Conditions: Hypertriglyceridemia Type 2 Diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 233
Healthy volunteers: no

Brief summary:
To assess the efficacy and safety of orally administered Epeleuton capsules versus placebo, in the treatment of adult patients with hypertriglyceridemia and type 2 diabetes

Detailed description:
This was a randomised, double-blind, Placebo-controlled, 3-arm, multi-centre Phase IIb study consisting of 26 weeks of active treatment and a 2-week post-treatment follow-up period in adult patients with hypertriglyceridemia and concomitant type 2 diabetes.

The screening period consisted of up to 6-weeks lead-in during which all patients were to undergo diet and lifestyle stabilisation, washout of disallowed medications and optimisation of statins.

After screening, patients were randomised (1:1:1) at the baseline visit into the following treatment groups:

* Treatment Group A (Placebo): four Placebo capsules orally administered twice a day, i.e., eight capsules daily for 26 weeks.
* Treatment Group B (Epeleuton 2g): two Epeleuton 500 mg capsules and two Placebo capsules orally administered twice a day, i.e., eight capsules daily for 26 weeks.
* Treatment Group C (Epeleuton 4g): four Epeleuton 500 mg capsules orally administered twice a day, i.e., eight capsules daily for 26 weeks.

The observation period was 32-34 weeks (lead-in: 4-6 weeks, treatment duration: 26 weeks, follow-up period: 2 weeks). During the study, 10 visits to the clinic were scheduled: two screening visits (Visit 1 and Visit 2), one visit at the start of the comparative treatment period (baseline/Visit 3), six visits in the comparative treatment period (Visit 4/Week 4, Visit 5/Week 8, Visit 6/Week 12, Visit 7/Week 16, Visit 8/Week 20 and Visit 9/Week 26 or Early Termination) and one final safety follow-up visit (Visit 10/Week 28).

Arms:
arm 1: Participants in this group received 1000mg DS102 capsules twice daily. arm 2: Participants in this group received 2000mg DS102 capsules twice daily. arm 3: Participants in this group received placebo capsules twice daily.

Interventions: intervention 1: DS102 intervention 2: Placebo
Intervention descriptions: intervention 1: DS102 Epeleuton capsules intervention 2: Placebo capsules

Protocol document:
Prot_000.pdf: 
Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 1 of 90 
 
 
 
 
 
 
 
 
A Randomised, Double-Blind, Placebo-Controlled, Dose Finding 
Phase IIb Study to Assess the Efficacy and Safety of Orally 
Administered Epeleuton in Patients with Hypertriglyceridemia and 
Type 2 Diabetes.  
 
 
 
Short Title 
 
TRIglyceride And Glucose control with Epeleuton in Metabolic Syndrome Patients 
(TRIAGE) 
 
 
 
Protocol Number # DS102A-07-CV1 
Version 5.0 
 14 February 2022 
EudraCT No. 2020-000065-16 
Sponsor: 
Afimmune, 
Trintech Building, 
South County Business Park, 
Leopardstown, 
Dublin 18, 
Republic of Ireland. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 2 of 90 
 
 
CONTACT INFORMATION 
 
 
Chief Investigator: 
Prof. Deepak L. Bhatt 
Professor of Medicine, Harvard Medical School, 
Executive Director of Interventional 
Cardiovascular Programs, Brigham and 
Women’s Hospital Heart & Vascular Center,  
Boston, MA 
 
Sponsor Medical Expert: 
Dr. Markus Weissbach, Chief Medical Officer,  
Afimmune, 
Trintech Building, 
South County Business Park, Leopardstown, 
Dublin 18, 
Republic of Ireland.  
Tel: +353 1 294 6380 
Pharmacovigilance/Medical 
Monitor: 
 
 
spm2 – safety projects & more GmbH, 
Goldbeckstraße 5, 
69493 Hirschberg a.d. Bergstraße, 
Germany 
 
        Telephone: +49 (6201) 84640 - 0 
        Email: Afimmune-PhV@spm2-safety.com 
        24 hour contact details – Germany/Europe:  +49 6201 84640 601 
        24 hour contact details – USA:  800 831 4988 
        24 hour contact details – Latvia:  802 002 04 
        24 hour contact details – Israel:  1809 349 154 
        24 hour contact details – UK:  0800 931 4072 
        24 hour contact details – Georgia:  800 008 032 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 3 of 90 
 
TABLE OF CONTENTS 
 
CONTACT INFORMATION .............................................................................................................................................................. 2 
TABLE OF CONTENTS ................................................................................................................................................................... 3 
PROTOCOL SYNOPSIS ................................................................................................................................................................. 8 
LIST OF ABBREVIATIONS/ DEFINITIONS ................................................................................................................................... 19 
1 INTRODUCTION ........................................................................................................................................ 22 
1.1 
Therapeutic Area and Disease Background ......................................................................... 22 
1.2 
Standard Treatment ................................................................................................................ 22 
1.3 
Drug Class ............................................................................................................................... 23 
1.4 
Preclinical Pharmacology ...................................................................................................... 23 
1.5 
Toxicology ............................................................................................................................... 25 
1.6 
Previous Clinical Safety Studies with Epeleuton ................................................................. 25 
2 
RISK BENEFIT ASSESSMENT ........................................................................................................... 29 
3 
RATIONALE FOR THE STUDY ............................................................................................................ 30 
4 
STUDY OBJECTIVES........................................................................................................................... 31 
5 
STUDY ENDPOINTS ............................................................................................................................ 32 
5.1 
Primary Endpoints .................................................................................................................. 32 
5.2 
Secondary Endpoints ............................................................................................................. 32 
5.3 
Exploratory Endpoints ............................................................................................................ 33 
5.4 
Safety Variables....................................................................................................................... 35 
6 
STUDY DESIGN .................................................................................................................................... 36 
6.1 
General ..................................................................................................................................... 36 
6.2 
Rationale for Study Design and Dose Selection .................................................................. 37 
7 
PATIENTS AND SCREENING .............................................................................................................. 40 
7.1 
Source of Patients ................................................................................................................... 40 
7.2 
Inclusion Criteria ..................................................................................................................... 40 
7.3 
Exclusion Criteria .................................................................................................................... 41 
7.4 
Screening and Consent .......................................................................................................... 43 
7.5 
Withdrawal of Patients ............................................................................................................ 44 
7.6 
Patient Replacement ............................................................................................................... 45 
7.7 
Protocol Deviations................................................................................................................. 45 
8 
STUDY CONDUCT ............................................................................................................................... 46 
8.1 
Study Schedule ....................................................................................................................... 46 
8.2 
Clinic Visits .............................................................................................................................. 46 
8.2.1 
Screening Visit 1 (Visit 1) ................................................................................................................................................. 46 
8.2.2 
Screening Visit 2 (Visit 2) ................................................................................................................................................. 47 
8.2.3 
Treatment Period ............................................................................................................................................................. 47 
8.2.4 
Baseline (Visit 3) .............................................................................................................................................................. 49 
8.2.5 
Week 2 Telephone Call .................................................................................................................................................... 50 
8.2.6 
Visit 4/Week 4 .................................................................................................................................................................. 50 
8.2.7 
Visit 5/Week 8 .................................................................................................................................................................. 51 
8.2.8 
Visit 6/Week 12 ................................................................................................................................................................ 51 
8.2.9 
Visit 7/Week 16 ................................................................................................................................................................ 52 
8.2.10 
Visit 8/Week 20 ................................................................................................................................................................ 52 
8.2.11 
Visit 9/Week 26/ Early Termination .................................................................................................................................. 53 
8.2.12 
Visit 10/Week 28/ Follow up ............................................................................................................................................. 53 
9 
ASSESSMENTS ................................................................................................................................... 55 
9.1 
Efficacy Assessments ............................................................................................................ 55 
9.1.1 
Body weight, waist circumference, BMI ............................................................................................................................ 55 
9.1.2 
Blood pressure ................................................................................................................................................................. 55 
9.1.3 
Blood samples ................................................................................................................................................................. 55 
9.1.4 
Urinary albumin-to-creatinine ratio ................................................................................................................................... 57 
9.2 
Safety Assessments ............................................................................................................... 57 
9.2.1 
Pregnancy test and Contraception Counselling ................................................................................................................ 57 
9.2.2 
Adverse Events Assessment ............................................................................................................................................ 58 
9.2.3 
Medical History ................................................................................................................................................................ 58 
9.2.4 
Concomitant medication ................................................................................................................................................... 58 
9.2.5 
Electrocardiogram ............................................................................................................................................................ 59 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 4 of 90 
 
