Conditions: Non Alcoholic Fatty Liver Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
The purpose of this randomised, double-blind, placebo-controlled, parallel group study is to assess the safety and efficacy of orally administered Epeleuton capsules versus placebo in the treatment of adult patients with Non Alcoholic Fatty Liver Disease (NAFLD)

Detailed description:

Arms:
arm 1: 2 x placebo 500 mg capsules orally administered twice a day (4 capsules daily) for 16 weeks arm 2: 1 x Epeleuton 500 mg capsule and 1 x placebo 500 mg capsule orally administered twice a day (4 capsules daily) for 16 weeks arm 3: 2 x Epeleuton 500 mg capsules orally administered twice a day (4 capsules daily) for 16 weeks

Interventions: intervention 1: Placebo capsules intervention 2: Epeleuton
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
 
 
Confidential / Clinical Study Protocol No. DS102A-02 Version 6.0 
 
 
 
 
Page 1 of 61 
 
 
 
 
 
A Randomised, Double-Blind, Placebo-Controlled, Exploratory 
Phase IIa Study to Assess the Safety And Efficacy of Orally 
Administered DS102 in NAFLD Patients 
 
 
 
 
 
Protocol Number # DS102A-02 
 
Version 6.0 
  24 August 2018 
 
EudraCT No. 2016-000311-33 
 
 
 
 
Sponsor: 
 
 
 
 
 
 
Afimmune,  
Trintech Building,  
South County Business Park, 
Leopardstown,  
Dublin 18, 
Republic of Ireland. 
 
 
 
 


 
 
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CONTACT INFORMATION 
 
Chief Investigator: 
 
Prof. Philip Newsome 
Institute of Biomedical Research, 
Institute of Immunology and Immunotherapy, 
College of Medical and Dental Sciences, 
University of Birmingham, 
Edgbaston, 
Birmingham, 
B15 2TT, 
UK. 
 
 
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: 
Safety Physician, 
Product Life Ltd., 
The Jeffreys Building, 
St. John’s Innovation Park,  
Cowley Road, 
Cambridge CB4 0DS,  
United Kingdom. 
Tel: +44 (0) 1223 402660 
Email: safety@productlife-group.com 
 
 
 
 
 
 


 
 
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TABLE OF CONTENTS 
CONTACT INFORMATION .................................................................................................................. 2 
TABLE OF CONTENTS ....................................................................................................................... 3 
PRINCIPAL SITE INVESTIGATOR SIGNATURE PAGE ................................................................... 7 
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 
1.5 
TOXICOLOGY ............................................................................................................................ 18 
1.6 
PREVIOUS CLINICAL SAFETY STUDIES WITH 15(S)-HEPE ............................................................. 19 
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 
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 ......................................................................................................... 28 
7.5 
WITHDRAWAL OF PATIENTS ....................................................................................................... 28 
7.5.1 
Complete Withdrawal ........................................................................................................... 29 
7.5.2 
Withdrawals from Investigational Product ............................................................................. 29 
7.6 
PATIENT REPLACEMENT ............................................................................................................ 29 
7.7 
PROTOCOL VIOLATIONS ............................................................................................................ 29 
8 
STUDY CONDUCT ..................................................................................................................... 30 
8.1 
STUDY SCHEDULE ..................................................................................................................... 30 
8.2 
CLINIC VISITS ........................................................................................................................... 30 
A TABULATED FLOW CHART OF THE STUDY IS PRESENTED IN APPENDIX 1. .................................................. 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 
Week 2 (Visit 3) ................................................................................................................... 32 
8.2.5 
Week 4 (Visit 4) ................................................................................................................... 33 
8.2.6 
Week 6 (Visit 5) ................................................................................................................... 33 
8.2.7 
Week 8 (Visit 6) ................................................................................................................... 34 
8.2.8 
Week 10 (Visit 7) ................................................................................................................. 35 
8.2.9 
Week 12 (Visit 8) ................................................................................................................. 35 
8.2.10 
Week 14 (Visit 9) ............................................................................................................. 36 
8.2.11 
Week 16 (Visit 10) or Early Withdrawal ............................................................................. 36 


 
 
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8.2.12 
Follow up Visit (Week 20/Visit 11) .................................................................................... 37 
9 
ASSESSMENTS .......................................................................................................................... 39 
9.1 
EFFICACY ASSESSMENTS ........................................................................................................... 39 
9.1.1 
ALT, AST, ALT:AST Ratio .................................................................................................... 39 
9.1.2 
HOMA-IR/Adipo-IR ............................................................................................................. 39 
9.1.3 
ELF .................................................................................................................................... 39 
9.1.4 
Liver Stiffness and CAP ........................................................................................................ 39 
9.1.5 
FIB-4 Index ......................................................................................................................... 40 
9.1.6 
NFS .................................................................................................................................... 40 
9.2 
SAFETY ASSESSMENTS .............................................................................................................. 40 
9.2.1 
Medical History ................................................................................................................... 40 
9.2.2 
Physical Examination ........................................................................................................... 40 
9.2.3 
ECG ................................................................................................................................... 41 
9.2.4 
Vital Signs ........................................................................................................................... 41 
9.2.5 
Clinical Laboratory Safety Tests: Haematology, Serum Biochemistry, Coagulation, Lipid Profile, 
and Urinalysis ................................................................................................................................. 41 
9.2.6 
Virology .............................................................................................................................. 42 
9.2.7 
Pregnancy Test .................................................................................................................... 42 
9.2.8 
Blood Sampling ................................................................................................................... 42 
9.2.9 
Urine DOA and Alcohol Breath Test...................................................................................... 42 
9.2.10 
Adverse Event Assessment ................................................................................................ 43 
9.2.11 
Concomitant Medication .................................................................................................. 43 
9.2.12 
Bioanalysis ...................................................................................................................... 43 
9.2.13 
Sample Storage, Handling and Shipping ............................................................................ 43 
9.2.14 
Restrictions ..................................................................................................................... 43 
10 
INVESTIGATIONAL PRODUCT / INVESTIGATIONAL DRUG .............................................. 44 
10.1 
SUPPLY, PACKAGING, LABELLING, HANDLING AND STORAGE ....................................................... 44 
10.2 
DOSAGE AND ADMINISTRATION ................................................................................................. 44 
10.3 
DURATION OF TREATMENT ........................................................................................................ 45 
10.4 
DRUG ACCOUNTABILITY ........................................................................................................... 45 
11 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......................................................... 46 
11.1 
DEFINITIONS OF ADVERSE EVENTS ............................................................................................. 46 
11.1.1 
Seriousness ..................................................................................................................... 46 
11.1.2 
Severity ........................................................................................................................... 47 
11.1.3 
Relationship to IMP ......................................................................................................... 47 
11.1.4 
Reporting of AEs and SAEs ............................................................................................... 47 
11.2 
DRUG-INDUCED LIVER INJURY ................................................................................................... 48 
11.3 
SERIOUS ADVERSE REACTIONS AND UNEXPECTED ADVERSE REACTIONS ....................................... 48 
11.3.1 
Definitions ...................................................................................................................... 48 
11.3.2 
Reporting of suspected unexpected serious adverse reactions .............................................. 49 
11.4 
PREGNANCY REPORTING ........................................................................................................... 49 
12 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT ............................................. 50 
12.1 
STUDY DESIGN ......................................................................................................................... 50 
12.2 
RANDOMISATION ...................................................................................................................... 50 
12.3 
ESTIMATION OF SAMPLE SIZE ..................................................................................................... 50 
12.4 
BLINDING AND CODE BREAKING INSTRUCTIONS .......................................................................... 51 
12.5 
INTERIM ANALYSIS AND DATA MONITORING ............................................................................... 51 
12.6 
DATA ANALYSIS ....................................................................................................................... 51 
12.7 
CLINICALLY MEANINGFUL RESPONSE ......................................................................................... 51 
12.8 
ANALYSIS SETS ........................................................................................................................ 51 
12.9 
SAFETY ANALYSIS .................................................................................................................... 52 
12.10 STATISTICAL ANALYSIS PLAN .................................................................................................... 53 


 
 
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12.10.1 
Pharmacokinetic Analysis ................................................................................................. 53 
12.10.2 
Primary variables ............................................................................................................ 53 
12.10.3 
Secondary variables ......................................................................................................... 53 
12.11 DATA COLLECTION / CASE REPORT FORMS ................................................................................. 53 
12.12 DATA MANAGEMENT ................................................................................................................ 54 
12.13 PROTOCOL DEVIATIONS ............................................................................................................ 54 
 
13 
REGULATORY AND ADMINISTRATIVE PROCEDURES ...................................................... 55 
13.1 
DATA AND SAFETY MONITORING BOARD .................................................................................... 55 
13.2 
INSTITUTIONAL REVIEW ............................................................................................................ 55 
13.3 
GCP ........................................................................................................................................ 55 
13.4 
ESSENTIAL DOCUMENTS ............................................................................................................ 55 
13.5 
RECORD RETENTION ................................................................................................................. 55 
13.6 
MONITORING / QUALITY CONTROL ............................................................................................. 56 
13.7 
QUALITY ASSURANCE ............................................................................................................... 56 
13.8 
INSURANCE AND LIABILITY ........................................................................................................ 56 
13.9 
END OF TRIAL .......................................................................................................................... 56 
13.10 CONFIDENTIALITY .................................................................................................................... 56 
13.11 REPORT AND PUBLICATION ........................................................................................................ 56 
14 
REFERENCES ............................................................................................................................ 57 
15 
APPENDICES ............................................................................................................................. 60 
15.1 
APPENDIX 1: STUDY FLOW-CHART ............................................................................................. 60 
 
LIST OF FIGURES 
Figure 1. Structure of 15(S)-HEPE EE (DS102) .............................................................. 16 
Figure 2: Schematic summarising the results of 4 in vivo studies performed using the 
STAM™ Model (DS-PC-26, DS-PC-27, DS-PC-28, DS-PC-29). ............ 18 
Figure 3: Study Outline ..................................................................................................... 24 
 
LIST OF TABLES 
Table 1: DS102 Mechanism of Action Summary ............................................................. 17 
 
 
 
 






 
 
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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 Harmonization (ICH) Good Clinical 
Practices Guidelines, 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, Exploratory 
Phase IIa Study To Assess The Safety And Efficacy Of Orally 
Administered DS102 In Patients with NAFLD 
SHORT TITLE: 
Safety And Efficacy Study Of Orally Administered DS102 In Patients 
With NAFLD 
PHASE: 
IIa 
STUDY DURATION: 
24 weeks (Treatment Duration: 16 weeks) 
INVESTIGATIONAL 
PRODUCT: 
DS102 Capsule  
Placebo (paraffin oil) 
OBJECTIVES: 
To assess the safety and efficacy of orally administered DS102 
capsules versus placebo in the treatment of adult patients with Non-
Alcoholic Fatty Liver Disease (NAFLD) 
ENDPOINTS: 
Primary Endpoints 
 
Efficacy 
 
Change in serum ALT (alanine aminotransferase) from 
baseline to week 16 
 
Change in liver stiffness measurements by Transient 
Elastography from baseline to week 16 
 
Safety 
 
Number of Treatment Emergent Adverse Events (TEAEs) in each 
treatment group leading to treatment discontinuation 
 
Secondary Endpoints 
 
 
Change in serum ALT (alanine aminotransferase) from baseline 
to weeks 2, 4, 8 and 12 
 
Change in AST (aspartate aminotransferase) from baseline to 
weeks 2, 4, 8, 12 and 16 
 
Change in AST:ALT ratio from baseline to weeks 2, 4, 8, 12 and 
16 
 
Change in FIB-4 Index from baseline to week 16 
 
Change in NAFLD fibrosis score (NFS) from baseline to week 16 
 
Change in hepatic fat measured by CAP (controlled attenuation 
parameter) from baseline to week 16 
 
Change in ELF (Enhanced Liver Fibrosis score) from baseline to 
week 16 
Change in HOMA-IR/Adipo-IR (Homeostatic model assessment 
Insulin Resistance / Adipose tissue Insulin Resistance) from 
baseline to weeks 2, 4, 8, 12 and  16 


 
 
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STUDY DESIGN: 
This study will involve two dose levels of DS102 1000mg per day 
(500mg BD), 2000mg per day (1000mg BD) or placebo BD for 16 
weeks using three treatment groups consisting of 32 patients each.  
The sample size may be increased up to a maximum of 150 patients 
based on the recommendation of the independent DSMB after interim 
analysis. 
Patients with diagnosed NAFLD (Non-Alcoholic Fatty Liver Disease) 
will be enrolled in the study. After assessment and documentation of 
the baseline disease characteristics by the investigator, the patient will 
be randomly assigned to one of the above mentioned treatment 
groups. The patient will be provided with study medication containing 
one of the assigned doses of DS102 or placebo according to the 
randomisation. During the 16 weeks of treatment patients will take 
one of the treatments twice daily with or after food (morning and 
evening). 
  
Evaluation of efficacy will be performed throughout the study. A 
follow-up visit will be performed 4 weeks after the last date of 
treatment to monitor the treatment effects in comparison to the end of 
treatment. 
TOTAL NUMBER OF 
RANDOMISED 
PATIENTS: 
96 patients total. This may be increased up to a maximum of 150 
patients based on interim analysis. 
STUDY POPULATION: 
Inclusion criteria:  
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Patients diagnosed with NAFLD by the presence of hepatic 
steatosis on imaging or histology in the absence of any secondary 
causes. 
2. Patients with an ALT ≥ 1.5 ULN and < 5 ULN on two occasions 
7 or more days apart during screening. 
 
