rationale .............................................................................................................. 5 
Overview of Study and Planned Analysis .................................................................................. 5 
Scope ........................................................................................................................................ 5 
Compliance ............................................................................................................................... 5 
Protocol Summary ........................................................................................................................ 6 
Study Design ............................................................................................................................. 6 
Subject Population .................................................................................................................... 6 
Treatment Administration........................................................................................................... 6 
Sampling Design ....................................................................................................................... 6 
Input Data Handling ...................................................................................................................... 8 
Evaluability Criteria .................................................................................................................... 8 
Off-time Sample Times .............................................................................................................. 8 
Out of Range Data..................................................................................................................... 8 
Detectable Pre-dose Concentrations ......................................................................................... 8 
Outlying Data ............................................................................................................................. 8 
Missing Data.............................................................................................................................. 8 
Clinical Observations ................................................................................................................. 8 
Input Datafile Creation ............................................................................................................... 9 
Data Analysis .............................................................................................................................. 10 
Planned Pharmacokinetic Assessments .................................................................................. 10 
Planned Statistical Assessments ............................................................................................. 10 
Analysis Output/Summarization .................................................................................................. 11 
Summarization ........................................................................................................................ 11 
Datasets .................................................................................................................................. 11 
Data Displays .......................................................................................................................... 11 
Mock Data Displays .................................................................................................................... 14 
 
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15 Sep 2018 
Abbreviations 
 
 
%Extrap 
Percentage of AUCinf obtained by extrapolation 
ALQ 
Above the upper limit of assay quantification 
AUCinf 
Area under the plasma concentration-time curve  
from time 0 extrapolated to infinite time  
AUCt 
Area under the plasma concentration-time curve from  
time 0 to the time of the last quantifiable concentration  
AUCtau 
Area under the plasma concentration-time curve over a dosage interval 
BD 
Twice daily administration 
BLQ 
Below the limit of assay quantification 
Cavg 
Average plasma concentration over a dosage interval 
Clast 
Last quantifiable plasma concentration 
Cmax 
Maximum observed plasma concentration 
CV% 
Percent coefficient of variation 
D 
Dose 
DAP 
Data analysis plan 
dp 
Number of decimal points 
DSMB 
Data safety monitoring board 
Flucp 
Fluctuation at pharmacokinetic steady-state 
GeoMean 
Geometric mean 
Kel 
Apparent first-order terminal elimination rate constant  
LC/MS-MS 
Liquid chromatography tandem mass spectrometry 
PC 
CDISC-compliant concentration dataset 
PK 
Pharmacokinetic(s) 
PP 
CDISC-compliant pharmacokinetic dataset 
Rac 
Accumulation ratio at pharmacokinetic steady-state 
SD 
Standard deviation 
SOP 
Standard operating procedure 
t½ 
Apparent first-order terminal elimination half-life  
tlast 
Time to reach the last quantifiable plasma concentration 
tmax 
Time of maximum observed plasma concentration 
tss 
Time to achieve pharmacokinetic steady state 
15(S)-HEPE EE 
15-hydroxy eicosapentaenoic acid ethyl ester 
 
 
 
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15 Sep 2018 
Objectives and Rationale 
Overview of Study and Planned Analysis 
The objectives of this randomized, double-blind, placebo-controlled, Phase II study are as follows. 
Efficacy Objective: 
orally administered DS102 versus placebo, in the treatment of 
adult patients with severe acute decompensated Alcoholic Hepatitis (AH). 
Safety Objective: 
versus placebo, in the treatment of 
adult patients with severe acute decompensated AH. 
Pharmacokinetic Objective: 
 pharmacokinetics (PK) of 15(S)-HEPE following orally administered 
DS102 capsules, in six adult patients with AH in an initial pilot phase of the study, followed 
by trough level assessment of 15(S)-HEPE in all study participants. 
Scope  
The 3rd objective listed above is the focus of this data analysis plan.  This data analysis project 
covers data receipt and handling, pharmacokinetic data analysis, data display preparation, and 
summarization of the plasma free and total 15(S)-HEPE concentrations from the Pilot phase of 
this study.  Note:  Although included in the Mock Displays, data display preparation for the 
Treatment phase of this study is outside the scope of this analysis plan and will be conducted 
separately. 
Compliance  
This analysis is to be done in compliance with current PKPD Strategies Standard Operating 
Procedures (SOPs) and all applicable regulations and guidances. 
 