9.2.6 
Physical Examination ....................................................................................................................................................... 59 
9.2.7 
Vital Signs ........................................................................................................................................................................ 59 
9.2.8 
Self-monitoring of blood glucose (SMBG) and hypoglycaemia assessment ...................................................................... 60 
9.2.8.1 Hypoglycaemia assessment ............................................................................................................................................. 60 
9.2.9 
Clinical Laboratory Safety Tests: Haematology, Serum Biochemistry, and Coagulation ................................................... 61 
9.2.10 
Urinalysis ......................................................................................................................................................................... 62 
9.3 
Pharmacokinetic sampling ..................................................................................................... 62 
9.4 
Exploratory Blood Sampling .................................................................................................. 62 
9.5 
Sample Storage, Handling and Shipping .............................................................................. 62 
10 
INVESTIGATIONAL PRODUCT/INVESTIGATIONAL DRUG ............................................................... 63 
10.1 
Investigational Medicinal Product (IMP) ............................................................................... 63 
10.2 
Supply, Packaging, Labelling, Handling and Storage ......................................................... 63 
10.3 
Dosage and Administration ................................................................................................... 63 
10.4 
Duration of Treatment ............................................................................................................. 64 
10.5 
Method for Assigning Patients to Treatment ....................................................................... 65 
10.6 
Drug Accountability ................................................................................................................ 65 
11 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................................................. 66 
11.1 
Definitions and Reporting of Adverse Events ...................................................................... 66 
11.1.1 
Definitions ........................................................................................................................................................................ 66 
11.1.2 
Severity ............................................................................................................................................................................ 67 
11.1.3 
Causality .......................................................................................................................................................................... 68 
11.1.4 
Reporting of AEs and SAEs ............................................................................................................................................. 69 
11.1.5 
Follow-up of Missing Information/Response to Sponsor Queries ...................................................................................... 69 
11.2 
Serious Adverse Reactions and Unexpected Adverse Reactions ..................................... 70 
11.2.1 
Definitions ................................................................................................................................ 70 
11.2.2 
Reporting of suspected unexpected serious adverse reactions (SUSARs) ..................... 70 
11.3 
Pregnancy Reporting .............................................................................................................. 71 
11.4 
Unblinding for Regulatory Reporting or Medical Necessity ............................................... 71 
11.4.1 
Unblinding for studies conducted in the EU ...................................................................................................................... 72 
11.4.2 
Unblinding for studies conducted in the US ...................................................................................................................... 72 
12 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT ............................................................ 73 
12.1 
Study Design ........................................................................................................................... 73 
12.2 
Randomisation ........................................................................................................................ 73 
12.3 
Estimation of Sample Size ..................................................................................................... 74 
12.4 
Blinding and Code Breaking Instructions ............................................................................ 74 
12.5 
Data Analysis ........................................................................................................................... 75 
12.6 
Analysis Populations .............................................................................................................. 75 
12.7 
Safety Analysis ........................................................................................................................ 75 
12.8 
Statistical Analysis Plan ......................................................................................................... 76 
12.8.1 
Primary Variables .................................................................................................................... 76 
12.8.2 
Secondary variables ............................................................................................................... 76 
12.8.3 
Missing data and sensitivity analyses .................................................................................. 77 
12.9 
Interim Analysis....................................................................................................................... 77 
12.10 
Data Collection/Electronic Case Report Forms ................................................................... 78 
12.11 
Data Management.................................................................................................................... 78 
12.12 
Protocol Deviations................................................................................................................. 78 
13 
REGULATORY AND ADMINISTRATIVE PROCEDURES .................................................................... 79 
13.1 
Institutional Review ................................................................................................................ 79 
13.2 
Good Clinical Practice ............................................................................................................ 79 
13.3 
Essential Documents .............................................................................................................. 79 
13.4 
Record Retention .................................................................................................................... 79 
13.5 
Monitoring/Quality Control ..................................................................................................... 80 
13.6 
Quality Assurance ................................................................................................................... 80 
13.7 
Insurance and Liability ........................................................................................................... 80 
13.8 
End of Trial ............................................................................................................................... 80 
13.9 
Confidentiality ......................................................................................................................... 80 
13.10 
Data Protection ........................................................................................................................ 80 
13.11 
Report and Publication ........................................................................................................... 81 
13.12 
COVID-19 Contingency ........................................................................................................... 81 
14 
REFERENCES ...................................................................................................................................... 83 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 5 of 90 
 
15 
APPENDICES ....................................................................................................................................... 86 
15.1 
Appendix 1. Flow Chart .......................................................................................................... 86 
15.2 
Appendix 2. Table of Central Laboratory Assessments ..................................................... 88 
15.3 
Appendix 3: Hypoglycaemic Episode Form ......................................................................... 89 
15.4 
Appendix 4: COVID-19 Contingency Investigator Assessment Phone Visits .................. 90 
 
 
 
LIST OF FIGURES 
 
Figure 1. Structure of 15(S)-HEPE EE (Epeleuton) ........................................................................................................ 23 
Figure 2. Streptozocin and High Fat Diet Mouse Study - Concentrations of Serum Triglycerides and Cholesterol at 
End of Treatment .......................................................................................................................................... 24 
Figure 3. Study Outline ................................................................................................................................................ 36 
Figure 4. DS102A-02 study – Median change in triglycerides in patients receiving Epeleuton 2g/day or Epeleuton 
1g/day  .......................................................................................................................................................... 38 
Figure 5. DS102A-02 study - Mean Change in HbA1C from Baseline to Week 16 (End-of-treatment) ........................ 39 
Figure 6. Walleted Blister Packs ................................................................................................................................... 64 
 
 
 
LIST OF TABLES 
 
Table 1. 
ADA/EASD classification of hypoglycaemia ................................................................................................... 58 
Table 2. 
Sample size estimation using effect size (Cohen's d from -0.02 to -0.75) .................................................... 74 
 




Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 7 of 90 
 
 
PRINCIPAL SITE INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
 
 
Investigator name: 
Signature: 
Date: 
Institution Name: 
By my signature, I agree to personally supervise the conduct of this study at my study site 
and to ensure its conduct is in compliance with the protocol, informed consent, 
Independent Ethics Committee (IEC) procedures, instructions from Afimmune 
representatives, the Declaration of Helsinki, International Conference on Harmonisation 
(ICH) Good Clinical Practices Guidelines (GCP), and national/local regulations governing the 
conduct of clinical studies. 
The signature also confirms that the Investigator agrees that the results of this study may 
be used for submission to national and/or international registration and supervising 
authorities. The authorities will be notified of the Investigators name, address, qualifications 
and extent of involvement. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 8 of 90 
 
PROTOCOL SYNOPSIS 
 
STUDY TITLE: 
A Randomised, Double-Blind, Placebo-Controlled, Dose Finding Phase IIb 
Study to Assess the Efficacy and Safety of Orally Administered Epeleuton 
in Patients with Hypertriglyceridemia and Type 2 Diabetes. 
SHORT TITLE: 
TRIglyceride lowering And Glycemic control with Epeleuton in metabolic 
syndrome patients: TRIAGE 
PHASE: 
IIb 
STUDY DURATION: 
32 - 34 weeks (4 - 6 weeks lead-in, 26 weeks treatment, two weeks post-
treatment follow-up) 
INVESTIGATIONAL 
PRODUCT: 
Epeleuton Capsules  
Placebo (light liquid paraffin) 
OBJECTIVES: 
Efficacy Objective: 
• 
To assess the efficacy of orally administered Epeleuton capsules 
versus placebo, in the treatment of adult patients with 
hypertriglyceridemia and type 2 diabetes. 
Safety Objective: 
• 
To assess the safety of orally administered Epeleuton capsules versus 
placebo, in the treatment of adult patients with hypertriglyceridemia 
and type 2 diabetes. 
 
 
PRIMARY ENDPOINTS: 
 
• 
Percent change in triglycerides from baseline to week 16. 
 
• 
Change in HbA1c from baseline to week 26. 
Note: 
• 
Each of the independent primary endpoints will be analysed 
separately. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 9 of 90 
 
SECONDARY ENDPOINTS: 
 
• 
Percent change in triglycerides from baseline to weeks 4, 8, 12, 20 
and 26. 
 
• 
Change in HbA1c from baseline to weeks 4, 8, 12, 16 and 20. 
 
• 
Proportion of patients achieving a HbA1c below 7.0% at weeks 4, 8, 
12, 16, 20 and 26. 
 
• 
Percent change in very low-density lipoprotein cholesterol (VLDL-C) 
from baseline to weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Percent change in non-high-density lipoprotein cholesterol (non-
HDL-C) from baseline to weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Percent change in total cholesterol from baseline to weeks 4, 8, 12, 
16, 20 and 26. 
 
• 
Change in fasting plasma glucose from baseline to weeks 4, 8, 12, 
16, 20 and 26. 
 
• 
Proportion of patients achieving a HbA1c below 6.5% at weeks 4, 8, 
12, 16, 20 and 26. 
 