3. Patients with historical liver biopsy showing NASH and/or ≥ F1 
fibrosis OR NFS  ≥ -1.455 OR FIB-4  ≥ 1.3 OR Fibroscan  ≥8kPa 
within 3 months of screening.  
 
4. Patients with a body mass index (BMI) between 25.0 and 40.0 
kg/m² inclusive. Patients with a history of controlled obesity or 
controlled diabetes are allowed on the study.  
5. Patients whose pre-study clinical laboratory findings do not 
interfere with their participation in the study, in the opinion of the 
Investigator. 
6. Patients aged between 18 and 75 years inclusive. 
7. Female patients and male patients with female partners of child 
bearing potential must use adequate contraception or have a 
sterilized partner for the duration of the study. Adequate 
contraception is defined as: systemic hormonal contraceptives, 


 
 
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intrauterine device or barrier method of contraception; in 
conjunction with spermicide; or agree to sexual abstinence, 
defined as a patient refraining from heterosexual intercourse 
during the entire period of risk associated with the study 
treatments and in line with their preferred and usual lifestyle. 
Hormonal contraceptives must be on a stable dose for at least one 
month before baseline 
8. Patients who are able to communicate well with the Investigator, 
to understand and comply with the requirements of the study, and 
understand and sign the written informed consent. 
Exclusion criteria: 
1. Patients with an unstable metabolic condition such as weight 
change > 5% in the 3 months prior to inclusion. 
2. Patients with medical/surgical history of gastric bypass surgery, 
orthotopic liver transplant (OLT) or listed for OLT. 
3. Patients with uncontrolled diabetes mellitus type 2, i.e. HbA1c ≥ 
9% (75mmol/mol) at the time of screening. 
4. Patients with decompensated or severe liver disease as evidenced 
by one or more of the following: confirmed cirrhosis or suspicion 
of cirrhosis, esophageal varices, ascites, suspicion of portal 
hypertension, hospitalization for liver disease within 60 days of 
screening, bilirubin ≥ 2 x ULN, or ALT or AST ≥ 5 x ULN. 
Patient’s with Gilbert’s syndrome are eligible if the conjugated 
bilirubin is ≤1.5 x ULN. 
5. Patients with inflammatory bowel disease that is either active or 
requiring medical therapy. 
6. Patients with diagnosed or suspected autoimmune diseases such 
as systemic lupus erythematosus (SLE) and/or rheumatoid 
arthritis (RA). 
7. Patients with a history of or active non-liver malignancies other 
than curatively treated skin cancer (basal cell or squamous cell 
carcinomas). 
8. Patients with significant systemic or major illness other than liver 
disease, including coronary artery disease, cerebrovascular 
disease, pulmonary disease, renal insufficiency, serious 
psychiatric disease, respiratory or hypertensive disease, as well 
as diabetes and arthritis that, in the opinion of the Investigator, 
would preclude the patient from participating in and completing 
the study. 


 
 
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9. Patients requiring anti-diabetic treatment (including insulin 
sensitizing agents), and/or lipid lowering treatment, and who are 
not on a stable dose for at least 3 months prior to screening should 
be excluded.  If patients are insulin dependent this treatment 
should have commenced at least 3 months prior to screening, 
however changes in dose are permitted.  
10. Patients with known hypersensitivity to any ingredients of the 
study treatment. 
11. Patients with a positive test for human immunodeficiency virus 
(HIV) antibodies, Hepatitis B surface antigen or Hepatitis C 
antibodies at screening.  
12. Patients with liver disease of other aetiologies such as drug-
induced, autoimmune hepatitis, PBC, PSC, haemochromatosis, 
A1AT deficiency or Wilson’s disease.  
13. Patients with a significant history of drug/solvent abuse, in the 
opinion of the investigator. 
14. Patients with a history of alcohol abuse in the opinion of the 
Investigator, or who currently drinks in excess of 21 units per 
week (males) or 14 units per week (females), whereby a unit 
consists of 10ml or 8mg of pure alcohol. 
15. Patients who have used dietary supplements rich in omega-3 or 
omega-6 fatty acids in the 4 weeks prior to baseline. 
16. Patients who have participated in any other clinical study with an 
investigational drug within 3 months before the first day of 
administration of study treatment. 
17. Patients who are pregnant, planning pregnancy, breastfeeding 
and/or are unwilling to use adequate contraception (as specified 
in inclusion criterion 7) during the trial. 
18. Patients, in the opinion of the Investigator, not suitable to 
participate in the study. 
Dietary restrictions: 
Patients should avoid ingesting food supplements rich in omega-3 or 
omega-6 fatty acids (e.g. cod liver oil capsules) both during the study 
and for 4 weeks prior to baseline. 
TEST PRODUCT, 
DOSE, AND MODE OF 
ADMINISTRATION: 
DS102 will be provided in a capsule, containing 500mg of 15-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. 


 
 
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This study will involve two dose levels for 16 weeks 1000 mg per day 
(500mg BD), 2000mg per day (1000mg BD) or placebo BD using 
three treatment groups consisting of 32 Patients each.  
EVALUATION 
CRITERIA: 
Efficacy: 
 
ALT 
 
AST 
 
Hepatic Fat measurement by CAP 
 
Liver stiffness measurement by Transient Elastography 
 
ELF 
 
FIB-4 
 
NFS 
 
AST:ALT Ratio 
 
HOMA-IR/Adipo-IR 
 
Safety: 
 
Physical examination, including height and weight 
 
12-lead ECG 
 
Vital signs, including blood pressure (BP), pulse and temperature. 
 
Clinical 
laboratory 
tests 
(haematology, 
coagulation, 
biochemistry, lipid profile, virology and urinalysis) 
 
Pregnancy test for females of child bearing potential 
 
Adverse Events (AEs) 
 
Concomitant medications 
PHARMACOKINETICS Plasma concentrations of DS102: Predose Ctrough levels taken at Visit 
2/Baseline, Visit 3/Week 2, Visit 4/Week 4, Visit 6/Week 8, Visit 
8/Week 12, Visit 10/Week 16 and Follow up Visit 11/Week 20. 
EXPLORATORY 
Blood will be collected throughout the study (at the timepoints 
specified in the Study Flow Chart [Appendix 1]) and will be stored 
for potential biomarker analysis.  
Blood will also be collected and stored for potential exploratory gene 
array analysis or additional testing at a later date. 
STATISTICS 
Sample Size: 
Assuming a 20% delta in the percentage response between active drug 
and placebo arms, a standard deviation of 25% and a drop out rate of 
20%, this results in 32 patients per group with 5% level of 
significance, and 80% power. 
The sample size may be re-estimated at an interim analysis based on 
recommendation from an unblinded, independent DSMB. The sample 
size may be increased up to a maximum of 150 patients in total to 
achieve a conditional power of 80% for the primary endpoint. 


 
 
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Methods: 
The active treatment groups will be compared against placebo via an 
analysis of variance (ANOVA) model. The comparisons against 
placebo will be done according to Dunnett’s multiple testing 
procedure. 
A clinically meaningful response is defined as a mean or median 
difference of the active treatment groups to placebo of either 20% for 
ALT or Liver Stiffness or a difference of 10% for both ALT and Liver 
Stiffness 
SPONSOR: 
Afimmune 
 


 
 
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LIST OF ABBREVIATIONS 
15(S)-HEPE EE 
15(S)-Hydroxy-Eicosapentaenoic Acid Ethyl Ester 
AE 
ALT 
AST 
Adverse Event 
Alanine Aminotransferase 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BP 
CAP 
Blood Pressure 
Controlled Attenuation Parameter 
CRF 
Case Report Form 
DOA 
DSMB 
EC 
Drugs of Abuse 
Data and Safety Monitoring Board 
Ethics Committee 
ECG 
ELF 
Electrocardiogram 
Enhanced Liver Fibrosis Score 
EPA 
Eicosapentanoic Acid 
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 
ISF 
Investigator Site File 
LC-MS/MS 
MCP-1 
Liquid Chromatography Tandem Mass Spectrometry 
Monocyte Chemoattractant Protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
 
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MHRA 
NAFLD 
NASH 
NFS  
Medicines and Healthcare products Regulatory Agency 
Non-Alcoholic Fatty Liver Disease 
Non-Alcoholic Steatohepatitis 
NAFLD Fibrosis Score 
NOAEL 
No Observed Adverse Effect Levels 
OTC 
PBMC 
PIS 
Over the Counter 
Peripheral Blood Mononuclear Cells  
Patient Information Sheet 
PK 
Pharmacokinetic 
PV CRO 
Pharmacovigilance Contract Research Organisation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
SUSAR 
TGF-β 
TNF-α 
Suspected Unexpected Serious Adverse Reaction 
Transforming Growth Factor – Beta 
Tumour Necrosis Factor - Alpha 
 
 
 
 


 
 
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1 
INTRODUCTION  
1.1 
Therapeutic Area and Disease Background 
Non-alcoholic fatty liver disease (NAFLD) is a form of chronic liver damage that affects a wide range 
of individuals. It is estimated that up to 31% of adults in the United States and 33% of adults in Europe 
are affected and that the prevalence will continue to increase. The most commonly documented 
comorbidities that have been associated with NAFLD include obesity, impaired insulin sensitivity and 
dyslipidemia. NAFLD exists as a spectrum and is best characterised histologically. Important features 
include steatosis, inflammation, hepatocellular ballooning and fibrosis. NAFLD can be classified as 
non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). In NAFL there is an 
accumulation of fat in the liver but hepatocellular injury is absent, whereas NASH involves the presence 
of steatosis and inflammation with hepatocyte damage, with or without fibrosis. Once present, these 
specific changes mediate the risk of future disease progression (Malhotra and Beaton et al. 2015). About 
20-40% of patients with NASH have some degree of fibrosis in their initial biopsy. Data on progression 
to cirrhosis is sparse but patients with NASH cirrhosis and cryptogenic cirrhosis account for 10-12% of 
liver transplants (Adams et al. 2005). Hepatocellular carcinoma occurs in 2-4% of patients with NASH 
cirrhosis but occasionally patients with NASH cirrhosis present with hepatocellular carcinoma also 
(Bullock et al. 2004).  
 
1.2 
Standard Treatment 
There are currently no approved drugs for NAFLD. The current standards of care include lifestyle 
management with a goal of sustained weight loss, treating associated features of the metabolic syndrome 
to reduce cardiovascular risk and in some cases transplantation. The off-label use of oral hypoglycemic 
agents and vitamin E has not been proven. Developing bariatric surgical techniques are promising, but 
additional studies with long-term follow up are needed before they can be widely recommended. 
Finally, liver transplantation is an increasingly frequent consideration once complications of end-stage 
disease have developed (Malhotra and Beaton et al. 2015). There is an obvious unmet need for advanced 
treatment in this disease area. 
 
1.3 
Drug Class 
DS102 is an endogenously occurring essential fatty acid 15-Hydroxy-Eicosapentaenoic Acid Ethyl 
Ester (15-HEPE EE). 
Figure 1. Structure of 15(S)-HEPE EE (DS102) 
 
 


 
 
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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, 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 LPS induced inflammation in 
Peripheral Blood Mononuclear cells (PBMCs) showing a significant decrease in Tumour Necrosis 
Factor-alpha (TNF-alpha), IL-6, IL-8 and IL-23. Anti-fibrotic effects of DS102 were observed in 
Transforming Growth Factor-beta (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 NASH.  
 
 
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.  
 
A subcutaneous injection of streptozotocin was administered to newborn mice followed by a high fat 
diet from 4 weeks of age. Results presented represent overall outcomes from 4 studies performed. NAS 
score is separated into three components: steatosis, lobular inflammation and hepatocyte ballooning. 
Light arrows signify a decrease. Dark arrows signify a significant decrease.  
 
 
 
 


 
 
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Figure 2: Schematic summarising the results of 4 in vivo studies performed using the STAM™ Model 
(DS-PC-26, DS-PC-27, DS-PC-28, DS-PC-29).  
 
 
 
          
 
 
 
 
Treatment with DS102 at 500 mg/kg significantly decreased plasma ALT, a liver injury marker, and 
plasma TGF-beta, 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 it’s 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 findings are important, because reduction of NAS is one of the major clinical endpoints for 
assessing the drug efficacy in NASH patients (Sanyal AJ. et al., 2011). Thus, the results suggested that 
DS102 has potential hepatoprotective and anti-inflammatory effects against steatohepatitis.   
Perisinusoidal fibrosis around the central vein is predominantly observed in human NASH (Brunt EM 
et al.1999) and reported to be associated with poor prognosis of NASH (Brunt EM et al. 2005). 
Therefore perisinusoidal collagen deposition is an important factor to estimate the disease condition of 
NASH. The reduction of fibrosis area suggests that DS102 treatment could contribute to achieve better 
prognosis in NASH.   
 
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 NASH. 
 