 
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15 Sep 2018 
Protocol Summary 
  
Study Design 
This is a multicenter, double blind, placebo controlled, 2-arm parallel group comparison Phase 2 
study. In an initial pilot phase, six patients will receive open label treatment with DS102 1000 mg 
orally twice daily (BD) within 30 minutes after a meal for 28 days. After the pilot phase, all patients 
will either receive 1000 mg DS102 (BD) or placebo (BD), in addition to standard of care therapy, 
within 30 minutes after a meal for 28 days in the two treatment groups of 60 patients each. 
 
DS102 exhibits a tmax of approximately 4 to 8 hours and a short elimination half-life (t½) of 
approximately 2 hours. High pharmacokinetic (PK) variability has been observed following both 
single and multiple dosing, and DS102 did not exhibit a linear correlation between increasing dose 
and resultant systemic exposure. Co-administration with food increased DS102 bioavailability, 
although there was no difference in bioavailability between normal and high fat diet fed conditions.  
Subject Population 
Subjects in this study will be male or female patients, aged 18 years or older, with evident severe 
acute decompensated alcoholic hepatitis.  
 
 
Treatment Administration 
DS102 will be provided as a capsule containing 500 mg of 15(S)-HEPE EE with 5% w/w of 
colloidal silicon dioxide as viscosity modifier.   In the open label pilot phase, 2000 mg 
(1000 mg BD) will be orally administered as 2 capsules within 30 minutes after a meal for 28 
days.  In the double-blind phase of the study either 1000 mg (BD) or placebo (BD) will be orally 
administered, in addition to standard of care therapy, within 30 minutes after a meal for 28 days.  
Treatment label will be 1000 mg DS102 BD.   
 
After the completion of the open-label phase of the study the DSMB will evaluate the safety and 
pharmacokinetic data and might recommend a dose adjustment for the double blind randomised 
phase of the study.  The decision to proceed with the double-blind phase of this study will be 
determined by the DSMB following review of the data from the pilot phase. 
 
Available information on concomitant standard-of-care treatment or medications used to treat 
comorbidities during the trial will be assessed for potential impact on observed pharmacokinetic 
results.   
 
Sampling Design 
During the study, 8 visits to the clinic are scheduled after the screening visit (Visit 1): one at the 
start of the comparative treatment period (Baseline/Visit 2) and six in the comparative treatment 
period (Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, Visit 8/Day 28 or 
Early Termination). 
 
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15 Sep 2018 
Blood samples for PK analysis will be collected via direct venipuncture as per the Study Flow 
Chart at Visit 2/Baseline, Visit 3/Day 3, Visit 4/Day 5, Visit 5/Day 7, Visit 6/Day 14, Visit 7/Day 21, 
and Visit 6/Day 28/Early Termination. Trough plasma samples will be obtained from all patients 
(pilot and double-blind phases) prior to first daily dose on the indicated days. Additional post-dose 
serial plasma samples will be obtained from the 6 patients of the Pilot phase for full PK 
characterization on Days 0 and 7 at 0.5, 1, 2, 3, 4, 6, 7, 8, 10, and 12 (before next dose) hours 
post-dose. A 1 mL blood sample will be taken at each time point. Following centrifugation, plasma 
samples will be split in two and a back-up sample will be handled as described in the laboratory 
manual. 
 
Plasma free and total 15(S)-HEPE concentrations will be determined by Charles River 
Laboratories (Edinburgh Ltd) using validated liquid chromatography tandem mass spectrometry 
(LC-MS/MS) methods. 
 
 
DocuSign Envelope ID: 48CDB6F0-2DB3-4F28-BA09-C054F65F86FE


 
 
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15 Sep 2018 
Input Data Handling 
 
Evaluability Criteria 
The Pharmacokinetic (PK) Set will consist of those patients who have at least one quantifiable 
post-dose plasma 15(S)-HEPE concentration. Patients will be analysed according to the treatment 
actually taken.  An evaluable profile allows the determination of one or more PK parameters and 
will be determined at the discretion of the pharmacokineticist. The Pharmacokinetic set will be 
used for the summaries of all PK data. 
 
Off-time Sample Times 
Actual sampling times will be used for all analyses.  Nominal time will be used to tabulate plasma 
15(S)-HEPE concentrations by time and for all figures.   
 