• 
Percent change in apolipoprotein B (ApoB) from baseline to weeks 
16 and 26. 
 
• 
Percent change in remnant lipoprotein cholesterol (RLP-C) from 
baseline to weeks 8, 16 and 26. 
 
• 
Percent change in high-density lipoprotein cholesterol (HDL-C) from 
baseline to weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Percent change in low-density lipoprotein cholesterol (LDL-C) 
(preparative ultracentrifugation) from baseline to weeks 16 and 26. 
 
• 
Change in body weight (kg) from baseline to weeks 4, 8, 12, 16, 20 
and 26. 
 
• 
Change in high-sensitivity C-reactive protein (hsCRP) from baseline 
to weeks 8, 16 and 26. 
 
• 
Change in systolic blood pressure from baseline to weeks 4, 8, 12, 
16, 20 and 26. 
 
• 
Change in diastolic blood pressure from baseline to weeks 4, 8, 12, 
16, 20 and 26. 
 
• 
Change in urinary albumin-to-creatinine ratio (UACR) from baseline 
to week 26 in the sub-group of patients with microalbuminuria at 
baseline. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 10 of 90 
 
EXPLORATORY ENDPOINTS • 
Change in waist circumference from baseline to weeks 8, 16 and 26. 
 
• 
Percent change in apolipoprotein CIII (ApoCIII) from baseline to 
weeks 16 and 26. 
 
• 
Percent change in apolipoprotein A1 (ApoA1) from baseline to 
weeks 16 and 26. 
 
• 
Percent change in lipoprotein (a) (Lp(a)) from baseline to weeks 16 
and 26. 
 
• 
Percent change in high-density lipoprotein particle concentration 
(HDL-P) from baseline to weeks 16 and 26. 
 
• 
Percent change in small low-density lipoprotein particle 
concentration (Small LDL-P) from baseline to weeks 16 and 26. 
 
• 
Percent change in large low-density lipoprotein particle 
concentration (Large LDL-P) from baseline to weeks 16 and 26. 
 
• 
Percent change in low-density lipoprotein size (LDL size) from 
baseline to weeks 16 and 26. 
 
• 
Percent change in very low-density lipoprotein size (VLDL size) from 
baseline to weeks 16 and 26. 
 
• 
Percent change in high-density lipoprotein size (HDL size) from 
baseline to weeks 16 and 26. 
 
• 
Change in fasting plasma insulin from baseline to weeks 16 and 26. 
 
• 
Change in Homeostatic model assessment insulin resistance 
(HOMA-IR) from baseline to weeks 16 and 26. 
 
• 
Change in Homeostatic model assessment β-cell function (HOMA-β) 
from baseline to weeks 16 and 26. 
 
• 
Change in interleukin 6 (IL-6) from baseline to week 26. 
 
• 
Change in interleukin 1β (IL-1β) from baseline to week 26. 
 
• 
Change in plasminogen activator inhibitor 1 (PAI-1) from baseline to 
week 26. 
 
• 
Change in vascular cell adhesion molecule 1 (VCAM-1) from 
baseline to week 26. 
 
• 
Change in intercellular adhesion molecule 1 (ICAM-1) from baseline 
to week 26. 
 
• 
Change in monocyte chemoattractant protein 1 (MCP-1) from 
baseline to week 26. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 11 of 90 
 
• 
Change in red cell distribution width (RDW) from baseline to weeks 
16 and 26. 
 
• 
Change in haemoglobin from baseline to weeks 16 and 26. 
 
• 
Change in reticulocyte count from baseline to weeks 16 and 26. 
 
• 
Change in erythrocyte (red blood cell) count from baseline to weeks 
16 and 26. 
 
• 
Trough plasma concentrations of total and unesterified 15-hydroxy 
eicosapentaenoic acid (15(S)-HEPE) in treated population compared 
to placebo population at Baseline/Day 0, Week 4, Week 8, Week 16 
and Week 26. 
 
• 
Trough plasma concentrations of eicosapentaenoic acid (EPA) in 
treated population compared to placebo population at 
Baseline/Day 0, Week 4, Week 8, Week 16 and Week 26. 
 
• 
Determination of exploratory serum biomarkers in treated 
population compared to placebo population at Baseline and Week 
26. 
 
SAFETY VARIABLES 
• Incidence of treatment-emergent level 2 and level 3 hypoglycaemic 
episodes 
o Level 2 – Glucose <54 mg/dL, with or without symptoms 
o Level 3 – A severe event characterized by altered mental and/or 
physical status requiring assistance for treatment of 
hypoglycaemia. 
 
• Adverse event (AE) and serious adverse event (SAE) frequency and 
severity. 
 
• Safety laboratory parameters (haematology, clinical chemistry, 
coagulation). 
 
• Urinalysis 
 
• Electrocardiograms (ECGs) 
 
• Vital signs (heart rate, temperature, blood pressure) 
 
• Physical examination. 
 
• Pregnancy 
 
STUDY DESIGN: 
This is a multi-centre, double blind, placebo controlled, 3-arm, phase IIb 
study consisting of 26 weeks of active treatment and a 2 week follow up 
period.  
 
The screening period will consist of up to 6-weeks lead-in during which all 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 12 of 90 
 
patients will undergo diet and lifestyle stabilisation, washout of 
disallowed medications and optimisation of statins. 
 
Lipid qualification criteria include a fasting triglyceride level ≥200 mg/dL 
and <750mg/dL (inclusion #3) and LDL cholesterol<130mg/dL (inclusion 
#6). Triglycerides and LDL cholesterol will be checked at Screening #1 and 
a second qualifying visit (Screening #2). which will take place one week 
before randomisation at the baseline visit. Patients who meet the 
inclusion criteria at both screening visits will be eligible to participate in 
the study. Eligible patients will be randomised one week after Screening 
#2 at the baseline visit. 
 
Patients will be randomised (1:1:1) at baseline visit to either receive 
Epeleuton 4g/day (2g twice daily), Epeleuton 2g/day (1g twice daily) or 
placebo twice daily for 26 weeks. 
 
TOTAL 
NUMBER 
OF 
RANDOMISED PATIENTS: 
Approximately 240 male or female patients, aged 18 years or older; i.e. 
80 patients per treatment group 
STUDY POPULATION: 
INCLUSION CRITERIA: 
1. Patients diagnosed with type 2 diabetes mellitus at least 90 days prior 
to the first screening visit. 
 
2. Patients with a HbA1C (glycosylated haemoglobin) between 7.0 - 
10.0% (53-86mmol/mol) (both inclusive) 
 
3. Patients with a fasting triglyceride level ≥200 mg/dL (2.26 mmol/L) 
and <750 mg/dL (8.46 mmol/L) at both screening visits. 
 
Note: If the triglyceride level is outside the required range at the 
second screening visit, an additional measurement can be obtained 
1 week later, to confirm eligibility. 
 
Note: If a large difference in triglyceride level (>15%) is observed 
between Screening 1 and Screening 2, an additional measurement 
may be requested or patient may be deemed not eligible.  
 
4. Patients who have been educated regarding diet and exercise at or 
before visit 1 (screening 1) and are willing to maintain and not alter 
a stable diet and activity routine throughout the study. 
 
5. Patients who have been on a stable statin therapy at doses that are 
likely to achieve optimal LDL cholesterol and who are willing to 
continue this treatment throughout the study. 
 
Note: Stable statin therapy may consist of a statin with or without 
ezetimibe.  
 
6. Patients with an LDL cholesterol level <130mg/dL (3.34 mmol/L) at 
both screening visits. 
 
7. Patients who have a body mass index (BMI) ≥ 25kg/m2 and 
<50kg/m2. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 13 of 90 
 
8. Patients who have been on a stable daily dose of metformin (at least 
1500mg or maximum tolerated dose for metformin monotherapy as 
documented in the subject medical record) and/or a sulfonylurea 
and/or a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or a sodium-
glucose transport protein 2 inhibitor (SGLT2i) and/or a glucagon-like 
peptide 1 receptor agonist (GLP1-RA) and/or basal insulin for at least 
90 days prior to the day of first screening visit. 
 
Note: Dose of GLP1-RA must be stable for 6 months prior to baseline 
with no weight change >2kg for 3 months prior to baseline.  
 
Note: Dose of basal insulin must be stable for 4 months prior to 
baseline. All types of basal insulin are permitted, including insulin 
glargine, insulin degludec, insulin detemir, NPH insulin and pre-
mixed insulin 
 
9. Female patients and male patients with female partners of 
childbearing potential must use highly effective contraceptive 
methods or have a sterilised partner for the duration of the study. 
Highly effective contraceptive methods are defined as methods that 
can achieve a failure rate of less than 1% per year when used 
consistently and correctly. Such methods include hormonal 
contraception, intrauterine device or sexual abstinence. 
 