1.5 
Toxicology 
A number of 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 2000 mg/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 have 


 
 
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sponsored a 9 month dog and 6 month rat study that are currently ongoing. An interim 18 week report 
on the 9 month dog study concluded that DS102 well tolerated and safe with no haematology, 
coagulation or clinical chemistry changes or any urinary composition change attributed to treatment 
with DS102.    
1.6 
Previous Clinical Safety Studies with 15(S)-HEPE 
The company sponsored a phase I study, DS102A-01 (EudraCT 2015-001153-33, MHRA Ref No. 
41175/0002/001-0001), 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 3 males and 3 females per cohort) in each cohort. One of the cohorts (500mg 
QD for 28 days) enrolled 9 subjects to compensate for discontinued subjects. 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 half-life of 
approximately 2hrs and a Tmax of approximately 4-8hrs. Results across dose levels studied showed 
high variability in the single and multiple dose cohorts and do 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 SAEs reported. 
 
 
 


 
 
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2 
RISK BENEFIT ASSESSMENT 
The company have shown the therapeutic effects of DS102 in a number of preclinical mechanistic 
studies with clinically relevant endpoints in NASH, namely ALT, the histological NAFLD activity 
score and fibrosis. Toxicological safety studies to date demonstrate safety of the drug substance up to 
2000mg/kg in two species and safety up to 18 weeks has been shown in an interim report of a 9 month 
dog study. The phase I study conducted in healthy volunteers demonstrated DS102 to be safe and well 
tolerated with no SAEs reported over 28 day dosing. 
 
Based on the summary above of both the favourable safety profile and the therapeutic potential of 
DS102 in a disease that currently lacks effective therapies, it can be concluded that there is a positive 
risk-benefit ratio for the continued investigation of oral DS102. 
 


 
 
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3 
RATIONALE FOR THE STUDY 
There is a clear rationale for the development of DS102 as a treatment for patients with NAFLD. 
Preclincially, DS102 has been shown to have significant effects on clinically relevant endpoints, 
including serum ALT and both NAFLD activity score and fibrosis in a STAM™ model of non-alcoholic 
steatohepatitis (DS-PC-26, DS-PC-27, DS-PC-28, DS-PC-29). 
Based on the positive safety results of the first-in-man phase I trial in healthy volunteers, DS102 showed 
that up to 2000mg once daily in healthy patients was safe and well tolerated.  
The rationale for this study is therefore to examine the safety and efficacy of DS102 up to 2000mg per 
day for 16 weeks given in divided doses in non-alcoholic fatty liver disease patients (NAFLD).  
 
 
 


 
 
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4 
STUDY OBJECTIVES 
The objective of the study is to assess the safety and efficacy of orally administered DS102 capsules 
versus placebo in the treatment of adult patients with Non-Alcoholic Fatty Liver Disease (NAFLD). 


 
 
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5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
 
Efficacy 
 
 
Change in serum ALT (alanine aminotransferase) from baseline  to week 16 
 
 
Change in liver stiffness measurements by Transient Elastography from baseline to week 16 
 
 
Safety 
 
 
Number of Treatment Emergent Adverse Events (TEAEs) in each treatment group leading to 
treatment discontinuation 
 
5.2 
Secondary Endpoints 
 
 
Change in serum ALT (alanine aminotransferase) from baseline to weeks 2, 4, 8 and 12 
 
Change in AST (aspartate aminotransferase) from baseline to weeks 2, 4, 8, 12 and 16 
 
Change in AST:ALT ratio from baseline to weeks 2, 4, 8, 12 and 16 
 
Change in FIB-4 Index from baseline to week 16 
 
Change in NAFLD fibrosis score (NFS) from baseline to week 16 
 
Change in hepatic fat measured by CAP (controlled attenuation parameter) from baseline to week 
16 
 
Change in ELF (Enhanced Liver Fibrosis score) from baseline to week 16 
 
Change in HOMA-IR/Adipo-IR (Homeostatic model assessment Insulin Resistance / Adipose 
tissue Insulin Resistance) from baseline to weeks 2, 4, 8, 12 and  16 
 
 


 
 
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6 
STUDY DESIGN 
6.1 
General 
This is a randomised, placebo-controlled, double-blind, parallel group, multi-centre exploratory 
phase IIa study to investigate the safety and efficacy of orally administered DS102 capsules and the 
dose-response relationship between two doses of DS102 and placebo in NAFLD patients aged 18 to 75 
years inclusive. Three parallel groups of patients with confirmed NAFLD will be investigated in this 
study to compare two different doses of DS102 with placebo over a 16 week treatment period. It is 
planned that 96 evaluable patients, 32 patients per treatment group will be randomized. The sample size 
may be re-estimated at an interim analysis based on at least 50% of the patients. 
The study consists of a screening period of 28 days, a 16 week treatment period and a 4 week follow up 
period. At the screening visit, after giving informed consent to participate, patients will be assessed 
using the screening examinations. Patients who meet the inclusion criteria and who do not meet the 
exclusion criteria will be enrolled.  
A schematic diagram of the overall timeframe of the study is given in Figure 3. 
Figure 3: Study Outline 
 
Once patients are enrolled on the study they will be restricted from using any other treatment for 
NAFLD. Any medication (prescription as well as over the counter (OTC) drugs) 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 unless they are included in the list 
of ‘Concomitant Medications’ (Section 9.2.11). 
Before the comparative treatment period can commence, patients will return to the site for a baseline 
assessment of their disease and eligible patients will be randomly allocated to one of the three parallel 
group treatment regimens in a 1:1:1 randomization: 


 
 
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 
Treatment group A: 2 x Placebo 500mg capsules orally administered twice a day (4 capsules 
daily) for 16 weeks 
 
Treatment group B: 1 x DS102 500mg capsule & 1 x Placebo 500mg capsule orally 
administered twice a day (4 capsules daily) for 16 weeks  
 
Treatment group C: 2 x DS102 500mg capsules orally administered twice a day (4 capsules 
daily) for 16 weeks 
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. 
The study consists of a treatment period of 16 weeks and was designed in order to assess the safety and 
efficacy of dosing of DS102 BD (total daily doses of 1000mg and 2000mg) in NAFLD patients. 
Studies in rats and dogs treated for up to four weeks have demonstrated 15-HEPE EE did not indicate 
any limiting toxicity and resulted in a NOAEL of 2000 mg/kg/day in both species (CRL-527943, 
527959). 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.  The dose selection in this trial is therefore based on the phase I trial 
and the intention to characterize the safety and efficacy of up to 2000mg per day given in divided doses 
with or after food to NAFLD patients. 
 
 


 
 
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7 
PATIENTS AND SCREENING 
In order to participate in this study the patients must meet all of the following inclusion criteria and 
must not meet any of the following 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). 
 
7.1 
Source of Patients 
The study population will consist of NAFLD male and female patients aged between 18 and 75 years 
inclusive.  
 
7.2 
Inclusion Criteria 
1. 
Patients diagnosed with NAFLD by the presence of hepatic steatosis on imaging or histology in 
the absence of any secondary causes. 
2. Patients with an ALT ≥ 1.5 ULN and < 5 ULN on two occasions 7 or more days apart during 
screening. 
 
3. Patients with historical liver biopsy showing NASH and/or ≥ F1 fibrosis OR NFS ≥ -1.455 OR Fib-
4 ≥ 1.3 OR Fibroscan ≥8kPa within 3 months of screening.  
 
4. Patients with a body mass index (BMI) between 25.0 and 40.0 kg/m² inclusive. Patients with a 
history of controlled obesity or controlled diabetes are allowed on the study. 
5. Patients whose pre-study clinical laboratory findings do not interfere with their participation in the 
study, in the opinion of the Investigator. 
6. Patients aged between 18 and 75 years inclusive. 
7. 
Female patients and male patients with female partners of child bearing potential must use adequate 
contraception or have a sterilized partner for the duration of the study. Adequate contraception is 
defined as: systemic hormonal contraceptives; intrauterine device or barrier method of 
contraception in conjunction with spermicide; or agree to sexual abstinence, defined as a patient 
refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments and in line with their preferred and usual lifestyle. Hormonal contraceptives must be on 
a stable dose for at least one month before baseline. 
8. 
Patients who are able to communicate well with the Investigator, to understand and comply with 
the requirements of the study, and understand and sign the written informed consent. 
 
 
7.3 
Exclusion Criteria  
1. 
Patients with an unstable metabolic condition such as weight change > 5% in the 3 months prior 
to inclusion. 
2. Patients with medical/surgical history of gastric bypass surgery, orthotopic liver transplant (OLT) 
or listed for OLT. 


 
 
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3. Patients with uncontrolled diabetes mellitus type 2, i.e. HbA1c ≥ 9% (75mmol/mol) at the time of 
screening. 
4. Patients with decompensated or severe liver disease as evidenced by one or more of the following: 
confirmed cirrhosis or suspicion of cirrhosis, esophageal varices, ascites, suspicion of portal 
hypertension, hospitalization for liver disease within 60 days of screening, bilirubin ≥ 2 x ULN, or 
ALT or AST ≥ 5 x ULN. Patients with Gilbert’s syndrome are eligible if the conjugated bilirubin 
is ≤ 1.5 x ULN. 
5. Patients with inflammatory bowel disease that is either active or requiring medical therapy. 
6. Patients with diagnosed or suspected autoimmune diseases such as systemic lupus erythematosus 
(SLE) and/or rheumatoid arthritis (RA). 
7. Patients with a history of or active non-liver malignancies other than curatively treated skin cancer 
(basal cell or squamous cell carcinomas). 
8. Patients with a significant systemic or major illness other than liver disease, including coronary 
artery disease, cerebrovascular disease, pulmonary disease, renal insufficiency, serious psychiatric 
disease, respiratory or hypertensive disease, as well as diabetes and arthritis that, in the opinion of 
the Investigator, would preclude the patient from participating in and completing the study. 
9. 
Patients requiring anti-diabetic treatment (including insulin sensitizing agents), and/or lipid 
lowering treatment, and who are not on a stable dose for at least 3 months prior to screening should 
be excluded.  If patients are insulin dependent this treatment should have commenced at least 3 
months prior to screening, however changes in dose are permitted.  
10. Patients with known hypersensitivity to any ingredients of the study treatment. 
11. Patients with a positive test for human immunodeficiency virus (HIV) antibodies, Hepatitis B 
surface antigen or Hepatitis C antibodies at screening.  
12. Patients with liver disease of other aetiologies such as drug-induced, autoimmune hepatitis, PBC, 
PSC, haemochromatosis, A1AT deficiency or Wilson’s disease.  
13. Patients with a significant history of drug/solvent abuse, in the opinion of the investigator. 
14. Patients with a history of alcohol abuse in the opinion of the Investigator, or who currently drinks 
in excess of 21 units per week (males) or 14 units per week (females), whereby a unit consists of 
10ml or 8mg of pure alcohol. 
15. Patients who have used dietary supplements rich in omega-3 or omega-6 fatty acids in the 4 weeks 
prior to baseline. 
16. Patients who have participated in any other clinical study with an investigational drug within 
3 months before the first day of administration of study treatment. 
17. Patients who are pregnant, planning pregnancy, breastfeeding and/or are unwilling to use adequate 
contraception (as specified in criterion 7) during the trial. 


 
 
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18. Patients, in the opinion of the Investigator, not suitable to participate in the study. 
 
7.4 
Screening and 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. Patients 
will be given the opportunity to ask questions to the investigational team. It must also be explained to 
the patients that they are completely free to refuse to enter the study or to withdraw from it at any time 
for any reason. The patient will be given sufficient time to consider participation in the study. If, after 
this, the patient agrees to participate, they will be asked to sign and date one original copy of the written 
informed consent form (ICF). The patients will then receive a copy of the signed and dated patient 
information sheet (PIS)/informed consent form (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 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 Board/Institutional Review Board. 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. Any written 
information given to potential patients will be submitted to, and approved by, the respective Ethics 
Committee(s) (EC) prior to implementation.  
The Investigator will maintain a Patient Screening Log to collect information on all patients who sign 
an 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. 
 
7.5 
Withdrawal of Patients 
Patients have the right to withdraw from the study at any time for any reason without penalty. 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. 
 
The investigator or one of his or her staff members should 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 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 or an abnormal laboratory test 
result, the principal specific event or test will be recorded. Patients who discontinue the study before 
week 16 visit will be asked to come for an early termination visit as soon as possible and have the 
assessments listed at week 16 performed. They will also be asked to return two weeks later for the safety 
assessments listed at week 20. 
 


 
 
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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: 
 
Patients decision (withdrawal of consent to participate) 
 
Patient lost to follow-up 
 
7.5.2 
Withdrawals from Investigational Product 
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 adverse events 
 
Patient request 
 
Investigator’s discretion 
 
Intercurrent illness 
 
Pregnancy 
 
7.6 
Patient Replacement 
Patients who are withdrawn from the study due to an adverse event or lack of efficacy will not be 
replaced. Patients who are withdrawn for other reasons (such as lost to follow up) may be replaced. 
 
7.7 
Protocol Violations 
All protocol violations 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. 
 
 


 
 
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8 
STUDY CONDUCT 
 
8.1 
Study Schedule 
During the study, ten visits to the clinic are scheduled after the screening visit: one at the start of the 
comparative treatment period/baseline (Day 0/Visit 2) and eight in the comparative treatment period 
(Week2/Visit 3, Week 4/Visit 4, Week 6/Visit 5, Week 8/Visit 6, Week 10/Visit 7, Week 12/Visit 8, 
Week 14/Visit 9, Week 16/Visit 10). A final safety follow-up visit (Visit 11) will be conducted four 
weeks after Visit 10 or two weeks after the final visit attended if the patient does not complete the study. 
 