Out of Range Data 
Plasma 15(S)-HEPE concentration-time data will be reviewed to confirm all reported values are 
valid and are within the lower and upper limits of assay quantitation.  Values below or above these 
limits will be identified as BLQ and ALQ, respectively.  BLQ values will be treated either as zero 
for concentrations prior to the first Cmax or as missing values in all other pharmacokinetic 
analyses and data presentations.  ALQ values will be treated as missing in all analyses and 
presentations. 
 
Detectable Pre-dose Concentrations 
Plasma 15(S)-HEPE concentration data will be reviewed for detectable pre-dose concentrations.  
Detectable values will be handled according to procedures described in applicable PKPD 
Strategies SOPs.   
 
Outlying Data 
Plasma 15(S)-HEPE concentration data will be reviewed for outlying or unexpected post-dose 
concentrations.  Questionable values will be queried for possible reassay, and may be used or 
excluded at the discretion of the pharmacokineticist with concurrence from the sponsor. 
 
Missing Data 
Plasma 15(S)-HEPE concentration data will be reviewed for missing concentrations.  Reasons for 
missing values will be assessed and followed up accordingly.   
 
For any known hemolyzed plasma samples, consistency of the sample concentration with that 
-time profile will be assessed.   If considered inconsistent by the 
pharmacokineticist, the affected profile may be analyzed either without the concentration for the 
sample in question or analyzed with and without, whichever is more appropriate at the discretion 
of the pharmacokineticist with concurrence from the sponsor.   
 
Clinical Observations 
If available, clinical observations pertinent to the pharmacokinetic analysis such as body weight, 
BMI, emesis or concomitant medications may be assessed for potential impact on the outcome of 
the analysis.   
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15 Sep 2018 
 
Input Datafile Creation  
 
 
Source 
Data will be obtained directly from the Sponsor or their designee. 
 
 
Format 
Concentration and associated elapsed time (sampling time minus prior dosing time) results will be 
received in an Excel-readable file format and will be identified by Study Period, Treatment, 
Subject, and Nominal Time.  Data format has not been prespecified, and will be used as received 
from the Sponsor or their designee. 
 
 
Precision 
Data precision has not been prespecified, and will be used as received.  Precision of reported 
results will follow applicable PKPD Strategy SOPs. 
 
 
Units 
Time is to be reported in hours and plasma 15(S)-HEPE concentrations are to be reported in 
ng/mL.   
 
 
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15 Sep 2018 
Data Analysis 
  
 
Planned Pharmacokinetic Assessments 
Plasma free and total 15(S)-HEPE concentration-time results will be processed according to 
standard noncompartmental pharmacokinetic analysis procedures using actual sampling times.  
The software programs to be used are Phoenix WinNonlin Version 6.4 (Certara Corporation, 
USA), Microsoft Office Excel 2010, and Microsoft Office Word 2010.   
 
Where feasible, the following non-compartmental PK parameters will be generated:  
 
Parameter
Definition
Units
Precision
%Extrap 
Percentage of AUCinf obtained by extrapolation 
% 
1 dp 
AUCinf 
Area under the plasma concentration-time curve  
from time 0 extrapolated to infinite time  
1 dp 
AUCt 
Area under the plasma concentration-time curve from  
time 0 to the time of the last quantifiable concentration  
1 dp 
AUCtau 
Area under the plasma concentration-time curve over a 
dosage interval 
1 dp 
Cavg 
Average plasma concentration over a dosage interval 
ng/mL 
3 dp 
Clast 
Last quantifiable plasma concentration 
ng/mL 
3 dp 
Cmax 
Maximum observed plasma concentration 
ng/mL 
3 dp 
Flucp 
Fluctuation at pharmacokinetic steady-state 
% 
1 dp 
Kel 
Apparent first-order terminal elimination rate constant  
1/hr 
4 dp 
Rac 
Accumulation ratio at pharmacokinetic steady-state 
% 
1 dp 
t½ 
Apparent first-order terminal elimination half-life  
hr 
1 dp 
tlast 
Time to reach the last quantifiable plasma concentration 
hr 
1 dp 
tmax 
Time of maximum observed plasma concentration 
hr 
1 dp 
tss 
Time to achieve pharmacokinetic steady state 
hr 
1 dp 
 
 
Planned Statistical Assessments 
Descriptive statistics will be used to summarize plasma free and total 15(S)-HEPE concentrations 
and resultant pharmacokinetic parameters by treatment across study subjects. Summary statistics 
will include number of non-missing observations, geometric mean, mean, standard deviation, 
coefficient of variation, minimum, median, and maximum as appropriate.  
 