Note: A woman is considered of childbearing potential (WOCBP), i.e. 
fertile, following menarche and until becoming post-menopausal 
unless permanently sterile. Permanent sterilisation methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
 
Note: Hormonal contraceptives must be on a stable dose for at least 
one month before baseline. 
 
Note: Sexual abstinence is considered a highly effective method only 
if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient. 
 
10. Patients whose pre-study or screening clinical laboratory findings do 
not interfere with their participation in the study, in the opinion of 
the Investigator, and do not violate any inclusion or exclusion criteria 
 
11. Male or female patients aged 18 years and older on the day of signing 
the informed consent form (ICF). 
 
12. 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 prior to initiation 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 14 of 90 
 
of any study specific activities or procedures. 
EXCLUSION CRITERIA: 
1. Patients who have a history of intolerance or hypersensitivity to any 
substance in epeleuton capsules, placebo capsules or statins.  
 
2. Patients with uncontrolled hypertension defined as a systolic blood 
pressure ≥160 mmHg or a diastolic blood pressure ≥100mmHg. 
3. Patients who have a body mass index (BMI) <25kg/m2 or ≥ 50kg/m2. 
4. Patients who have a weight change >2kg from the first screening visit 
to the baseline visit. 
5. Patients who have type 1 diabetes mellitus. 
6. Patients who have thyroid stimulating hormone (TSH) levels >1.5 
times the upper limit of normal. 
7. Patients with known familial lipoprotein lipase deficiency (Fredriksen 
type I), apolipoprotein C-II deficiency or familial dysbetaliproteinemia 
(Fredriksen type III). 
8. Patients with significant liver disease or liver function impairment 
defined as any of the following; cirrhosis, hepatitis, biliary obstruction 
with hyperbilirubinemia (total bilirubin >2 times the upper limit of 
normal) and aspartate aminotransferase (AST) or alanine 
aminotransferase levels (ALT) >3 times the upper limit of normal. 
 
9. Patients with renal impairment defined as an estimated glomerular 
filtration rate <50mL/min/1.73m2 as per the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula. 
10. Patients with a history of malignancies within the past 5 years other 
than curatively treated non-melanoma skin cancer (basal cell or 
squamous cell carcinomas). 
11. Patients who have been treated with any investigational product 
within 60 days prior to visit 1 (Screening 1), or 5 half-lives (whichever 
is longer). Patients cannot participate in any other investigational 
medication or medical device trial while participating in this study. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 15 of 90 
 
12. Patients who have used dietary supplements or prescription products 
rich in omega-3 or omega-6 fatty acids in the four weeks prior to 
baseline. 
13. Patients who have been treated with any medication for diabetes or 
obesity in the four weeks before the baseline visit, except for 
metformin, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors, basal 
insulin, GLP1-RAs (must be on a stable dose for at least 6 months) 
and short-term insulin treatment for acute illness for a total of 
below or equal to 14 days. 
14. Patients who have been treated with fibrates, proprotein 
convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bile acid 
sequestrants, niacin, niacin analogues or dietary supplements for 
the purpose of lowering triglycerides or cholesterol in the six weeks 
prior to baseline. 
 
15. Patients who have a family or personal history of multiple endocrine 
neoplasia type 2 or medullary thyroid carcinomas. 
 
16. Patients who have a history of acute or chronic pancreatitis. 
 
17. Patients who have a history of major surgical procedures involving 
the stomach potentially affecting absorption of investigational 
medicinal product (e.g. subtotal and total gastrectomy, sleeve 
gastrectomy, gastric bypass surgery) 
18. Patients who have planned major surgical procedures, coronary 
intervention (such as stent placement or heart bypass), carotid or 
peripheral revascularisation. 
 
19. Patients who have a history of myocardial infarction, stroke, 
coronary revascularisation or hospitalisation for unstable angina in 
the 3 months prior to screening. 
 
20. Patients with creatine kinase concentrations > 10 times the upper 
limit of normal or creatine kinase elevation due to known muscle 
disease at visit 1 (screening 1) 
 
21. Patients who are classified as being in New York Heart Association 
(NYHA) Class IV heart failure. 
22. Patients who have a history of diabetic ketoacidosis. 
 
23. Patients with known proliferative retinopathy or maculopathy 
requiring acute treatment. 
24. Patients with significant systemic or major illnesses that, in the 
opinion of the Investigator, would preclude or interfere with 
treatment with Epeleuton, adequate follow up and/or compliance 
with the protocol. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 16 of 90 
 
 
25. Patients who are pregnant, planning pregnancy, breastfeeding 
and/or are unwilling to use adequate contraception (as specified in 
Inclusion Criterion 9) during the trial. 
 
26. Patients with active infectious diseases or chronic infectious disease 
(e.g. human immunodeficiency virus or tuberculosis). 
 
27. Patients who have recently received a vaccination or for whom a 
vaccination is planned (apart from flu, SARS-COV2 and 
pneumococcal vaccines which are permitted at any time). 
 
28. Patients who have previously been randomised into the study. 
 
29. Patients, in the opinion of the Investigator, not suitable to participate 
in the study. 
TEST PRODUCT, DOSE, 
AND MODE OF 
ADMINISTRATION: 
Epeleuton will be provided as a capsule, containing 500mg of 15(S)-HEPE 
EE with 2.5% w/w of colloidal silicon dioxide as viscosity modifier. 
 
Placebo (light liquid paraffin) will be provided in a capsule containing 
equivalent fill weight of light liquid paraffin. 
 
This study will involve 2 dose levels of Epeleuton administered for 26 
weeks; 4g/day (2g BID = 4 Epeleuton capsules BID), 2g/day (1g BID = 2 
Epeleuton capsules and 2 placebo capsules BID) or placebo (4 placebo 
capsules BID). 
 
Investigational Medicinal Product (IMP) will be administered with or after 
food at the same time each day. 
SAFETY EVALUATION 
CRITERIA 
• Physical examination 
• ECG (12-lead) 
• Vital signs, including blood pressure (BP), heart rate and 
temperature 
• Clinical laboratory tests (haematology, coagulation, and 
biochemistry) 
• Urinalysis 
• Pregnancy test for females of child-bearing potential 
• Adverse events (AEs) 
• Concomitant medications (CMs) 
• Self-monitoring of blood glucose (SMBG) 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 17 of 90 
 
SAMPLE SIZE 
The sample size was estimated based on results of post hoc analyses of 
triglycerides and HbA1C from a phase II trial of Epeleuton in patients 
with non-alcoholic fatty liver disease (NAFLD). Changes in triglycerides 
and HbA1C at the highest tested dose (2g/day) at week 16 (end-of-
treatment) were used to estimate relative effect sizes (Cohen’s D).  
 
To discover a conservative relative effect size (Cohen’s d) between each 
epeleuton group and placebo of 0.6 in triglyceride change from baseline 
with 80% power, 45 patients per group are necessary under ideal 
assumptions using the t-test for independent samples (alpha=0.05, two-
sided). 
 
To discover a conservative relative effect size (Cohen’s d) between each 
epeleuton group and placebo of 0.48 in HbA1C change from baseline 
with 80% power, 70 patients per group are necessary under ideal 
assumptions using the t-test for independent samples (alpha=0.05, two-
sided). 
 
To power the study for both primary endpoints and take deviations 
from ideal parametric conditions and drop-outs into account 80 patients 
per group will be randomised. 
 
STATISTICS 
The primary analysis will be conducted in the full analysis set (FAS) 
population which will be a modified intention-to-treat (mITT) population 
consisting of all randomised patients who received at least one dose of 
the study drug and have one post-baseline measurement. 
 
For continuous variables, descriptive statistics will include: the number 
of patients reflected in the calculation (n), mean, median, standard 
deviation, interquartile range, minimum, and maximum. 
 
For categorical data, frequencies and percentages will be displayed for 
each category. 
 
Analysis of changes and percentage changes of triglycerides will be 
performed using a Wilcoxon rank sum test with the Hodges Lehmann 
median and 95% confidence intervals estimates. For analysis of 
triglycerides, baseline will be defined as the mean of the Baseline (Visit 
3) and Screening 2/Week -1 (Visit 2) measurements. 
 
Changes from baseline of HbA1c at each visit will be analysed using 
mixed model analysis of covariance (ANCOVA) with baseline value as a 
covariate. 
 
Secondary and exploratory endpoints will be analysed by either an 
ANCOVA mixed model if the data for that endpoint are normally 
distributed, or a Wilcoxon-rank-sum test if the data are not normally 
distributed.  
 
Logistic regression with baseline HbA1C as a covariate will be used to 
analyse the percentage of patients with HbA1c < 7.0% and the 
percentage of patients with HbA1c < 6.5% at week 16. 
 