Patients who discontinue the study early will be asked to attend the investigative site as soon as possible 
so that assessments scheduled for Visit 10 can be conducted. 
 
8.2 
Clinic Visits 
A tabulated flow chart of the study is presented in Appendix 1. 
 
8.2.1 
Screening Visit (Visit 1) 
 
The patient must sign and date the ICF before any study-specific procedures are conducted.  
 
Once informed consent has been obtained, the investigator will assign a Patient Screening Number. 
Ideally the patient should be fasted. 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) 
 
Physical examination (as detailed in Section 9.2.2) 
 
12-lead ECG (as detailed in Section 9.2.3) 
 
Vital signs (blood pressures, 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) 
 
Virology (as detailed in Section 9.2.6) 
 
Pregnancy test (for female patients of child-bearing potential, as detailed in Section 9.2.7) 
 
ALT, AST tests (ALT to be measured on two occasions during screening as detailed in Section 
9.1.1) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
Unscheduled visits may occur when a patient needs to make a visit in between the scheduled visit dates 
due to an adverse event (AE), difficulty complying with the study protocol requirements, or a significant 
change in their disease state. All procedures that are medically necessary should be followed. If 
qualified, before leaving the clinic the patient will be instructed not to have any breakfast before the 
next visit to allow a minimum fasting period of 8 hours. 
 


 
 
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8.2.2 
Treatment Period 
Following completion of a successful screening visit, patients will begin the comparative treatment 
period (16 weeks).  
 
At the start of the comparative treatment period, after confirmation of continued eligibility, patients will 
be randomly assigned to one of the three treatment regimens.  
 
Patients will take the allocated IMP (DS102 capsule or placebo capsule) twice-daily throughout the 
comparative treatment period. Each self-administration of IMP will be recorded in a patient diary card.  
 
Patients will be instructed to take DS102 in the morning and in the evening with or after food (except 
on the mornings of clinic visits 3, 4, 6, 8 and 10 when patients will be instructed to abstain from taking 
DS102 prior to the visit and to take DS102 as soon as possible after the clinic visit).  
 
Unscheduled visits may occur when a patient needs to make a visit in between the scheduled visit dates 
due to an adverse event (AE), difficulty complying with the study protocol requirements, or a significant 
change in their disease state. All procedures that are medically necessary should be followed.  
 
Patients who discontinue the study early will have all study procedures scheduled for Visit 10 (see 
Section 9.2.11) performed as soon as possible after patient withdrawal so that all study-related 
information can be recorded. 
 
At the discretion of investigator, urine DOA and alcohol breath test can be performed at any time during 
the conduct of the trial, as detailed in section 9.2.9. 
8.2.3 
Baseline (Visit 2) 
 
Patients will attend the investigational site at Visit 2 when the following assessments/sample collections 
will be performed. The patient will be asked if they have fasted for a minimum of 8hrs prior to visit. If 
this is not the case, the duration of fasting period will be documented and the patient will be reinstructed 
about the duration of the fasting period. Blood sampling will be the first assessment carried out. 
Following this the patient will be provided with a light breakfast (e.g. tea or orange juice and toast):  
 
 
Verification of inclusion/exclusion criteria (Sections 7.2 & 7.3) 
 
Medical history (as detailed in Section 9.2.1) 
 
Physical examination (as detailed in Section 9.2.2) 
 
12-lead ECG (as detailed in Section 9.2.3) 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.8.1) 
 
Vital signs (blood pressures, 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) 
 
Lipid Profile (as detailed in Section 9.2.5) 
 
Urinalysis (as detailed in Section 9.2.5) 
 
Pregnancy test (for female patients of child-bearing potential, as detailed in Section 9.2.7) 
 
ALT, AST tests (as detailed in Section 9.1.1) 
 
HOMA-IR/Adipo-IR (as detailed in Section 9.1.2) 
 
ELF (as detailed in Section 9.1.3) 
 
Liver stiffness and CAP (as detailed in Section 9.1.4) 
 
FIB-4 (as detailed in Section 9.1.5) 
 
NFS [including BMI] (as detailed in Section 9.1.6) 


 
 
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 
Biomarkers blood sample (as detailed in Section 9.2.8.3) 
 
Exploratory blood sample (as detailed in Section 9.2.8.2) 
 
Patient Randomisation (as detailed in Section 12.2) 
 
Study drug/Placebo Administration 
 
AE assessment (as detailed in Section 11) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
If all study entry criteria are satisfied the investigator will randomize 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. 
 
Patients will be given a patient diary card. Clinical staff will explain to the patient how to use the diary 
card to document IMP administration compliance. 
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in two weeks at Visit 3 and to bring with them the unused IMP/placebo blister packs, 
the used IMP/placebo blister packs, and the patient diary card. Patients should not take IMP or placebo 
on the morning of their return site visit (Visit 3). Before leaving the clinic the patient will be instructed 
not to have any breakfast before the next visit to allow a minimum fasting period of 8 hours. 
 
8.2.4 
Week 2 (Visit 3) 
 
Patients will return to the investigational site at Visit 3. Patients should not take IMP or placebo on the 
morning of Visit 3.  
 
For accountability purposes, patients will be required to bring both the used and unused IMP/placebo 
blister packs supplied at Visit 2. Patients will be required to provide the patient diary card for 
confirmation of compliance. The patient will be asked if they have fasted for a minimum of 8hrs prior 
to visit. If this is not the case, the duration of fasting period will be documented and the patient will be 
reinstructed about the duration of the fasting period.  Following this the patient will be provided with a 
light breakfast (e.g. tea or orange juice and toast). 
 
The following assessments will be performed: 
 
 
Physical examination (as detailed in Section 9.2.2) 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.8.1) 
 
Vital signs (blood pressures, heart rate and body temperature), as detailed in Section 9.2.4) 
 
ALT, AST tests (as detailed in Section 9.1.1) 
 
HOMA-IR/Adipo-IR (as detailed in Section 9.1.2) 
 
AE assessment (as detailed in Section 11) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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 capsules will continue to be administered twice-daily. The patient diary card will be 
provided to the patient who will be instructed to complete this as before.  
 


 
 
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On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in two weeks at Visit 4 and to bring with them the unused IMP/placebo blister packs, 
the used IMP/placebo blister packs, and the patient diary card. Patients should not take IMP or placebo 
on the morning of their return site visit (Visit 4). Before leaving the clinic the patient will be instructed 
not to have any breakfast before the next visit to allow a minimum fasting period of 8 hours. 
 
8.2.5 
Week 4 (Visit 4) 
 
Patients will return to the investigational site at Visit 4. Patients should not take IMP or placebo on the 
morning of Visit 4.  
 
For accountability purposes, patients will be required to bring both the used and unused IMP/placebo 
blister packs supplied at Visit 3. Patients will be required to provide the patient diary card for 
confirmation of compliance. The patient will be asked if they have fasted for a minimum of 8hrs prior 
to visit. If this is not the case, the duration of fasting period will be documented and the patient will be 
reinstructed about the duration of the fasting period. Following this the patient will be provided with a 
light breakfast (e.g. tea or orange juice and toast). 
 
The following assessments will be performed: 
 
 
Physical examination (as detailed in Section 9.2.2) 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.8.1) 
 
Vital signs (blood pressures, 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) 
 
Pregnancy test (for female patients of child-bearing potential, as detailed in Section 9.2.7) 
 
ALT, AST tests (as detailed in Section 9.1.1) 
 
HOMA-IR/Adipo-IR (as detailed in Section 9.1.2) 
 
AE assessment (as detailed in Section 11) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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. The patient diary card will be 
provided to the patient who will be instructed to complete this as before.  
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in two weeks at Visit 5 and to bring with them the unused IMP/placebo blister packs, 
the used IMP/placebo blister packs, and the patient diary card. Patients should not take IMP or placebo 
on the morning of their return site visit (Visit 5). 
8.2.6 
Week 6 (Visit 5) 
 
Patients will return to the investigational site at Visit 5.  
 
For accountability purposes, patients will be required to bring both the used and unused IMP/placebo 
blister packs supplied at Visit 4. Patients will be required to provide the patient diary card for 
confirmation of compliance.  
 
The following assessments will be performed: 


 
 
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 
AE assessment (as detailed in Section 11) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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. The patient diary card will be 
provided to the patient who will be instructed to complete this as before.  
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in two weeks at Visit 6 and to bring with them the unused IMP/placebo blister packs, 
the used IMP/placebo blister packs, and the patient diary card. Patients should not take IMP or placebo 
on the morning of their return site visit (Visit 6). Before leaving the clinic the patient will be instructed 
not to have any breakfast before the next visit to allow a minimum fasting period of 8 hours. 
8.2.7 
Week 8 (Visit 6) 
 
Patients will return to the investigational site at Visit 6. Patients should not take IMP or placebo on the 
morning of Visit 6.  
 
For accountability purposes, patients will be required to bring both the used and unused IMP/placebo 
blister packs supplied at Visit 5. Patients will be required to provide the patient diary card for 
confirmation of compliance.  
 
The patient will be asked if they have fasted for a minimum of 8hrs prior to visit. If this is not the case, 
the duration of fasting period will be documented and the patient will be reinstructed about the duration 
of the fasting period. Blood sampling will be the first assessment carried out. Following this the patient 
will be provided with a light breakfast (e.g. tea or orange juice and toast): 
 
The following assessments will be performed: 
 
 
Physical examination (as detailed in Section 9.2.2) 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.8.1) 
 
Vital signs (blood pressures, 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) 
 
Lipid Profile (as detailed in Section 9.2.5) 
 
Pregnancy test (for female patients of child-bearing potential, as detailed in Section 9.2.7) 
 
ALT, AST tests (as detailed in Section 9.1.1) 
 
HOMA-IR/Adipo-IR (as detailed in Section 9.1.2) 
 
Biomarker blood samples (as detailed in Section 9.2.8.3) 
 
AE assessment (as detailed in Section 11) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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. The patient diary card will be 
provided to the patient who will be instructed to complete this as before.  
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in two weeks at Visit 7 and to bring with them the unused IMP/placebo blister packs, 


 
 
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the used IMP/placebo blister packs, and the patient diary card. Patients should not take IMP or placebo 
on the morning of their return site visit (Visit 7). 
 
8.2.8 
Week 10 (Visit 7) 
 
Patients will return to the investigational site at Visit 7.  
 
For accountability purposes, patients will be required to bring both the used and unused IMP/placebo 
blister packs supplied at Visit 6. Patients will be required to provide the patient diary card for 
confirmation of compliance.  
 
The following assessments will be performed: 
 
 
AE assessment (as detailed in Section 11) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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. The patient diary card will be 
provided to the patient who will be instructed to complete this as before.  
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in two weeks at Visit 8 and to bring with them the unused IMP/placebo blister packs, 
the used IMP/placebo blister packs, and the patient diary card. Patients should not take IMP or placebo 
on the morning of their return site visit (Visit 8). Before leaving the clinic the patient will be instructed 
not to have any breakfast before the next visit to allow a minimum fasting period of 8 hours. 
 
8.2.9 
Week 12 (Visit 8) 
 
Patients will return to the investigational site at Visit 8. Patients should not take IMP or placebo on the 
morning of Visit 8.  
 
For accountability purposes, patients will be required to bring both the used and unused IMP/placebo 
blister packs supplied at Visit 7. The patient will be asked if they have fasted for a minimum of 8hrs 
prior to visit. If this is not the case, the duration of fasting period will be documented and the patient 
will be reinstructed about the duration of the fasting period. Following this the patient will be provided 
with a light breakfast (e.g. tea or orange juice and toast). Patients will be required to provide the patient 
diary card for confirmation of compliance.  
 
The following assessments will be performed: 
 
 
Physical examination (as detailed in Section 9.2.2) 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.8.1) 
 
Vital signs (blood pressures, 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) 
 
Pregnancy test (for female patients of child-bearing potential, as detailed in Section 9.2.7) 
 
ALT, AST tests (as detailed in Section 9.1.1) 
 
HOMA-IR/Adipo-IR (as detailed in Section 9.1.2) 


 
 
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 
AE assessment (as detailed in Section 11) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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. The patient diary card will be 
provided to the patient who will be instructed to complete this as before.  
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in two weeks at Visit 9 and to bring with them the unused IMP/placebo blister packs, 
the used IMP/placebo blister packs, and the patient diary card. Patients should not take IMP or placebo 
on the morning of their return site visit (Visit 9). 
 
8.2.10 Week 14 (Visit 9) 
 
Patients will return to the investigational site at Visit 9.  
 
For accountability purposes, patients will be required to bring both the used and unused IMP/placebo 
blister packs supplied at Visit 8. Patients will be required to provide the patient diary card for 
confirmation of compliance.  
 
The following assessments will be performed: 
 
 
AE assessment (as detailed in Section 11) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
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. The patient diary card will be 
provided to the patient who will be instructed to complete this as before.  
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in two weeks at Visit 10 and to bring with them the unused IMP/placebo blister 
packs, the used IMP/placebo blister packs, and the patient diary card. Patients should not take IMP or 
placebo on the morning of their return site visit (Visit 10). Before leaving the clinic the patient will be 
instructed not to have any breakfast before the next visit to allow a minimum fasting period of 8 hours. 
 