 
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15 Sep 2018 
Analysis Output/Summarization 
Data displays for patients from the pilot phase and the double-blind phase of the study will be 
presented separately. Should the study be discontinued after the pilot phase, the listings 
described in the sections below will be produced for the pilot phase only.  
 
Summarization 
Pharmacokinetic analysis methods, results, and conclusions will be summarized in a separate PK 
Report, with pertinent information included in the clinical study report.  Results for plasma 
15(S)-HEPE concentrations and 15(S)-HEPE pharmacokinetic parameters will be summarized 
and discussed relative to differences between treatments and prior study results.  Conclusions 
related to the study objectives will be presented.  
 
Datasets 
Plasma 15(S)-HEPE concentration time data used for input into the PK analysis will be provided 
as a CDISC-compliant PC dataset.  Resultant 15(S)-HEPE PK parameter results will be provided 
as a CDISC-compliant PP dataset.   
Data Displays  
Planned data displays are listed as follows.   
 
TABLES 
In-Text: 
Table A.  Descriptive Statistics for Plasma Free 15(S)-HEPE Pharmacokinetic Results for 1000 
mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis (Protocol 
DS102A-05-AH1  Pilot Phase).      
 
Table B.  Descriptive Statistics for Plasma Total 15(S)-HEPE Pharmacokinetic Results for 1000 
mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis (Protocol 
DS102A-05-AH1  Pilot Phase).     
 
 
End-of-Text: 
Table 1.  Individual Plasma Free 15(S)-HEPE Concentrations (ng/mL) and Descriptive Statistics 
for 1000 mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis 
(Protocol DS102A-05-AH1  Pilot Phase, Day 0) 
 
Table 2.  Individual Plasma Free 15(S)-HEPE Concentrations (ng/mL) and Descriptive Statistics 
for 1000 mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis 
(Protocol DS102A-05-AH1  Pilot Phase, Day 7) 
 
Table 3.  Individual Plasma Free 15(S)-HEPE Concentrations (ng/mL) and Descriptive Statistics 
for 1000 mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis 
(Protocol DS102A-05-AH1  Pilot Phase, Troughs) 
 
Table 4.  Individual Plasma Total 15(S)-HEPE Concentrations (ng/mL) and Descriptive Statistics 
for 1000 mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis 
(Protocol DS102A-05-AH1  Pilot Phase, Day 0) 
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15 Sep 2018 
 
Table 5.  Individual Plasma Total 15(S)-HEPE Concentrations (ng/mL) and Descriptive Statistics 
for 1000 mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis 
(Protocol DS102A-05-AH1  Pilot Phase, Day 7) 
 
Table 6.  Individual Plasma Total 15(S)-HEPE Concentrations (ng/mL) and Descriptive Statistics 
for 1000 mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis 
(Protocol DS102A-05-AH1  Pilot Phase, Troughs) 
 
Table 7.  Individual Plasma Free 15(S)-HEPE Pharmacokinetic Parameter Values and Descriptive 
Statistics for 1000 mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic 
Hepatitis (Protocol DS102A-05-AH1  Pilot Phase) 
 
Table 8.  Individual Plasma Free 15(S)-HEPE Pharmacokinetic Parameter Values and Descriptive 
Statistics for 1000 mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic 
Hepatitis (Protocol DS102A-05-AH1  Pilot Phase) 
   
 
FIGURES 
In-Text: 
Figure A.  Mean (+/-SD) Day-overlay Plasma Free 15(S)-HEPE Concentrations (ng/mL) versus 
Time (linear and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily 
to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Pilot Phase, Days 0 and 7).       
 
Figure B.  Mean (+/-SD) Day-overlay Plasma Total 15(S)-HEPE Concentrations (ng/mL) versus 
Time (linear and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily 
to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Pilot Phase, Days 0 and 7).       
 