Exploratory analyses pooling the two doses vs. placebo for all pre-


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 18 of 90 
 
 
 
 
 
specified endpoints will be performed. 
 
Missing data will be accounted for using a multiple imputation 
approach.  Sensitivity analyses will be conducted for the primary 
endpoints using a last observation carried forward (LOCF) missing data 
handling approach. 
 
A two-sided p-value less than 0.05 is considered statistically significant 
for all comparisons. 
SPONSOR 
 Afimmune Ltd. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 19 of 90 
 
LIST OF ABBREVIATIONS/ DEFINITIONS 
 
15(S)-HEPE 
15-Hydroxy-Eicosapentaenoic Acid 
15(S)-HEPE EE 
15-Hydroxy-Eicosapentaenoic Acid Ethyl Ester, Epeleuton 
AE 
Adverse Event 
AH 
Alcoholic Hepatitis 
AHA 
American Heart Association 
ANCOVA 
Analysis of Covariance 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
ApoCIII 
Apolipoprotein CIII 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BDRM 
Blind Data Review Meeting 
BID 
Twice Daily 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum Observed Concentration 
COPD 
Chronic Obstructive Pulmonary Disease 
CRA 
Clinical Research Associate 
CRF / eCRF 
Case Report Form / Electronic Case Report Form 
CRO 
Clinical Research Organisation 
CRP 
C-Reactive Protein 
CSR 
Clinical Study Report 
CTA 
Clinical Trial Agreement 
CV 
Cardiovascular 
CVD 
Cardiovascular Disease 
DHA 
Docosahexaenoic Acid 
DM 
Data Manager 
DPP4 
Dipeptidyl Peptidase 4 
DPP4i 
Dipeptidyl Peptidase 4 Inhibitors 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCTD 
Electronic Common Technical Document 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EPA 
Eicosapentanoic Acid 
Eudravigilance database 
EMA system for managing and analysing suspected adverse 
reactions to medicines and investigational medicinal products 
in clinical trials in the European Economic Area (EEA) 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl Transferase 
GLP 
Good Laboratory Practice 
GLP-1 RA 
Glucagon-like Peptide 1 Receptor Agonists 
GMP 
Good Manufacturing Practice 
HDL-C 
High Density Lipoprotein Cholesterol 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 20 of 90 
 
HDL-P 
High Density Lipoprotein Particle Concentration 
HDL Size 
High Density Lipoprotein Size 
HOMA-β 
Homeostatic Model Assessment of β-cell Function 
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
hsCRP 
High-Sensitivity C-Reactive Protein 
IB 
Investigator’s Brochure 
ICAM-1 
Intercellular Adhesion Molecule 1 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IL- 
Interleukin- 
IND 
Investigational New Drug 
INR 
International Normalised Ratio 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
IWRS 
Interactive Web Response System 
LDL-C 
Low-Density Lipoprotein Cholesterol 
LDL-P 
Low-Density Lipoprotein Particle Concentration 
LDL Size 
Low-Density Lipoprotein Size 
LOCF 
Last Observation Carried Forward 
Lp(a) 
Lipoprotein (a) 
LPLV 
Last Patient Last Visit 
MCP-1 
Monocyte Chemoattractant Protein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention to Treat 
NAFLD 
Non-Alcoholic Fatty Liver Disease 
NASH 
Non-Alcoholic Steatohepatitis 
nMR 
Nuclear Magnetic Resonance 
NOAEL 
No Observed Adverse Effect Levels 
Non-HDL-C 
Non-High-Density Lipoprotein Cholesterol 
NYHA 
New York Heart Association 
PAI-1 
Plasminogen Activator Inhibitor 1 
PCSK9 
Proprotein Convertase Subtilisin/Kexin Type 9 
PI 
Principal Investigator 
PIS 
Patient Information Sheet 
PK 
Pharmacokinetics 
PPS 
Per Protocol Set 
PT 
Prothrombin Time 
RDW 
Red Cell Distribution Width 
REC 
Research Ethics Committee 
RLP 
Remnant Lipoprotein Cholesterol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SDV 
Source Data Verification 
SGLT2 
Sodium Glucose Co-transporter 2 
SGLT2i 
Sodium Glucose Co-transporter 2 Inhibitors 
SMBG 
Self-monitoring of Blood Glucose 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 21 of 90 
 
T1/2 
Apparent first-order terminal elimination half-life 
TEAE 
Treatment-Emergent Adverse Event 
Tmax 
Time of maximum observed concentration 
TSH 
Thyroid Stimulating Hormone 
TZD 
Thiazolidinediones 
UACR 
Urinary albumin-to-creatinine ratio 
UAE 
Unexpected Adverse Event 
VCAM-1 
Vascular Cell Adhesion Molecule 1 
VLDL 
Very Low-Density Lipoprotein 
VLDL-C 
Very Low-Density Lipoprotein Cholesterol 
VLDL Size 
Very Low-Density Lipoprotein Size 
WBC 
White Blood Cells 
WHODD 
World Health Organisation Drug Dictionary 
WOCBP 
Women of Child-Bearing Potential 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 22 of 90 
 
1 INTRODUCTION 
 
1.1 
Therapeutic Area and Disease Background 
Type 2 diabetes mellitus is a progressive metabolic disease primarily characterised by abnormal 
glucose metabolism. The pathogenesis is heterogeneous involving environmental, lifestyle and 
genetic factors leading to chronic hyperglycaemia caused by peripheral tissue insulin resistance, 
impaired insulin secretion due to abnormal beta-cell function and abnormal glucose metabolism in 
the liver. Type 2 diabetes is associated with multiple comorbidities including hypertriglyceridemia 
and non-alcoholic fatty liver disease (NAFLD), and ultimately microvascular and macrovascular 
complications (American Diabetes Association 2019a). 
 
Type 2 diabetes is large and increasing public health challenge, estimated to affect 9.4% (30.3 
million people) of the US population with 1.5 million cases diagnosed every year, with similar 
prevalence reported globally. Among people aged 65 years and older prevalence is even higher, at 
25.2% or 12.0 million. It is was reported to be the seventh leading cause of death in the United 
States in 2015 and its prevalence is increasing. In 2015, 84.1 million Americans aged 18 and older 
were prediabetic (American Diabetes Association, 2019b). 
 
Hypertriglyceridemia and its many comorbidities affect a large and increasing segment of many 
populations. It is estimated that approximately 30% of the US population may have elevated 
triglyceride levels which are associated with increased cardiovascular risk (Toth et al. 2018. A small 
proportion of patients with hypertriglyceridemia have severe hypertriglyceridemia (>500 mg/dL) 
which is associated with acute pancreatitis, a potentially fatal complication (Grundy et al. 2018). 
 
Atherosclerotic cardiovascular disease remains a leading cause of morbidity and mortality globally 
with persistently high rates of ischemic events reported especially in at risk populations such as 
individuals with diabetes or hypertriglyceridemia. It is estimated that $37.3 billion per year in 
cardiovascular-related spending alone is associated with diabetes. Additionally, despite the advent 
of statins, ischemic heart disease remains the leading cause of premature adult mortality globally 
(American Diabetes Association 2019a). 
 
1.2 
Standard Treatment 
Optimal glycaemic control is the treatment goal in patients with type 2 diabetes, in order to prevent 
long term complications associated with chronic hyperglycaemia including microvascular and 
macrovascular complications. Ongoing patient self-management, education and support are critical 
to preventing acute complications and reducing the risk of long-term complications (American 
Diabetes Association 2019c). 
 
Current pharmacological standard of care treatment is based on a patient-centred approach which 
includes consideration of efficacy and patient-specific factors. Commonly recommended 
treatments include metformin as first-line therapy, sulfonylureas, dipeptidyl peptidase 4 inhibitors 
(DPP4i), glucagon-like peptide 1 receptor agonists (GLP-1RA), sodium glucose co-transporter 2 
inhibitors (SGLT2i) and thiazolidinediones (TZD) (American Diabetes Association 2019d). 
 
However, despite the availability of several anti-hyperglycaemic drugs, a significant proportion of 
patients with type 2 diabetes do not achieve the recommended targets for glycaemic control. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 23 of 90 
 
Current standard of care for hypertriglyceridemia typically consists of lifestyle modification. 
However, emergence of data from the REDUCE-IT cardiovascular (CV) outcomes study of icosapent 
ethyl, the ester of the omega 3 fatty acid eicosapentaenoic acid (EPA) suggests that EPA-axis therapy 
reduces cardiovascular risk in patients with hypertriglyceridemia (Bhatt et al. 2019). In contrast, 
EPA/DHA mixtures are not associated with a cardiovascular benefit as evidenced by the lack of 
benefit reported in a recent large CV outcome study (STRENGTH) of Epanova (omega 3 carboxylic 
acids - EPA/DHA). 
 