8.2.11 Week 16 (Visit 10) or Early Withdrawal 
 
Patients will return to the investigational site at Visit 10. Patients should not take IMP or placebo on the 
morning of Visit 10.  
 
For accountability purposes, patients will be required to bring both the used and unused IMP/placebo 
blister packs supplied at Visit 9. Patients will be required to provide the patient diary card for 
confirmation of compliance.  
 
The patient will be asked if they have fasted for a minimum of 8hrs prior to visit. If this is not the case, 
the duration of fasting period will be documented and the patient will be reinstructed about the duration 


 
 
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of the fasting period. Blood sampling will be the first assessment carried out. Following this the patient 
will be provided with a light breakfast (e.g. tea or orange juice and toast): 
 
The following assessments will be performed: 
 
 
Physical examination (as detailed in Section 9.2.2) 
 
12-lead ECG (as detailed in Section 9.2.3) 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.8.1) 
 
Vital signs (blood pressures, 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) 
 
Urinalysis (as detailed in Section 9.2.5) 
 
Lipid Profile (as detailed in Section 9.2.5) 
 
Pregnancy test (for female patients of child-bearing potential, as detailed in Section 9.2.7) 
 
ALT, AST tests (as detailed in Section 9.1.1) 
 
HOMA-IR/Adipo-IR (as detailed in Section 9.1.2) 
 
ELF (as detailed in Section 9.1.3) 
 
Liver stiffness and CAP (as detailed in Section 9.1.4) 
 
FIB-4 (as detailed in Section 9.1.5) 
 
NFS [including BMI] (as detailed in Section 9.1.6) 
 
Biomarker blood samples (as detailed in Section 9.2.8.3) 
 
Exploratory blood sample (as detailed in Section 9.2.8.2) 
 
AE assessment (as detailed in Section 11) 
 
Concomitant medication assessment (as detailed in Section 9.2.11) 
 
The IMP or placebo will be returned. No further IMP or placebo blister packs or patient diary cards will 
be issued. Following completion of the study assessments at this visit, there will be continued study 
restrictions in line with those described in section 9.2.11 and section 9.2.14.  
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in four weeks at Visit 11 to assess any AEs since this visit, and conduct safety and 
efficacy assessments. Before leaving the clinic the patient will be instructed not to have any breakfast 
before the next visit to allow a minimum fasting period of 8 hours. 
 
8.2.12 Follow up Visit (Week 20/Visit 11) 
 
Four weeks after Visit 10 (or 2 weeks after early withdrawal visit), patients will return to the 
investigational site. The patient will be asked if they have fasted for a minimum of 8hrs prior to visit. 
If this is not the case, the duration of fasting period will be documented and the patient will be 
reinstructed about the duration of the fasting period. Following this the patient will be provided with a 
light breakfast (e.g. tea or orange juice and toast). The following assessments will be carried out: 
 
 
Physical examination (as detailed in Section 9.2.2) 
 
Pharmacokinetic Sampling (as detailed in Section 9.2.8.1) 
 
Vital signs (blood pressures, 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) 
 
Pregnancy test (for female patients of child-bearing potential, as detailed in Section 9.2.7) 
 
ALT, AST tests (as detailed in Section 9.1.1) 


 
 
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 
HOMA-IR/Adipo-IR (as detailed in Section 9.1.2) 
 
Biomarkers (as detailed in Section 9.2.8.3); 
 
AE assessment (as detailed in Section 11) 
 
Concomitant medication assessment (as detailed in Section 9.2.11)


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9 
ASSESSMENTS 
9.1 
Efficacy Assessments 
9.1.1 
ALT, AST, ALT:AST Ratio 
Increased liver enzymes (ALT and AST) are a marker of liver injury and will be assessed at Visit 
1/Screening (On two occasions during screening 7 or more days apart), Visit 2/Baseline, Visit 
3/Week 2, Visit 4/Week 4, Visit 6/Week 8, Visit 8/Week 12, Visit 10/Week16 and Follow up Visit 
11/Week 20. 
9.1.2 
HOMA-IR/Adipo-IR 
HOMA-IR/Adipo-IR, measuring insulin resistance. HOMA-IR is calculated multiplying fasting 
plasma insulin (FPI) by fasting plasma glucose (FPG), then dividing by the constant 405. Adipo-
IR is calculated by multiplying fasting non-esterified fatty acids (NEFA) × fasting insulin. Blood 
samples will be taken to assess HOMA-IR and Adipo-IR at Visit 2/Baseline, Visit 3/Week 2, Visit 
4/Week 4, Visit 6/Week 8, Visit 8/Week 12, Visit 10/Week16 and Follow up Visit 11/Week 20. 
All subjects must be fasted for a minimum of 8hrs prior to blood sampling. If subjects have not 
fasted for a minimum of 8 hrs, the duration of fasting time should be recorded and subjects 
encouraged to fast appropriately for the next clinical visit. 
9.1.3 
ELF 
Enhance Liver Fibrosis score is an extracellular matrix marker set consisting of tissue inhibitor of 
metalloproteinases 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP) and 
hyaluronic acid (HA). Blood samples will be taken to perform this assessment at baseline (Visit 2) 
and week 16 (Visit 10).  
9.1.4 
Liver Stiffness and CAP 
Liver stiffness and Controlled attenuation parameter will be assessed using transient elastography 
(FibroScan® 502 Touch model or equivalent). Patients should be fasted and should be scanned at 
the same time of the day, if possible, for baseline (week 0) and Visit 10 (week 16).  
 
1. Patient must be lying in dorsal decubitus position with the right arm in maximal abduction 
behind the head, in a similar position to that used for LB (Liver Biopsy). 
2. The tip of the transducer must be placed on the skin between the ribs over the right lobe of 
the liver. The physician will take the measurements with the probe placed in the intercostal 
space.  
3. During the FibroScan® examination the choice of M+ or XL+ probe will be determined by 
the Automatic Probe Selection tool (APS). If, the APS tool advises to use the “XL+ probe” or 
“switch” continuously between “M+ and XL+ probe”, only the XL+ probe must be used. 
4. The operator, assisted by an ultrasonic time motion image, will locate a portion of the liver 
which is free of large vascular structures. The depth of measurement will be between 35-75 
mm for the XL+ probe and 25-65 mm for the M+ probe and the explored volume will be 3 
cm3.  
 
Once all the conditions mentioned above are met, the operator will be able to trigger a 
measurement. 
 


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5. For each patient, the operator will perform an examination including at least 10 valid 
measurements or a maximum of 20 attempts, with the XL+ or M+ probe, at the same spot. 
The entire examination should last no more than 10-15 minutes. 
6. The final stiffness and CAP values will be recorded as median values of valid measurements. 
 
9.1.5 
FIB-4 Index 
This index is based on age, platelet count, ALT level, and AST level and will be assessed at Baseline 
(Visit 2) and week 16 (Visit 10). 
 
 
FIB4 =                 Age (years) x AST (U/L) 
                   Platelet count (109/L) x √ALT (U/L) 
9.1.6 
NFS  
The NFS is based on age, hyperglycemia, BMI, platelet count, albumin level, and AST/ALT ratio. 
NAFLD fibrosis score = −1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × IFG/diabetes 
(yes = 1, no = 0) + 0.99 × AST/ALT ratio − 0.013 × platelet (×109/l) − 0.66 × albumin (g/dl).   NFS 
will be assessed at Baseline (Visit 2) and week 16 (Visit 10). 
 
 
http://nafldscore.com/ 
 
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 Screening visit (Visit 1) and Baseline (Visit 2) 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. 
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) at Visit 1/Screening, Visit 2/Baseline, Visit 3/Week 2, Visit 
4/Week 4, Visit 6/Week 8, Visit 8/Week 12, Visit 10/Week16 and Follow up Visit 11/Week 20 in 
accordance with local practices. This examination will be completed in full at baseline and 
symptom-directed thereafter, 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 
ECG 
 
Electrocardiogram Recording 
A 12-lead 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 5 minutes before the ECG is taken. Recordings will 
be made on the days indicated in Study Flow Chart (Appendix 1) at Visit 1/Screening, Visit 
2/Baseline and Visit 10/Week 16. 
9.2.4 
Vital Signs 
 
Vital signs measurements will be performed as per the Study Flow Chart (Appendix 1) at Visit 
1/Screening, Visit 2/Baseline, Visit 3/Week 2, Visit 4/Week 4, Visit 6/Week 8, Visit 8/Week 12, 
Visit 10/Week16 and Follow up Visit 11/Week 20. Measurements to be taken include: 
- 
Blood pressure: will be performed as supine (after at least 5 minutes of rest) systolic and 
diastolic blood pressure (in mmHg) 
- 
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, Coagulation, 
Lipid Profile, and Urinalysis 
Blood and urine samples will be taken as per the Study Flow Chart (Appendix 1) for routine 
haematology, serum biochemistry, coagulation and urinalysis tests, along with a Lipid Profile (as 
per Study Flow Chart [Appendix 1]). All samples will be analysed in the central laboratory. All 
subjects must be fasted for a minimum of 8hrs prior to blood sampling. If subjects have not fasted 
for a minimum of 8 hrs, the duration of fasting time should be recorded and subjects encouraged to 
fast appropriately for the next clinical visit. 
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), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), ALT/AST 
ratio, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), 
albumin, total protein, cholesterol, triglycerides, glucose, C-reactive 
protein (CRP). 
Coagulation: 
PT (prothrombin time), INR (international normalized ratio) and APTT 
(activated partial prothrombin time)  


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Lipid Profile: 
LDL (Low Density Lipoprotein) HDL (High density), VLDL (very low 
density),  
Urinalysis: 
pH, protein, glucose, blood, ketones, leukocytes, leukocyte esterase, 
bilirubin, specific gravity, urobilinogen and nitrate. Reflex micro if 
blood, protein, leukocyte esterase or nitrate/nitrite are present. 
9.2.6 
Virology 
 
A blood sample will be taken to perform virology tests including HIV, Hep C and Hep B as detailed 
in Study Flow Chart (Appendix 1).  
9.2.7 
Pregnancy Test 
For female patients of childbearing potential, a pregnancy test will be carried out as per the Study 
Flow Chart (Appendix 1) at Visit 1/Screening, Visit 2/Baseline, Visit 4/Week 4, Visit 6/Week 8, 
Visit 8/Week 12, Visit 10/Week 16 and Visit 11/Week 20. 
9.2.8 
Blood Sampling 
Details of the volume of blood or urine 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 PK analysis will be collected via direct venepuncture as per the Study Flow 
Chart (Appendix 1) at Visit 2/Baseline, Visit 3/Week 2, Visit 4/Week 4, Visit 6/Week 8, Visit 
8/Week 12, Visit 10/Week16 and Follow up Visit 11/Week 20.  
A 1 mL blood sample will be taken at each timepoint.  Following centrifugation, plasma samples 
will be split in two and a back-up sample will be kept at the central laboratory until bioanalytical 
assays have been completed. 
9.2.8.2 
Exploratory Blood Collection 
Blood will be collected as per the Study Flow Chart (Appendix 1) at baseline (Week 0) and Visit 
10/Week 16 and stored for potential gene array analysis or additional exploratory testing at a later 
date. 
9.2.8.3 
Biomarker Blood Collection 
Blood will be collected as per the Study Flow Chart (Appendix 1) at baseline (Week 0), Visit 
6/Week 8, Visit 10/Week 16 and Follow up Visit 11/Week 20 and will be stored for potential 
biomarker analysis.  
9.2.9 
Urine DOA and Alcohol Breath Test 
As clinically appropriate at the discretion of the investigator, an alcohol breath test will be 
performed and a urine sample will be taken from patients at any time during the conduct of the trial 
and testing will be done to detect the following: amphetamine, barbiturate, benzodiazepine, 
cocaine, cannabinoids, and opiates.  
 


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9.2.10 Adverse Event Assessment 
See section 11. 
9.2.11 Concomitant Medication 
Patients must be on a stable dose of any concomitant medications for at least 3 months prior to 
screening and that dose should remain stable for the entire study duration. If patients are insulin 
dependent this treatment should have commenced at least 3 months prior to screening, however 
changes in dose are permitted.    
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 Restrictions 
 
Diet 
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). 
Alcohol 
Patient should avoid alcohol consumption in excess of 21 units per week (males) or 14 units per 
week (females), whereby a unit consists of 10ml or 8mg of pure alcohol. 
Caffeine 
There are no restrictions on caffeine intake prior to or during the study. 
Physical Activity 
Patients should avoid exercise and strenuous physical activity for at least 3 to 4 hours before the 
safety laboratory test (biochemistry). 


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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 cabinet 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 the inclusion and none of the exclusion criteria may be accepted in the study. 
Each patient must read and sign an informed consent form (ICF) prior to any screening procedures 
being performed. This study involves a comparison of DS102 with placebo, administered orally 
twice daily for a total duration of 16 weeks. The last study drug administration should occur on the 
day preceding week 16 visit / Early Termination (ET) visit. Patients will be randomized to one of 
the three treatment groups in a 1:1:1 ratio: 
 
 
Treatment group A:   2 x Placebo 500mg capsules twice a day (4 capsules daily) 
 
 
Treatment group B:   1 x DS102 500mg capsule & 1 x Placebo 500mg capsule twice a day 
(4 capsules daily)  
 
 
Treatment Group C:   2 x DS102 500mg capsules twice a day (4 capsules daily) 


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Patients will be required to take the capsules with or after food. Medication(s) for other conditions 
that are permitted in the study can be taken as usual. 
 