Figure C.  Mean (+/-SD) Plasma Free 15(S)-HEPE Concentrations (ng/mL) versus Time (linear 
and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily to Patients 
with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Pilot Phase, Trough Concentrations). 
 
Figure D.   Mean (+/-SD) Plasma Total 15(S)-HEPE Concentrations (ng/mL) versus Time (linear 
and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily to Patients 
with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Pilot Phase, Trough Concentrations). 
 
 
End-of-Text: 
Figure 1.  Individual Subject-overlay Plasma Free 15(S)-HEPE Concentrations (ng/mL) versus 
Time (linear and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily 
to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Pilot Phase, Day 0).       
 
Figure 2.  Individual Subject-overlay Plasma Total 15(S)-HEPE Concentrations (ng/mL) versus 
Time (linear and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily 
to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Pilot Phase, Day 0).       
 
Figure 3.  Individual Subject-overlay Plasma Free 15(S)-HEPE Concentrations (ng/mL) versus 
Time (linear and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily 
to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Pilot Phase, Day 7).       
 
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15 Sep 2018 
Figure 4.  Individual Subject-overlay Plasma Total 15(S)-HEPE Concentrations (ng/mL) versus 
Time (linear and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily 
to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Pilot Phase, Day 7).       
 
Figure 5.  Individual Subject-overlay Plasma Free 15(S)-HEPE Concentrations (ng/mL) versus 
Time (linear and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily 
to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Pilot Phase, Trough 
Concentrations). 
 
Figure 6.  Individual Subject-overlay Plasma Total 15(S)-HEPE Concentrations (ng/mL) versus 
Time (linear and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily 
to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Pilot Phase, Trough 
Concentrations). 
 
 
APPENDICES 
Appendix Figures 1.1-1.6.  Individual Plasma Free 15(S)-HEPE Concentrations (ng/mL) versus 
Time (semilogarithmic scale only) and Terminal Phase Regressions, by Subject for 1000 mg BD 
DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis (Protocol DS102A-05-
AH1- Pilot Phase, Days 0 and 7).      
 
Appendix Figures 1.7-1.12.  Individual Plasma Total 15(S)-HEPE Concentrations (ng/mL) versus 
Time (semilogarithmic scale only) and Terminal Phase Regressions, by Subject for 1000 mg BD 
DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis (Protocol DS102A-05-
AH1- Pilot Phase, Days 0 and 7).      
 
 
DATA DISPLAYS FOR TREATMENT STUDY-PHASE (prepared separately) 
 
Table x1.  Descriptive Statistics for Plasma Free 15(S)-HEPE Concentrations (ng/mL) for 1000 
mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis (Protocol 
DS102A-05-AH1  Treatment Phase).   
 
Table x2.  Descriptive Statistics for Plasma Total 15(S)-HEPE Concentrations (ng/mL) for 1000 
mg BD DS102 Administered Orally Twice-daily to Patients with Alcoholic Hepatitis (Protocol 
DS102A-05-AH1  Treatment Phase).   
 
Table x3.  Individual Plasma Free 15(S)-HEPE Concentrations (ng/mL) for 1000 mg BD DS102 
Administered Orally Twice-daily to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  
Treatment Phase).   
 
Table x4.  Individual Plasma Total 15(S)-HEPE Concentrations (ng/mL) for 1000 mg BD DS102 
Administered Orally Twice-daily to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  
Treatment Phase).   
 
Figure x1.  Mean (+/-SD) Plasma Free 15(S)-HEPE Concentrations (ng/mL) versus Time (linear 
and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily to Patients 
with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Treatment Phase).   
 
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15 Sep 2018 
Figure x2.  Mean (+/-SD) Plasma Total 15(S)-HEPE Concentrations (ng/mL) versus Time (linear 
and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily to Patients 
with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Treatment Phase).   
   
Figure x3.  Individual Subject-overlay Plasma Free 15(S)-HEPE Concentrations (ng/mL) versus 
Time (linear and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily 
to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Treatment Phase).       
 
Figure x4.  Individual Subject-overlay Plasma Total 15(S)-HEPE Concentrations (ng/mL) versus 
Time (linear and semilogarithmic scales) for 1000 mg BD DS102 Administered Orally Twice-daily 
to Patients with Alcoholic Hepatitis (Protocol DS102A-05-AH1  Treatment Phase).       
Mock Data Displays 
Content and layout of the planned tables and figures are represented in the mock displays 
(provided separately from this document).  Final format and content may differ from these displays 
depending on the outcome of the data analysis.  
 