There is a persistent unmet need for patients with type 2 diabetes and patients with 
hypertriglyceridemia for additional treatments that improve biochemical parameters and 
ultimately improve clinical outcomes. 
 
1.3 
Drug Class 
Epeleuton is 15-hydroxy eicosapentaenoic acid (15(S)-HEPE) ethyl ester (15(S)-HEPE EE), a highly-
purified, semi-synthetic omega-3 fatty acid derivative of EPA. 
 
15(S)-HEPE, at much lower concentrations, is an endogenous downstream 15-lipoxygenase 
metabolite of EPA. 
 
Epeleuton has been associated with potent triglyceride lowering, anti-hyperglycaemic, anti-
inflammatory and anti-fibrotic effects in clinical and non-clinical studies. 
 
Figure 1: Structure of 15(S)-HEPE EE (Epeleuton) 
 
 
1.4 
Preclinical Pharmacology 
 
Similar to other omega-3 polyunsaturated fatty acids and their metabolites, Epeleuton is postulated 
to exert its therapeutic effects through pleiotropic mechanisms which include: 
• 
Incorporation into and re-ordering of cell membranes 
• 
Modulation of the expression and function of certain cell surface receptors, leading to 
regulation of cell signalling and alteration of the production of mediators including 
cytokines, leukotrienes and prostaglandins 
• 
Acting as an endogenous ligand for certain G-protein coupled receptors. 
• 
Further conversion by lipoxygenase enzymes into its downstream metabolites Lipoxin A5 
and Lipoxin B5. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 24 of 90 
 
The mechanism of action of the triglyceride lowering and antihyperglycemic effect of Epeleuton has 
not been fully elucidated. It is thought to be partially mediated through free fatty acid degradation 
leading to decreased very-low-density lipoprotein (VLDL) and increased clearance of diglycerides 
and triglycerides, in addition to other pleotropic mechanisms as described above. 
 
Epeleuton has been shown to decrease plasma triglycerides, total cholesterol, VLDL cholesterol and 
chylomicrons in non-clinical species. Administration of Epeleuton to streptozocin and high fat diet 
model mice (SMCN013-1411-8) produced dose-dependent reductions in triglycerides which notably 
exceeded the triglyceride reduction produced by the EPA positive control when administered at the 
same dose (Figure 2). Triglyceride levels were mirrored by dose-dependent decreases of VLDL 
cholesterol and chylomicron concentrations in serum. 
 
Figure 2. Streptozocin and High Fat Diet Mouse Study - Concentrations of Serum Triglycerides 
and Cholesterol at End of Treatment 
 
 
EPA  - 500 mg/kg, 15-HEPE EE low – 50 mg/kg, 15-HEPE EE high – 500 mg/kg 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 25 of 90 
 
Nonclinical toxicology studies with Epeleuton in normolipidemic rats also showed dose-dependent 
decreases in triglycerides and total cholesterol. In a 28-day repeat dose rat study (CRL 527943), 
dose-related decreases in triglycerides were observed in both sexes and were significant in males. 
A significant decrease in total cholesterol was also observed in females at 2g/kg/day. In a 26-week 
repeat dose rat study (CRL 529123), dose-related decreases in triglycerides and total cholesterol 
were observed in both sexes at week 13 and week 26 and were significant in males at 1g/kg/day at 
both time points. In a further 26-week repeat dose rat study (CRL509554), significant dose-related 
decreases in triglycerides and total cholesterol were observed at both tested doses, 2g/kg/day and 
3g/kg/day. 
 
Additionally, Epeleuton delayed and prevented the progression of end-organ effects in multiple 
animal models including mouse models of chronic kidney disease, liver fibrosis and lung fibrosis. In 
a unilateral ureteral obstruction model of tubulointerstitial nephritis and chronic kidney disease, 
Epeleuton decreased fibrosis area and collagen deposition (SLMC062-1805-5). In a streptozocin and 
high fat diet mouse model of dyslipidemia and non-alcoholic steatohepatitis (NASH), Epeleuton 
decreased urinary microalbuminuria in addition to delaying and preventing the progression of renal 
fibrosis, hepatic fibrosis and hepatic steatosis (SMCN013-1411-8).  Similarly, in a bile duct ligation 
model of liver fibrosis (SLMN063-1805-6), Epeleuton delayed the progression of liver fibrosis. In a 
bleomycin induced pulmonary fibrosis mouse model, treatment with Epeleuton decreased 
inflammatory cell influx in broncheoalveolar fluid and ultimately decreased lung fibrosis (DS-PC-30). 
 
1.5 
Toxicology 
A number of good laboratory practice (GLP) toxicology studies have been conducted by the 
company to assess the safety of Epeleuton in rats (CRL-527545, CRL-527943, CRL-529123, 
CRL509554) and dogs (CRL-527550, CRL-527959, CRL-529139). 
 
Repeated dose, once-daily oral administration of Epeleuton  in chronic toxicity studies in rats (4 and 
26 week duration at doses up to 2000 and 1000mg/kg/day, respectively) and dogs (4 and 39 weeks 
duration at doses up to 2000 and 1000mg/kg/day, respectively) was well tolerated and showed no 
adverse, treatment-related effects. The no observed adverse effect levels (NOAEL) for repeated 
dosing over four weeks in both species was the highest tested dose 2000mg/kg/day. The NOAEL for 
the 26-week rat and 39-week dog study was also the highest tested dose of 1000mg/kg/day. In 
addition, a 26-week study in rats has recently been completed and is currently being analysed, with 
the aim to evaluate the safety and toxicity of oral administration of Epeleuton at higher doses. 
 
1.6 
Previous Clinical Safety Studies with Epeleuton 
 
Safety of Epeleuton was assessed in: 
• 
three completed Phase I studies in healthy subjects (DS102A-01, DS102A-04 and DS102A-
06-HV3), 
• 
two completed Phase II studies in patients with NAFLD (DS102A-02) and patients with 
chronic obstructive pulmonary disease (COPD) (DS102A-03) and, 
• 
in the pilot phase of a Phase II study in patients with severe acute decompensated alcoholic 
hepatitis (AH) (DS102A-05-AH1). 
 
Overall, Epeleuton capsules at doses of up to 4 grams per day were well tolerated in studies of up 
to 16 weeks treatment duration, with a safety profile similar to placebo.  


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 26 of 90 
 
 
DS102A-01 
 
This Phase I first in man study was conducted in healthy volunteers, to assess the safety, 
pharmacokinetics (PK) and effect of food on orally administered Epeleuton. The study was 
conducted in a total of 57 healthy volunteers (27 female and 30 male subjects). Epeleuton capsules 
were administered to healthy volunteers in the following regimens: a single dose of 100mg, 500mg, 
1000mg, or 2000mg under fasted conditions; a single dose of 500mg under fed conditions (standard 
diet and high fat diet); and as multiple doses of 500mg, 1000mg or 2000mg doses taken once daily 
for 28 consecutive days. 
 
This first in man study showed that Epeleuton overall had a safety profile similar to placebo, a short 
elimination half-life of approximately two hours and a Tmax of approximately four to eight hours. 
Results across dose levels studied showed high variability in the single and multiple dose cohorts 
and did not show a clear linear correlation between increasing dose and that of systemic exposure. 
The study demonstrated that administration with food increased the bioavailability of 15(S)-HEPE 
EE, as mean plasma concentrations of 15(S)-HEPE EE were higher under fed conditions compared 
to fasted conditions. There was no difference in bioavailability between normal and high fat diet 
fed conditions.  
 
There were no deaths, serious adverse events (SAEs) or subject discontinuations due to adverse 
events (AEs) reported in this study. The majority of reported treatment emergent adverse events 
(TEAEs) were considered to be mild in intensity and not related to study treatment. The events of 
dysgeusia and eructation (following Epeleuton treatment), diarrhoea (following Epeleuton and 
placebo treatment), and nausea (following placebo) were considered related to the study 
treatment. Overall, Epeleuton was considered safe and well-tolerated with no SAEs reported. 
 
DS102A-02 
 
This was a randomised, double-blind, placebo-controlled, exploratory Phase IIa study assessing the 
safety and efficacy of orally administered Epeleuton capsules versus placebo in the treatment of 
adult patients with NAFLD, over a 16-week treatment period. 
 