Walleted blister packs will consist of 7 days of 4 capsules. Patients will be instructed to take the 2 
capsules from left to right, on the relevant day, as shown below: 
 
 
 
 
10.3 Duration of Treatment 
Patients will take assigned medication for 16 consecutive weeks. 
 
 
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 and the medication 
destroyed or returned to the Sponsor or designee. All study drug accountability forms and treatment 
logs must be retained in the Investigator’s study file. 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.  
Any study medication accidentally or deliberately destroyed will be accounted for. Any 
discrepancies between amounts dispensed and returned will 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):  
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 investigational IMP(s). All 
Adverse Events (AEs) must be recorded in the case report form, 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 serious adverse event after the first dose of the study drug, the event will 
be recorded as a serious adverse event.  
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any 
dose: 
 
results in death 
 
is life-threatening 
 
requires in-patient hospitalization or prolongation of existing hospitalization 
 
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 hospitalization but may jeopardize 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 hospitalization, or development 
of drug dependency or drug abuse. 
Unexpected Adverse Event (UAE):  
An experience not previously reported in the Investigator's Brochure 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 adverse event is transient and easily tolerated. 
 
Moderate: The adverse event causes the patient discomfort and interrupts the patient’s 
usual activities.  
 
Severe: The adverse event 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 case report form, defining relationship to IMP and severity.  
As soon as the Investigator is aware of a potential Serious Adverse Event (SAE), he/she should 
contact the Pharmacovigilance (PV) 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 Investigator Site File. 
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 PV CRO at the number provided in the Investigator Site File. The faxed SAE reporting form 
should be received to the PV CRO within 24 hours after 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 PV CRO within 5 days after the initial report. Where appropriate, hospitalisation or 
autopsy reports should be made available. All Serious Adverse Events will be followed up until 
resolution (i.e., asymptomatic, stabilisation or death).  
AE’s should be reported for the entire study duration 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.  
 


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11.2 Drug-induced Liver Injury 
 
1. 
Severe drug-induced liver injury 
Irrespective of perceived causation, in the event of severe drug-induced liver injury 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 rechallenged with the drug. 
Severe drug-induced liver injury stipulates evidence of hepatic impairment as demonstrated by a 
total bilirubin >2× ULN or INR >1.5. 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. 
2. 
Patients with abnormal baseline liver biochemistry  
A fold increase should be calculated against baseline levels instead of using the ULN. Thus a figure 
of 3× baseline ALT or AST (or >200 IU/L) should be followed by repeat testing within 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. 
 
11.3 Serious Adverse Reactions and Unexpected Adverse Reactions  
11.3.1 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 adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (e.g. Investigator's Brochure for an unauthorised investigational product or similar 
product information sheet such as the Summary of Products Characteristics (SPC). 
Suspected Unexpected Serious Adverse Reaction (SUSAR):  
Any serious adverse reaction that might be related to the IMP and are unexpected according to the 
definition above.  


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11.3.2 Reporting of suspected unexpected serious adverse reactions  
Suspected unexpected serious adverse reactions (SUSARs) will be reported by PV CRO according 
to appropriate Competent Authority and Ethics Committee requirements. SUSARs will be reported 
to Investigators according to ICH Good Clinical Practice and to local regulations. SUSAR reporting 
to the Competent Authorities and Ethics Committees 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 PV CRO as soon as possible to the 
Competent Authorities and Ethics Committees according to local regulations, and in any case no 
later than seven calendar days, after knowledge by 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 concerned and to the Ethics 
Committee concerned according to local regulations as soon as possible but within a maximum of 
fifteen days of first knowledge by PV CRO. 
11.4 Pregnancy Reporting 
If a patient or a patient’s partner becomes pregnant during the study, the patient should inform the 
study site as soon as possible. Upon confirmation of the pregnancy, the patient must be withdrawn 
from 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 is not itself 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 randomized, double-blind, placebo-controlled parallel group design. 
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 evaluation of 
safety and efficacy. The use of placebo as 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 
possible long-term irreversible damage that may be the result of placebo treatment. A full 
description of the study design is presented in Section 6 above. 
12.2 Randomisation 
 
Approximately 96 patients will be randomized into double-blind treatment groups in a 1:1:1 ratio 
as follows: 
 
 
Treatment group A:   2 x Placebo 500mg capsules twice a day (4 capsules daily) 
 
 
Treatment group B:   1 x DS102 500mg capsule & 1 x Placebo 500mg capsule twice a day 
(4 capsules daily)  
 
 
Treatment Group C:   2 x DS102 500mg capsules twice a day (4 capsules daily) 
 
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. 
 
The treatment assignment procedure will use blocks of sufficient size to maintain a blind and 
balance across treatment arms. Unique randomization numbers, generated according to the 
randomization specifications will be assigned and will determine the drug supply given to each 
patient. The Investigator will assign the lowest randomization number available at their site to the 
first patient randomized and proceed in increasing sequential order as patients are qualified for the 
study. A complete randomisation list containing details of all randomization numbers will be stored 
in an access-restricted folder at the CRO and accessible only to assigned CRO personnel not 
involved in the conduct of the study. 
12.3 Estimation of Sample Size 
Assuming a 20% delta in the percentage response between active drug and placebo arms, a standard 
deviation of 25% and a drop out rate of 20%, this results in a requirement of 32 patients per group 
for a statistical test with 5% level of significance, and 80% power.  
The sample size may be re-estimated at an interim analysis based on recommendation from an 
unblinded, independent DSMB. The sample size may be increased up to a maximum of 150 patients 
in total to achieve a conditional power of 80% for the primary endpoint. 
 


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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 authorized 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. 
Site will be provided with emergency code-break cards for all patients. The cards must not be 
opened for any other reason than a medical emergency. If a code break card is opened, the 
Investigator must note the date, time and reason for opening it and retain this information with the 
study documentation. The site monitor will check the integrity of the code-break cards at the site 
during routine monitoring visits. 
12.5 Interim Analysis and Data Monitoring 
An independent DSMB will monitor safety aspects of the study and perform an interim analysis 
for the primary and co-primary endpoints as well as the secondary endpoints. The procedures for 
performing the interim analysis by the DSMB are described in its charter.  
 
Under the direction of the DSMB, the interim analysis will be carried out to estimate the conditional 
power when at least 50% of the patients have completed their Week 16 visit. The interim analysis 
will be based on data collected for the primary and co-primary efficacy endpoints as well as the 
secondary endpoints and will be used to estimate the conditional power to achieve the primary 
study objective, to potentially re-estimate the sample size and to potentially drop the less effective 
treatment arm.  
 
The specific details regarding the DSMB organization and procedures will be outlined in the DSMB 
Charter and a statistical analysis plan (SAP) will be produced before the interim analysis covering 
the analysis required. 
 
For further details regarding the DSMB, refer to Section 13.1. 
 
12.6 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 SAP. 
12.7 Clinically Meaningful Response 
A clinically meaningful treatment difference is defined as follows: 
 
Higher mean or median reduction of at least 20% of ALT or Liver Stiffness compared to 
placebo 
 
Higher mean or median reduction of at least 10% of both ALT and Liver Stiffness 
compared to placebo 
 
12.8 Analysis Sets 
The Enrolled Set includes all patients who signed the informed consent form. 
Screen failures are patients from the Enrolled Population who do not meet the eligibility 
requirements and are withdrawn from the study prior to randomisation.  


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The Full Analysis Set (FAS) includes all randomised patients who received at least one 
administration of study treatment and have at least one post-baseline measurement. Patients will be 
analysed according to the treatment they were 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 
of FAS who had no major protocol violations. 
All protocol deviations will be assessed and documented on a case-by-case basis prior to the 
database lock, and major deviations considered as having a serious impact on the efficacy results 
will lead to the relevant patient being excluded from the PPS.   
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.   
The Pharmacokinetic (PK) Set will consist of those patients in the SAF who have at least one 
DS102 PK concentration. Patients will be analysed according to the treatment actually received. 
 
 
12.9 Safety Analysis 
Demographic, 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).  AEs will be 
tabulated and summarised by treatment, relationship to treatment, seriousness and severity. 
Clinical laboratory values (haematology, biochemistry, and urinalysis) 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. 
Alcohol breath test and DOA test results will be listed for each patient. 
Individual values of vital signs will be listed and summarised descriptively for each treatment and 
day. 
12-lead 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, 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. 


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12.10 Statistical Analysis Plan 
In addition to the summarised analysis plan outlined below, a separate document, Statistical 
Analysis Plan (SAP) for DS102A-02 will detail all analysis to be performed.  
 
12.10.1 Pharmacokinetic Analysis 
Plasma concentrations of 15(S)-HEPE will be tabulated and summarised descriptively.  Individual 
and mean plasma concentration-time profiles of 15(S)-HEPE will be presented graphically. 
12.10.2 Primary variables 
 
The primary efficacy variable will be the change from baseline in serum ALT at week 16 (Visit 
10). The active treatment groups will be compared against placebo via an analysis of covariance 
(ANCOVA) model, including the corresponding baseline value as covariate. The comparisons 
against placebo will be done according to Dunnett’s multiple testing procedure. For missing week 
16 values the last value available will be carried forward (LOCF). Similar methods will be applied 
for Liver Stiffness. For ALT, longitudinal modelling will be considered in addition. 
 
The increase of sample size at interim will only be considered if promising (promising zone 
approach). This does not require alpha adjustment. 
12.10.3 Secondary variables 
The secondary efficacy variables and their changes from baseline to week 16 (Visit 10) will be 
summarized with descriptive statistics per treatment group and visit. This applies to the AST, 
AST:ALT ratio, hepatic fat measured by CAP, liver stiffness measurements by transient 
elastography, FIB-4, NFS, ELF and HOMA-IR/Adipo-IR.  The change from baseline for the active 
treatment groups will be compared against placebo via an analysis of variance (ANOVA) model, 
including a term for centre effects. The 5% level of significance will be used for all treatment 
comparisons. 
12.11 Data Collection / Case Report Forms 
Data will be collected using a validated electronic data capture (EDC) solution. Electronic Case 
report forms (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 CRF 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 


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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 CRA respectively. 
Queries shall be resolved in a timely manner by a trained member of the site staff.  
12.12 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 the CRO Standard Operating 
Procedures (SOP). The handling of data, including data quality control, will comply with all 
applicable regulatory guidelines.  
12.13 Protocol Deviations 
Protocol deviations will be captured through site self-reporting, CRA source data verification and 
Data Management edit checks and will be recorded by the CRA throughout the study in both the 
monitoring visit reports and in a centralised log.  
 


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13 
REGULATORY AND ADMINISTRATIVE PROCEDURES 
13.1 Data and Safety Monitoring Board 
An independent DSMB will be formed to review ongoing safety and efficacy data. Members of the 
DSMB will not be allowed to participate as Investigators in this study and will not be affiliated in 
any way with the sponsor. The DSMB will consist of at least two physicians and a statistician. A 
DSMB charter will provide full guidance on the function and practices to be followed by the 
DSMB. 
 
13.2 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 Patient Information Sheet / Informed Consent Form will be approved by the 
relevant Competent Authorities and Ethics Committees, and possibly other public bodies according 
to local requirements before commencement. 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 Ethics Committees and possibly other public bodies according to local requirements 
for review and approval. The protocol amendment will not be implemented before 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 Ethics 
Committees according to local regulations.   
13.3 GCP 
The study will be managed and conducted according to the latest International Conference on 
Harmonisation (ICH) guidelines for Good Clinical Practice (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 Investigator Site File (ISF). 
13.4 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 Ethics Committee. A complete list of essential 
GCP documents can be found in the Investigator Site File. 
13.5 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 


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documents, copies of all CRFs, 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 International Conference on 
Harmonisation (ICH), local regulations, or as specified in the Clinical Trial Agreement (CTA), 
whichever is longest.  
13.6 Monitoring / Quality Control  
Monitoring visits will be conducted during the study at regular intervals. The 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 CRFs 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 is reviewed and signed by the PI. 
 
13.7 Quality Assurance  
The site may be audited during or after the study is completed by the 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. 
13.8 Insurance and Liability 
Insurance and liability for the study is the responsibility of the sponsor, Afimmune. 
13.9 End of Trial 
The end of the trial is defined as the date when the data for the final analysis are locked. The 
Competent Authorities and the Ethics Committees, as applicable, will be notified about the end of 
the trial. 
13.10 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. 
13.11 Report and Publication 
Production of a clinical study report in accordance with the ICH guidelines will be the responsibility 
of CRO.  No information from the study will be published without the prior written consent of the 
Sponsor. 
 
 


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14 
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 
FDA. 2012. 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202057_vascepa_toc.cfm 
 


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Page 58 of 61 
 
 
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) 
 
 
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. 
 
 
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 
 
 
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. 
 
 
Sanyal et al. 2011. Endpoints and clinical trial design for nonalcoholic steatohepatitis. 
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  
 
 
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 antiinflammatory and antiproliferative 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. 
 


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 
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. 
 