 
 
 
 
DocuSign Envelope ID: 48CDB6F0-2DB3-4F28-BA09-C054F65F86FE






















Plasma 15(S)-HEPE Concn (ng/mL)
Plasma 15(S)-HEPE Concn (ng/mL)


Plasma 15(S)-HEPE Concn (ng/mL)
Plasma 15(S)-HEPE Concn (ng/mL)


Plasma 15(S)-HEPE Concn (ng/mL)
Plasma 15(S)-HEPE Concn (ng/mL)


Plasma 15(S)-HEPE Concn (ng/mL)
Plasma 15(S)-HEPE Concn (ng/mL)


Plasma 15(S)-HEPE Concn (ng/mL)




Plasma 15(S)-HEPE Concn (ng/mL)
Plasma 15(S)-HEPE Concn (ng/mL)


Plasma 15(S)-HEPE Concn (ng/mL)
Plasma 15(S)-HEPE Concn (ng/mL)


Certificate Of Completion
Envelope Id: 48CDB6F02DB34F28BA09C054F65F86FE
Status: Completed
Subject: DS102A-05-AH1 (ANE18001): Statistical Analysis Plan for signature
Source Envelope: 
Document Pages: 58
Signatures: 3
Envelope Originator: 
Certificate Pages: 5
Initials: 0
Elizabeth Gardener
AutoNav: Enabled
EnvelopeId Stamping: Enabled
Time Zone: (UTC) Dublin, Edinburgh, Lisbon, London
Gostling House
Diss Business Park
Diss, Norfolk  IP22 4GT
elizabeth.gardener@synequanon.com
IP Address: 62.232.1.93
Record Tracking
Status: Original
             25 January 2019 | 15:22
Holder: Elizabeth Gardener
             elizabeth.gardener@synequanon.com
Location: DocuSign
Signer Events
Signature
Timestamp
Elizabeth Gardener
elizabeth.gardener@synequanon.com
Senior Statistician
Syne qua non
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
A40AC555-1C6B-49FB-A379-312B0D6DA509
Using IP Address: 62.232.1.93
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I am the author of this document
Sent: 25 January 2019 | 15:36
Viewed: 25 January 2019 | 19:02 
Signed: 25 January 2019 | 19:02
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
Winfried Koch
winfried.koch@bdskoch.de
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
BB319B10-1E3A-4170-945C-605D453A7759
Using IP Address: 78.42.144.114
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   Ich genehmige dieses Dokument
Sent: 25 January 2019 | 19:02
Viewed: 28 January 2019 | 11:50 
Signed: 28 January 2019 | 11:55
Electronic Record and Signature Disclosure: 
      Accepted: 28 January 2019 | 11:50
      ID: 314ee483-dc04-4103-ba69-2a0f5ac406ce


Signer Events
Signature
Timestamp
Moayed Hamza
M.Hamza@afimmune.com
Associate Medical Director
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
F78A7A14-E5FE-4BA7-ACC2-D9A71DAFFFF1
Using IP Address: 86.47.150.97
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 25 January 2019 | 19:02
Viewed: 28 January 2019 | 12:06 
Signed: 28 January 2019 | 12:07
Electronic Record and Signature Disclosure: 
      Accepted: 28 January 2019 | 12:06
      ID: ec97e976-2f7c-48d5-924f-4a43cb3bfc7b
In Person Signer Events
Signature
Timestamp
Editor Delivery Events
Status
Timestamp
Agent Delivery Events
Status
Timestamp
Intermediary Delivery Events
Status
Timestamp
Certified Delivery Events
Status
Timestamp
Carbon Copy Events
Status
Timestamp
Amelia Greenfield
amelia.greenfield@synequanon.com
Senior Project Manager
Syne qua non Ltd
Security Level: Email, Account Authentication 
(Required)
Sent: 28 January 2019 | 12:07
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
28 January 2019 | 12:07
Certified Delivered
Security Checked
28 January 2019 | 12:07
Signing Complete
Security Checked
28 January 2019 | 12:07
Completed
Security Checked
28 January 2019 | 12:07
Payment Events
Status
Timestamps
Electronic Record and Signature Disclosure