In total, 52 patients experienced 146 non-serious AEs while participating in the DS102A-02 trial. The 
most common AEs reported were diarrhoea (n=8), headache (n=8), increased CPK (n=6), upper 
respiratory tract infection (n=5), fatigue (n=4), nausea (n=4) and dyspepsia (n=4). Out of all AEs, 
seven events (preferred terms dysgeusia (n=3), eructation (n=1), dyspepsia (n=1), abdominal pain 
upper (n=1), and abdominal discomfort (n=1)) were considered related to Epeleuton capsules, thus 
most of the related TEAEs (i.e. all except dysgeusia) belong to the gastrointestinal disorders. All 
events related to Epeleuton capsules were mild in severity except one event of abdominal pain 
upper which was moderate. Two SAEs were reported during the study, schizophrenia in the 
epeleuton 2g/day group and pilonidal cyst in the placebo group, both of which were considered 
unrelated to study treatment. No deaths were observed during the study. 
 
DS102A-03 
 
This was a randomised, double-blind, placebo-controlled, exploratory Phase IIa study assessing the 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 27 of 90 
 
safety and efficacy of orally administered Epeleuton capsules versus placebo in the treatment of 
adult patients with COPD, over a 12-week treatment duration. 
 
Overall, a total of 78 TEAEs were reported by 33 patients. The most common TEAEs reported were 
headache (n=7), nasopharyngitis (n=6), productive cough (n=5), nocturnal dyspnoea (n=4), chronic 
obstructive pulmonary disease (n=4) and lower respiratory tract infection (n=4).  None of the TEAEs 
were considered related to Epeleuton (or placebo). All TEAEs were of mild or moderate severity 
except one event of CRP increase (Epeleuton 2g/day group), which was considered severe and not 
related to study drug. The event self-resolved without intervention and no additional laboratory 
results were reported for this patient. No SAEs and no deaths were observed during the study. 
 
DS102A-04 
 
This was a Phase I study in 11 healthy volunteers per treatment arm to assess the effect of a high 
fat meal on the PK of Epeleuton following single dose or twice daily oral administration of 1000mg 
Epeleuton. 
 
No serious AEs, and no AEs leading to death were reported in this study. There were no AEs 
considered as related to the study drug. 
 
Overall, no clinically significant changes in any of the blood chemistry or urinalysis parameters, 
physical examination, vital signs or electrocardiogram (ECG) findings were detected during the 
study. Overall, safety findings observed in this study were unremarkable. 
 
DS102A-05-AH1 
 
This was a randomised, double-blind Phase II study assessing the safety and efficacy of Epeleuton 
in the treatment of adult patients with AH. An open-label pilot phase was conducted prior to a 
randomised double-blind phase to assess the PK of Epeleuton in patients with severe acute 
decompensated AH. 
 
Seven patients experienced 30 non-serious AEs while participating in the open-label pilot phase of 
the DS102A-05-AH1 trial. All AEs were experienced by 1 patient only except for the AEs abdominal 
distension (n=2), aspartate aminotransferase increased (n=2) and fall (n=2). The majority of the AEs 
were of mild and moderate severity. Four out of the 30 AEs were assessed as severe. None of the 
non-serious AEs were considered related to Epeleuton capsules. 
 
In total eight SAEs were reported. One SAE, pulmonary edema initially reported as respiratory 
distress, was assessed as possibly related to study treatment. Due to the temporal relationship to 
study treatment, the causal role of study medication was considered as possible, although the event 
may have been caused by other reasons including excess alcohol consumption. There were in total 
5 SAEs with fatal outcome, all of which were deemed unrelated to study medication, and all were 
considered most likely related to the natural course of the underlying severe acute AH. Two 
additional SAEs were reported, renal failure and mental status changes. Neither of these SAEs were 
considered related to study medication. Overall the observed AE profile was consistent with the 
underlying disease of the study population. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 28 of 90 
 
DS102A-06-HV3 
 
This Phase I study was conducted in 24 healthy volunteers, to assess the safety and PK of Epeleuton. 
Epeleuton capsules were administered to healthy volunteers in the following regimens: a single 
dose of 1000mg or 2000mg under fed conditions; and as multiple doses of 2000mg per day (1000mg 
BID) or 4000mg per day (2000mg BID) for 14 consecutive days. 
 
There were no deaths, SAEs or subject discontinuations due to AEs reported in this study. The 
majority of reported TEAEs were considered to be mild or moderate in severity. The events of 
abdominal discomfort (Epeleuton 2000mg), nausea (Epeleuton 4000mg), vomiting (placebo) and 
increased white blood cells (WBC) (placebo) were considered possibly related to the study 
treatment. Overall, Epeleuton was well-tolerated, with a safety profile similar to placebo. 
 
 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 29 of 90 
 
2 
RISK BENEFIT ASSESSMENT 
 
Recent advances in primary and secondary prevention of cardiovascular events provide hope that 
new therapies targeting various cardiovascular risk factors including elevated triglycerides, 
hyperglycaemia and inflammation will produce additional benefits to LDL cholesterol management 
with statins and other prevention strategies. Therapies that target multiple factors associated with 
residual cardiovascular risk may further improve patient outcomes (American Diabetes Association 
2019a). 
 
Afimmune has conducted three Phase I studies in healthy subjects, two Phase II studies in patients 
with NAFLD and COPD, and a safety and PK pilot study in patients with severe acute AH. 
 
Studies conducted to date have demonstrated a very favourable safety profile for Epeleuton. Single 
ascending doses of 100mg, 500mg, 1000mg, and 2000mg Epeleuton, and multiple ascending doses 
of 500mg, 1000mg, 2000mg and 4000mg were well tolerated with similar safety to placebo in 
healthy subjects under fasted and fed conditions. 
 
Afimmune conducted a Phase IIa study in patients with NAFLD. Due to the overlap between NAFLD, 
dyslipidemia and type II diabetes, a post hoc analysis was undertaken to compare the lipid lowering, 
antihyperglycemic and anti-inflammatory effects of Epeleuton 2g/day and Epeleuton 1g/day with 
placebo. We hypothesised that Epeleuton may exert superior triglyceride lowering and anti-
inflammatory effects to its endogenous precursor EPA. 
 
The post hoc analyses revealed that treatment with Epeleuton for 16 weeks resulted in significant 
dose-dependent decreases of triglycerides, atherogenic lipids and lipoproteins, HbA1C, fasting 
glucose, insulin resistance indices and multiple markers of inflammation and endothelial 
dysfunction with no evidence of a plateau in treatment effect. The results of this study, while post 
hoc, have identified Epeleuton’s unique potential to synergistically address multiple axes of 
cardiovascular risk and several disease indications associated with cardiometabolic dysfunction, 
suggesting that Epeleuton may have substantial therapeutic potential for cardiovascular risk 
reduction by simultaneously targeting hypertriglyceridemia, hyperglycaemia and inflammation. 
 
Due to the unique triad of therapeutic effects demonstrated by Epeleuton and the safety profile 
demonstrated to date in GLP toxicology studies, Phase I studies in healthy volunteers and Phase II 
studies in patients with various disease indications, the company intends to perform this Phase II 
study (TRIAGE) in patients with concomitant hypertriglyceridemia and type 2 diabetes mellitus. The 
proposed Phase IIb dose-ranging study aims to prospectively assess the previously demonstrated 
antihyperglycemic, triglyceride lowering and anti-inflammatory effects of Epeleuton at 2g and 4g 
daily doses. 
 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 30 of 90 
 
3 
RATIONALE FOR THE STUDY 
 
The proposed study aims to investigate the triglyceride lowering, antihyperglycemic, and anti-
inflammatory effects of Epeleuton as surrogate markers of its potential to improve diabetic control 
and cardiovascular outcomes. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 31 of 90 
 
4 
STUDY OBJECTIVES 
 
Efficacy Objective: 
• To assess the efficacy of orally administered Epeleuton capsules versus placebo, in the 
treatment of adult patients with hypertriglyceridemia and type 2 diabetes. 
 
Safety Objective: 
• To assess the safety of orally administered Epeleuton capsules versus placebo, in the treatment 
of adult patients with hypertriglyceridemia and type 2 diabetes. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 32 of 90 
 
5 
STUDY ENDPOINTS 
 
5.1 
Primary Endpoints 
 
• 
Percent change in triglycerides from baseline to week 16. 
 
• 
Change in HbA1c from baseline to week 26. 
 
Note: 
• 
Each of the independent primary endpoints will be analysed separately. 
 
 
 
5.2 
Secondary Endpoints 
 
• 
Percent change in triglycerides from baseline to weeks 4, 8, 12, 20 and 26. 
 
• 
Change in HbA1c from baseline to weeks 4, 8, 12, 16 and 20. 
 
• 
Proportion of patients achieving a HbA1c below 7.0% at weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Percent change in very low-density lipoprotein cholesterol (VLDL-C) from baseline to weeks 4, 
8, 12, 16, 20 and 26. 
 
• 
Percent change in non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to 
weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Percent change in total cholesterol from baseline to weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Change in fasting plasma glucose from baseline to weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Proportion of patients achieving a HbA1c below 6.5% at weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Percent change in apolipoprotein B (ApoB) from baseline to weeks 16 and 26. 
 