 
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: Study Flow-Chart 
 
 
Screening/ 
Visit 1 
Baseline/ 
Visit 2 
Visit 3/ 
Week 2 
Visit 4/ 
Week 4 
Visit 5/ 
Week 6 
Visit 6/ 
Week 8 
Visit 7/ 
Week 
10 
Visit 8/ 
Week 
12 
Visit 9/ 
Week 14 
EOT/ 
Visit 10 / 
Week 16 
Follow Up/ 
Visit 11 / 
Week 20 
Study Procedure 
Day -28 to -1 
Day 0  
Day 14 
Day 28 
Day 42 
Day 56 
Day 70 
Day 84 
Day 98 
Day 112 
Day 140 
Visit Window 
 
 
+/-2 days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 
days 
+/-2 days 
+/-2 days 
+/-4 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
12-lead ECG 
X 
X 
 
 
 
 
 
 
 
X 
 
Plasma PK sampling1 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Vital signs 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
Clinical laboratory tests ² 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Lipid Profile ³ 
 
X 
 
 
 
X 
 
 
 
X 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
X 
 
Virology 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 4 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
ALT, AST 5 
XX 
X 
X 
X 
 
X 
 
X 
 
X 
X 
HOMA-IR/Adipo-IR 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
ELF 
 
X 
 
 
 
 
 
 
 
X 
 
Liver stiffness and CAP 
 
X 
 
 
 
 
 
 
 
X 
 
FIB-4 
 
X 
 
 
 
 
 
 
 
X 
 
NFS [including BMI] 
 
X 
 
 
 
 
 
 
 
X 
 
Biomarkers Blood Sample 
 
X 
 
 
 
X 
 
 
 
X 
X 
Exploratory Blood Sample 
 
X 
 
 
 
 
 
 
 
X 
 
Patient Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
IMP/Placebo Dispensing 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study drug/placebo administration  
 
X--------------------------------------------------------------------------------------------------------------------X 
 
IMP Accountability/Diary Card review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE assessment 
 
X---------------------------------------------------------------------------------------------------------------------------------------------------X 
Concomitant medication assessment 
X 
X-----------------------------------------------------------------------------------------------------------------------------------------------------------------X 


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¹ Pharmacokinetics Ctrough only. Sample will be taken pre-dose. 
² Includes biochemistry, haematology and coagulation tests. This will be taken fasting (Minimum of 8hrs). 
³ Lipid Profile will be taken fasting (Minimum of 8hrs).  
4 Female Patients of child bearing potential only. 
5ALT to be assessed on two occasions during screening 7 or more days apart. 
 
 
 
 

SAP_001.pdf: 
 
Confidential 
 
 
Statistical Analysis Plan: DS102A-02 
 
Document Title: 
DS102A-02 Statistical Analysis Plan 
Study Title: 
A Randomised, Double-Blind, Placebo-Controlled, Exploratory 
Phase IIa Study to Assess the Safety and Efficacy of Orally 
Administered DS102 in NAFLD Patients 
Study Number: 
DS102A-02 
Study Phase 
Phase IIa 
Product Name: 
DS102 
Sponsor: 
Afimmune, 
Trintech Building, 
South County Business Park, 
Leopardstown, 
Dublin 18,  
Republic of Ireland. 
Version 1.1: 
November 19, 2018 
 
 
 
 
 
 
Confidentiality Statement 
This document contains trade secrets as well as commercial and proprietary information that 
are properties of Afimmune. This confidential information is intended solely for the recipient 
clinical investigator(s), and related personnel, for evaluating and conducting clinical 
investigations. It must not be disclosed to any other party unless such disclosure is required 
by applicable law or regulations. Any other use will require written consent from Afimmune. 
 


BDS Koch, Statistical const,ltut 
Winflied Koch 	
, 	
 
Name 
Signattire 	
Date 
Statistical Analysis Plan: DS102A-02 
Compound DSI02 
Afimmune 
April  2017 
Signature 
I have carefully read this statistical analysis plan and agree to the described methods and proceedings. 
Afimmune, Associate Medical Director 
Moayed Ham-ia 
Name 	
Signature 
Afimmune, Clinical Project Manager 
1/ 
Karen Doyle  
Name 
Date 
cL!2( I 
Signature 	
Date 
Designated CR0 Authorized Representative, Brightech International LLC, Sr Blostatisticlan 
f?itJC eAu 
Name 
cto 	
U 141 /o(  
Signature 	
Date 
2 
Confidential 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................5 
1. 
INTRODUCTION .............................................................................................................6 
2. 
STUDY OBJECTIVES ......................................................................................................6 
3. 
STUDY DESIGN...............................................................................................................6 
4. 
STUDY POPULATIONS ..................................................................................................6 
4.1. Enrolled Set ...................................................................................................................6 
4.2. Full Analysis Set ...........................................................................................................7 
4.3. Safety Analysis Set .......................................................................................................7 
4.4. Per Protocol Set.............................................................................................................7 
5. 
STUDY ENDPOINTS .......................................................................................................7 
5.1. Primary Endpoints ........................................................................................................7 
5.2. Secondary Endpoints ....................................................................................................7 
6. 
STATISTICAL CONSIDERATIONS...............................................................................8 
6.1. Estimation of Sample Size ............................................................................................8 
6.2. General Considerations .................................................................................................8 
6.3. Analysis Definitions......................................................................................................8 
6.3.1. Naming Conventions for Study Day ....................................................................8 
6.3.2. Baseline Values and Changes from Baseline .......................................................8 
7. 
DATA ANALYSIS ............................................................................................................9 
7.1. Patient Disposition ........................................................................................................9 
7.2. Treatment Compliance ..................................................................................................9 
7.3. Protocol Deviations .......................................................................................................9 
7.4. Demographic and Baseline Characteristics ................................................................10 
7.5. Efficacy Evaluation .....................................................................................................10 
7.5.1. General Considerations ......................................................................................10 
7.5.2. Efficacy Analyses on ALT, AST, AST:ALT and HOMA-IR, Adipo-IR ..........10 
7.5.3. Efficacy Analyses on Liver stiffness, FIB-4, NFS, Hepatic fat and ELF ..........11 
7.5.4. Missing values ...................................................................................................11 
7.6. Safety Evaluation ........................................................................................................12 
7.6.1. Adverse Events ..................................................................................................12 
7.6.2. Laboratory Data .................................................................................................12 
7.6.3. Vital Signs ..........................................................................................................13 
7.6.4. Physical Examination.........................................................................................13 
7.6.5. Alcohol urine test and Drug of Abuse (DOA) test ............................................13 
7.6.6. ECG Assessment ................................................................................................13 
7.6.7. Virology Analysis ..............................................................................................13 
7.7. Pharmacokinetic Analysis ...........................................................................................14 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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7.8. Exploratory Assessment..............................................................................................14 
8. 
INTERIM ANALYSES ...................................................................................................14 
9. 
PLANNED SUMMARY TABLES AND LISTINGS .....................................................14 
10. REFERENCE ...................................................................................................................14 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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LIST OF ABBREVIATIONS 
15(S)-HEPE EE 
15(S)-Hydroxy-Eicosapentaenoic Acid Ethyl Ester 
Adipo-IR 
Adipose Tissue Insulin Resistance 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic-Chemical 
BMI 
Body Mass Index 
CAP 
Controlled Attenuation Parameter 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOA 
Drugs of Abuse 
ECG 
Electrocardiogram 
ELF 
Enhanced Liver Fibrosis score 
HOMA-IR 
Homeostatic model assessment Insulin Resistance 
LS Mean 
Least Square Mean 
MAR 
Missing at Random 
MedDRA™ 
medical dictionary for regulatory activities  
MMRM 
Mixed Model of Repeated Measurements 
NAFLD 
Non-Alcoholic Fatty Liver Disease 
NFS  
NAFLD Fibrosis Score 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAEs 
Treatment-Emergent Adverse Events 
WHODD 
World Health Organization Drug Dictionary 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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1. INTRODUCTION 
This statistical analysis plan (SAP) for study DS102A-02 describes the detailed procedures 
for executing the planned statistical analyses for this study. 
This version of SAP has been written to be in accordance with the Protocol dated August 24, 
2018 and the Case Report Form (CRF) dated November 28th, 2016. Any further changes to 
the protocol or CRF may necessitate updates to the SAP. This SAP was written as a separate 
document, completed after finalizing the protocol, and prior to locking and unblinding the 
clinical datasets. This SAP includes a more technical and detailed elaboration of the 
statistical analyses stated in the protocol. 
The statistical analyses will be conducted by Brightech International using the 
SAS® software version 9.2 or later. 
2. STUDY OBJECTIVES  
The objective of the study is to assess the safety and efficacy of orally administered DS102 
capsules versus placebo in the treatment of adult patients with Non-Alcoholic Fatty Liver 
Disease (NAFLD). 
3. STUDY DESIGN  
This study will involve two dose levels of DS102 1000mg per day (500mg BD), 2000mg per 
day (1000mg BD) or placebo BD for 16 weeks using three treatment groups consisting of 32 
patients each. 
Patients with diagnosed NAFLD (Non-Alcoholic Fatty Liver Disease) will be enrolled in the 
study. After assessment and documentation of the baseline disease characteristics by the 
investigator, the patient will be randomly assigned to one of the above-mentioned treatment 
groups. The patient will be provided with study medication containing one of the assigned 
doses of DS102 or placebo according to the randomization. During the 16 weeks of treatment 
patients will take one of the treatments twice daily with or after food (morning and evening). 
Evaluation of efficacy will be performed throughout the study. A follow-up visit will be 
performed 4 weeks after the last date of treatment to monitor the treatment effects in 
comparison to the end of treatment. 
4. STUDY POPULATIONS 
4.1. Enrolled Set 
The Enrolled Set includes all patients who signed the informed consent form. 
Screen failures are patients from the Enrolled Population who do not meet the eligibility 
requirements and are withdrawn from the study prior to randomization.  
 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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4.2. Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized patients who received at least one 
administration of study treatment and have at least one post-baseline measurement. 
Patients will be analyzed according to the treatment they were assigned to at 
randomization, irrespective of what treatment they actually received.  
 
4.3. Safety Analysis Set 
The Safety Analysis Set (SAF) consists of all patients who take at least one 
administration of study treatment. Patients will be analyzed according to the treatment 
actually taken. 
 
4.4. Per Protocol Set 
The Per-Protocol Set (PPS) will be a subset of the Full Analysis Set consisting of those 
patients in the FAS who had no major protocol violations.  
 
5. STUDY ENDPOINTS 
5.1. Primary Endpoints 
Primary Efficacy Endpoint 
• Change in serum ALT (alanine aminotransferase) from baseline to week 16. 
• 
Change in liver stiffness measurements by Transient Elastography from baseline to week 
16 
Primary Safety Endpoint 
Percent of subjects with treatment emergent adverse events (TEAEs) in each treatment 
group leading to treatment discontinuation. 
5.2. Secondary Endpoints 
• Change in serum ALT (alanine aminotransferase) from baseline to weeks 2, 4, 8 
and 12. 
• Change in serum AST (aspartate aminotransferase) from baseline to weeks 2, 4, 8, 
12 and 16. 
• Change in AST: ALT ratio from baseline to weeks 2, 4, 8, 12 and 16. 
• Change in FIB-4 Index from baseline to week 16. 
• Change in NAFLD fibrosis score (NFS) from baseline to week 16. 
• Change in hepatic fat measured by CAP (controlled attenuation parameter) from 
baseline to week 16. 
• Change in ELF (Enhanced Liver Fibrosis score) from baseline to week 16. 
• Change in HOMA-IR/Adipo-IR (Homeostatic model assessment Insulin 
Resistance / Adipose tissue Insulin Resistance) from baseline to weeks 2, 4, 8, 12 
and 16. 
 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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6. STATISTICAL CONSIDERATIONS 
6.1. Estimation of Sample Size 
Assuming a 20% delta in the percentage response between active drug and placebo arms, 
a standard deviation of 25% and a dropout rate of 20%, this results in 32 patients per 
group with 5% level of significance, and 80% power.  
The sample size may be re-estimated at an interim analysis based on recommendation 
from an unblinded, independent DSMB. The sample size may be increased up to a 
maximum of 150 patients in total to achieve a conditional power of 80% for the primary 
endpoint. 
6.2. General Considerations 
Summary statistics for continuous variables will include mean, standard deviation, 
median and range. Categorical variables will be presented as frequency counts and 
percentages. Data listings will be created to support tables and present data. 
All statistical analyses will be conducted using SAS® Version 9.2 or above (SAS 
Institute, Cary, NC). Graphical summaries will be produced using SAS®. All probability 
values under the null hypotheses shown in the tables will be rounded to 3 decimal places. 
If a rounded p-value is equal to 0.000, the result will be displayed as “<0.001” in the 
tables. For presentation of untransformed data, the mean and median will be presented to 
one decimal place greater than the original data, standard deviation will be to two 
decimal places greater than the original data, and the minimum and maximum will have 
the same number of decimal places as the original data.   
6.3. Analysis Definitions 
6.3.1.  Naming Conventions for Study Day 
For the purpose of statistical computation, the study day of all assessments that are 
performed on or after randomization will be calculated as: 
Study Day = date of the assessment – date of randomization + 1. 
For assessment performed before the date of randomization, the study day calculation 
is similar except without adding 1: 
Study Day= date of assessment – date of randomization. 
6.3.2.  Baseline Values and Changes from Baseline 
The baseline value of all efficacy and safety variables is defined as the last non-
missing data on or prior to randomization. 
Change from baseline is defined as post-baseline value – baseline. 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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7. DATA ANALYSIS 
7.1. Patient Disposition 
Patient disposition data will be summarized for all screened patients as well as for all 
randomized patients presented (for all analysis populations) by treatment group. The 
number of subjects who were screened will be presented; number of patients who failed 
screening, who were enrolled, who were randomized will also be presented, along with 
the percentages based on number of screened subjects. Percentage will also be calculated 
for randomized subjects based on number of patients enrolled. 
The following patient disposition data will be summarized with percentages based on the 
number of patients randomized: 
• The number and percentage of patients who completed the study. 
• The number and percentage of patients who were enrolled but discontinued, along 
with the reason for discontinuation (e.g., lost to follow-up, adverse event, death, 
withdraw by patients). 
 
7.2. Treatment Compliance 
Treatment compliance is defined as the number of capsules taken over the number of 
capsules that should have been taken: 
%Compliance = (number of capsules actually taken / 448) * 100% 
448 (the number of capsules supposed to be taken) = 2 * 2 capsules /day * 7 days/week * 
16 weeks 
For patients with premature termination, the number of capsules supposed to be taken 
will be adjusted for the actual duration of study participation.  
Drug exposure days is defined as the number of days from first treatment to last treatment 
including days in between when study drugs were not taken. Descriptive statistics of 
subjects’ drug exposure days, number of capsules taken, and treatment compliance will 
be tabulated by treatment group. Individual’s treatment compliance will be listed. 
7.3. Protocol Deviations 
Protocol deviations will be reviewed to determine if it is a major deviation, which would 
render the violators excluded from the per-protocol population.  
Number and percentage of subjects in each treatment group with major protocol 
deviations will be presented. Individual protocol deviations will be listed with detailed 
deviation term. 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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7.4. Demographic and Baseline Characteristics 
Statistical summaries and analysis of the demographic and baseline data will be based on 
the Safety and Full Analysis sets. Tables will be presented by treatment group. These 
variables may include the following: 
• Gender 
• Race 
• Ethnicity 
• Age (years) 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) 
 
For continuous variables (e.g., age, weight, etc.), descriptive summary statistics will 
include the number, mean, standard deviation, median, minimum and maximum values. 
For categorical variables (e.g., sex, race, etc.), descriptive summary statistics will include 
the frequency distribution (i.e., number and percentage) among the categories. 
Medical history data will be listed including information of start date, end date, severity, 
and treatment for the event or not.  
Prior and concomitant Medications verbatim terms will be encoded using WHO Drug 
Dictionary (WHODD) codes and presented by Anatomical Therapeutic-Chemical (ATC) 
classifications in alphabetical order by treatment group.  
7.5. Efficacy Evaluation 
7.5.1. General Considerations 
The primary efficacy variables (serum ALT and liver stiffness) will be the change 
from baseline to week 16 (Visit 10). For each primary efficacy variable, the two 
active treatment groups will be compared against placebo via an analysis of 
covariance (ANCOVA) model, including the corresponding baseline value as 
covariate. The comparisons against placebo will be done according to Dunnett’s 
multiple testing procedure (for multiple dose vs. placebo comparison). The two 
primary endpoints will be assessed independently in efficacy analyses. Efficacy 
analysis will be performed on the Full analysis set and per-protocol set. 
 
7.5.2. Efficacy Analyses on ALT, AST, AST:ALT and HOMA-IR, Adipo-IR 
ALT, AST, AST:ALT and HOMA-IR, Adipo-IR are all assessed at Baseline visit, 
visit 3/week 2, visit 4/week 4, visit 6/week 8, visit 8/week 12 and visit 10/week 16. 
ALT, AST, AST:ALT and HOMA-IR, Adipo-IR will be analyzed separately. 
The change from baseline to weeks 2, 4, 8, 12 and 16 of these efficacy variables will 
be calculated by the post-baseline assessment at respective time point minus the 
baseline assessment result. Descriptive statistics of actual values of ALT, AST, 
AST:ATL or HOMA-IR, Adipo-IR and change from baseline to weeks 2, 4, 8, 12 and 
16 will be presented by treatment group.  At each time point, the change from 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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baseline will be analyzed using an analysis of covariance (ANCOVA) model with 
terms of treatment, site, baseline and treatment-by-baseline interaction.  The pairwise 
comparisons among the treatment groups will also be presented.  Dunnett’s t-test will 
be used for the comparison between the two doses of DS102 and placebo.  
As an overall treatment effect analysis, the change from baseline of these variables 
over weeks 2, 4, 8, 12 and 16 will be analyzed using a mixed model of repeated 
measurements (MMRM) under assumption of missing at random (MAR). The model 
will include treatment group, visit (week 2, 4, 8, 12 and 16), treatment-by-visit 
interaction as fixed effects, and corresponding baseline as well as treatment-by-
baseline interaction terms. The model will be run using unstructured covariance 
assumptions. Degrees of freedom will be adjusted using the Kenward-Roger method.  
From this repeated measurement analysis, the least squares (LS) means and 
corresponding 95% confidence intervals (CI) for each treatment group, along with 
overall and pair-wise p-values will be presented. If only one null hypothesis for one 
primary endpoint is rejected, then the confidence intervals for the endpoint will be 
adjusted according to the Dunnett’s test.  
The LS means of these endpoints along with the 95% CI for each treatment group 
will be displayed as a figure over time. 
7.5.3. Efficacy Analyses on Liver stiffness, FIB-4, NFS, Hepatic fat and ELF 
Liver stiffness, FIB-4, NFS, Hepatic fat and ELF are all assessed at Baseline visit and 
visit 10/week 16. FIB-4, NFS, Hepatic fat, Liver stiffness and ELF will be analyzed 
separately. 
The change from baseline to week 16 of these efficacy variables is defined as the 
assessment result at week 16 minus baseline assessment result. Descriptive statistics 
of actual value of Liver stiffness, FIB-4, NFS, Hepatic fat, or ELF and change from 
baseline to week 16 will be presented by treatment group. 
The analyses of change from baseline to week 16 of these efficacy variables will use 
the Full Analysis Set data. To compare the group means, an analysis of covariance 
(ANCOVA) model will be used with baseline, treatment, treatment-by-baseline and 
site effects. The pairwise comparisons of treatment groups will be presented.  
This ANCOVA analysis will apply to both primary endpoints.  
Same ANCOVA model will be performed on per protocol set as supportive analyses. 
7.5.4. Missing values 
For missing data in efficacy endpoint, the last observation carried forward (LOCF) 
analysis will be performed. Further, a controlled multiple imputation approach based 
on pattern mixture models will be applied.  More specifically, missing data for those 
subjects taking DS102 who discontinued will be imputed based on the posterior 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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distribution of the placebo group.  All other missing data will be assumed under a 
MAR and imputed using the posterior distribution of the respective treatment group. 
7.6. Safety Evaluation 
The safety analyses will use the safety population. 
7.6.1. Adverse Events 
Adverse events (AEs) will be coded by Medical Dictionary for Regulatory Activities 
(MedDRA™) System Organ Class (SOC) and Preferred Term (PT). Causality 
(relationship to study drug) of AEs will be summarized.  If more than one adverse 
events are recorded for a patient within any SOC or PT term, the patient will only be 
counted once on the most severe grade and the closest relationship to treatment. 
Treatment-emergent adverse events (TEAEs) will be defined as the adverse events 
with date of onset (or worsening) on or after the date of first treatment. 
The following AE summaries will be presented in tables: 
• An overall summary of the AEs, including the number of AE reported, number of 
TEAE reported, number and percentage of patients reporting AE, the number and 
percentage of patients with AE possibly related or related to study treatment, 
number and percentage of patients reporting serious AE, the number and 
percentage of patients with serious AE possibly related or related to study 
treatment, the number and percentage of patients discontinuing treatment due to 
AE, the number and percentage of patients’ death due to AE, presented by 
treatment group. 
• A breakdown of the number and percentage of patients reporting TEAEs, 
categorized by SOC and PT, presented by treatment group. 
• A breakdown of the number and percentage of patients reporting TEAEs, 
categorized by SOC and PT, presented by treatment group and severity. 
• Number and percentage of patients reporting TEAEs, leading to treatment 
discontinuation, categorized by SOC and PT, presented by treatment group. 
Patients’ TEAEs leading to treatment discontinuation will also be listed. 
• Patients with TEAEs possibly related or related to study treatment, categorized by 
SOC and PT, presented by treatment group. 
• Patients with TEAEs possibly related or related to study treatment, categorized by 
SOC and PT, presented by treatment group and severity. 
• Number and percentage of patients reporting Serious AEs (SAEs), categorized by 
SOC and PT, presented by treatment group. 
• Number and percentage of patients reporting Serious AEs (SAEs), categorized by 
SOC and PT, presented by treatment group and severity. 
 
7.6.2. Laboratory Data 
Laboratory data will be presented in following ways: 
• Descriptive statistics will be tabulated for biochemistry, hematology, continuous 
urinalysis parameters, lipid profile and coagulation parameters by treatment group 
and visit. Number and percentages will be tabulated for qualitative urinalysis 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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parameters. Laboratory parameters will be grouped by panel (biochemistry, 
hematology, urinalysis, lipid profile and coagulation tests) and sorted 
alphabetically. 
• Shift tables comparing the baseline parameter classification (low, normal, high) to 
each post-baseline visit classification for all non-missing post-baseline data will 
be provided for biochemistry, hematology, urinalysis, lipid profile and 
coagulation tests data, by treatment group. 
• Abnormal clinically significant lab values will be tabulated by treatment group 
and visit. 
• Clinical laboratory values will be listed for each patient by treatment and study 
visit. 
7.6.3. Vital Signs 
Descriptive statistics of patients’ vital signs by treatment group and scheduled study 
visit will be summarized including number of patients, mean, standard deviation, 
median and range. 
Individual values of vital signs will be listed. 
The following equation will be used to calculate Body Mass Index (BMI): 
BMI = Weight (kg)/ (Height (m))2 
7.6.4. Physical Examination 
Exam results of physical examinations are recorded as “Normal”, “Abnormal, not 
clinically significant” or “Abnormal, clinically significant”. Number and percentage 
of subjects in each category will be summarized.  
7.6.5. Alcohol urine test and Drug of Abuse (DOA) test 
Findings of alcohol urine test and DOA test will be listed for each patient. 
7.6.6. ECG Assessment 
Number and percentage of subjects in each ECG evaluation result category (normal, 
abnormal not clinical significant, abnormal clinical significant) will be summarized 
by treatment group and study visit. 
Evaluation of 12-lead ECG assessment results will be presented by treatment group 
and study visit. 
12-lead ECG assessment will be listed for each patient with all associated comments 
and summarized by treatment group and study visit. 
7.6.7. Virology Analysis  
Number and percentage of subjects in each category of virology analyses results will 
be summarized 


Statistical Analysis Plan: DS102A-02                                                                                            Afimmune  
Compound: DS102                                                                                                                    November 19, 2018 
 
 
 
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Confidential 
7.7. Pharmacokinetic Analysis 
Plasma pharmacokinetic samples are planned to be collected pre-dose at Baseline Visit 
(Visit 2), Week 2 (Visit 3), Week 4 (Visit 4), Week 8 (Visit 6), Week 12 (Visit 8), Week 
16 (Visit 10) and Week 20 (Visit 11). Elapsed Time will be calculated as time difference 
between Time of Pharmacokinetic Sample Collection and Time of Study Drug 
Administration and listed for each subject. Descriptive statistics (mean, standard 
deviation, median, minimum and maximum) of plasma concentrations of 15(S)-HEPE 
(15(S)-Hydroxy-Eicosapentaenoic Acid Ethyl Ester) will be summarized by treatment 
group and visit. Mean plasma concentration-time profiles of 15(S)-HEPE will be 
presented by treatment group graphically. 
7.8. Exploratory Assessment 
Blood samples will be collected and stored for potential gene array analysis and 
biomarker analysis. Individual data will be listed for each patient by treatment group and 
study visit. 
8. INTERIM ANALYSES  
The sample size may be re-estimated at an interim analysis based on recommendation 
from an unblinded, independent DSMB. The sample size may be increased up to a 
maximum of 150 patients in total to achieve a conditional power of 80% for either of 
the primary endpoints or the secondary endpoints.   
• Futility will be declared if the conditional power is <=50% for both primary 
endpoints and all secondary endpoints and for both active groups compared to 
Placebo; this is equivalent to say that none of the four primary comparisons and 
the supportive secondary comparisons to Placebo shows an advantage of Active 
over Placebo. 
• High efficacy will be declared if the smallest p value of the 4 primary 
comparisons versus Placebo (adjusted by the Dunnett procedure) is smaller than 
p<0.01   
 
9. PLANNED SUMMARY TABLES AND LISTINGS  
Planned table numbering and title may be modified for the clinical study report (CSR), with 
the final list to be reflected in a separate table, figure and listing shell document. 
10. REFERENCE 
Clinical Trial Protocol: A Randomized, Double-Blind, Placebo-Controlled, Exploratory 
Phase IIa Study to Assess the Safety and Efficacy of Orally Administered DS102 in NAFLD 
Patients, DS102A-02 Version 6.0 August 2018, Afimmune,