• 
Percent change in remnant lipoprotein cholesterol (RLP-C) from baseline to weeks 8, 16 and 
26. 
 
• 
Percent change in high-density lipoprotein cholesterol (HDL-C) from baseline to weeks 4, 8, 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 33 of 90 
 
12, 16, 20 and 26. 
 
• 
Percent 
change 
in 
low-density 
lipoprotein 
cholesterol 
(LDL-C) 
(preparative 
ultracentrifugation) from baseline to weeks 16 and 26. 
 
• 
Change in body weight (kg) from baseline to weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Change in high-sensitivity C-reactive protein (hsCRP) from baseline to weeks 8, 16 and 26. 
 
• 
Change in systolic blood pressure from baseline to weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Change in diastolic blood pressure from baseline to weeks 4, 8, 12, 16, 20 and 26. 
 
• 
Change in urinary albumin-to-creatinine ratio (UACR) from baseline to week 26 in the sub-
group of patients with microalbuminuria at baseline. 
 
 
5.3 
Exploratory Endpoints 
 
• 
Change in waist circumference from baseline to weeks 8, 16 and 26. 
 
• 
Percent change in apolipoprotein CIII (ApoCIII) from baseline to weeks 16 and 26. 
 
• 
Percent change in apolipoprotein A1 (ApoA1) from baseline to weeks 16 and 26. 
 
• 
Percent change in lipoprotein (a) (Lp(a)) from baseline to weeks 16 and 26. 
 
• 
Percent change in high-density lipoprotein particle concentration (HDL-P) from baseline to 
weeks 16 and 26. 
 
• 
Percent change in small low-density lipoprotein particle concentration (Small LDL-P) from 
baseline to weeks 16 and 26. 
 
• 
Percent change in large low-density lipoprotein particle concentration (Large LDL-P) from 
baseline to weeks 16 and 26. 
 
• 
Percent change in low-density lipoprotein size (LDL size) from baseline to weeks 16 and 26. 
 
• 
Percent change in very low-density lipoprotein size (VLDL size) from baseline to weeks 16 and 
26. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 34 of 90 
 
 
• 
Percent change in high-density lipoprotein size (HDL size) from baseline to weeks 16 and 26. 
 
• 
Change in fasting plasma insulin from baseline to weeks 16 and 26. 
 
• 
Change in Homeostatic model assessment insulin resistance (HOMA-IR) from baseline to 
weeks 16 and 26. 
 
• 
Change in Homeostatic model assessment β-cell function (HOMA-β) from baseline to weeks 
16 and 26. 
 
• 
Change in interleukin 6 (IL-6) from baseline to week 26. 
 
• 
Change in interleukin 1β (IL-1β) from baseline to week 26. 
 
• 
Change in plasminogen activator inhibitor 1 (PAI-1) from baseline to week 26. 
 
• 
Change in vascular cell adhesion molecule 1 (VCAM-1) from baseline to week 26. 
 
• 
Change in intercellular adhesion molecule 1 (ICAM-1) from baseline to week 26. 
 
• 
Change in monocyte chemoattractant protein 1 (MCP-1) from baseline to week 26. 
 
• 
Change in red cell distribution width (RDW) from baseline to weeks 16 and 26. 
 
• 
Change in haemoglobin from baseline to weeks 16 and 26. 
 
• 
Change in reticulocyte count from baseline to weeks 16 and 26. 
 
• 
Change in erythrocyte (red blood cell) count from baseline to weeks 16 and 26. 
 
• 
Trough plasma concentrations of total and unesterified 15-hydroxy eicosapentaenoic acid 
(15(S)-HEPE) in treated population compared to placebo population at Baseline/Day 0, Week 
4, Week 8, Week 16 and Week 26. 
 
• 
Trough plasma concentrations of EPA in treated population compared to placebo population 
at Baseline/Day 0, Week 4, Week 8, Week 16 and Week 26. 
 
• 
Determination of exploratory serum biomarkers in treated population compared to placebo 
population at Baseline and Week 26. 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 35 of 90 
 
5.4 
Safety Variables 
 
• 
Incidence of treatment-emergent level 2 and level 3 hypoglycaemic episodes 
o Level 2 – Glucose <54 mg/dL (3.0 mmol/L), with or without symptoms 
o Level 3 – A severe event characterised by altered mental and/or physical status requiring 
assistance for treatment of hypoglycaemia. 
• 
AE and SAE frequency and severity. 
• 
Safety laboratory parameters (haematology, clinical chemistry, coagulation). 
• 
Urinalysis 
• 
ECGs 
• 
Vital signs (heart rate, temperature, blood pressure) 
• 
Physical examination 
• 
Pregnancy


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 36 of 90 
 
6 
STUDY DESIGN 
 
6.1 
General 
 
This is a randomised, double-blind, placebo controlled, 3-arm, multi-centre Phase IIb study 
consisting of 26 weeks of active treatment and a 2-week post-treatment follow up period in adult 
patients with hypertriglyceridemia and concomitant type 2 diabetes.  
 
The screening period will consist of up to 6-weeks lead-in during which all patients will undergo 
diet and lifestyle stabilisation, washout of disallowed medications and optimisation of statins. 
 
Lipid eligibility criteria include a fasting triglyceride level ≥200 mg/dL (2.26 mmol/L) and 
<750mg/dL (8.46 mmol/L) (inclusion #3) and LDL cholesterol <130mg/dL (3.34 mmol/L) (inclusion 
#6). Triglycerides and LDL cholesterol will be checked at Screening #1 and a second qualifying visit 
(Screening #2) which will take place one week before randomisation at the baseline visit. Patients 
who meet the inclusion criteria at both screening visits will be eligible to participate in the study. 
Eligible patients will be randomised one week after Screening #2 at the baseline visit. 
 
Patients will be randomised (1:1:1) at the baseline visit into the following treatment groups: 
 
• 
Treatment Group A (placebo): four placebo capsules orally administered twice a day, 
i.e. eight capsules daily for 26 weeks. 
• 
Treatment Group B (Epeleuton 2g): two Epeleuton 500mg capsules and two 
placebo capsules orally administered twice a day, i.e. eight capsules daily for 26 
weeks. 
• 
Treatment Group C (Epeleuton 4g): four Epeleuton 500mg capsules orally 
administered twice a day, i.e. eight capsules daily for 26 weeks. 
 
To maintain the double-blind conditions, the Epeleuton capsules and placebo capsules will be 
identical in appearance.  
 
A schematic diagram of the study is presented in Figure 3. 
 
Figure 3: Study Outline 
 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 37 of 90 
 
 
 
6.2 
Rationale for Study Design and Dose Selection 
This 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 26 weeks after a lead-in phase of four to six weeks 
and was designed in order to assess the efficacy and safety of two doses of Epeleuton (2 gram 
daily dose and 4 gram daily dose) in patients with hypertriglyceridemia and type 2 diabetes. 
 
Studies in rats and dogs treated for up to 26 weeks and 39 weeks respectively have demonstrated 
that Epeleuton did not indicate any significant toxicity and resulted in a NOAEL of 1000mg/kg/day 
in both species (CRL-529123, 529139). This information along with the Food and Drug 
Administration (FDA) and European Medicines Agency (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. 
 
Epeleuton at daily doses of 2000mg and 4000mg were administered to healthy volunteers for up 
to 28 days and 14 days respectively in Phase I studies, and at a daily dose of 2000mg for up to 16 
weeks in Phase II studies in patients with NAFLD and COPD. The results from the studies conducted 
to date indicate that Epeleuton is well tolerated, with a similar safety profile to placebo. 
 
The PK profile of Epeleuton seen in Phase I trials indicated that administration with food increased 
the bioavailability of Epeleuton, and its active moiety 15(S)-HEPE. 
 
In a Phase IIa trial in patients with NAFLD, Epeleuton produced significant decreases of 
triglycerides, total cholesterol and multiple atherogenic lipids without raising LDL cholesterol. 
Notably, decreases were greater in the higher dose group; and greater at both 1g and 2g daily 
doses in sub-groups with elevated triglycerides at baseline, suggesting that further decreases may 
be seen in prospectively designed studies in patients with hypertriglyceridemia and at a higher 
daily dose. 
 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 38 of 90 
 
Figure 4. DS102A-02 study – Median change in triglycerides in patients receiving Epeleuton 
2g/day or Epeleuton 1g/day 
 
 
P-values for between group comparisons of epeleuton vs placebo, Wilcoxon Rank Sum test with Hodges 
Lehmann estimates. mITT – modified intention-to-treat (n=93), Error bars – interquartile range 
 
 
Additionally, Epeleuton significantly decreased HbA1c. Notably, at week 16 (end-of-treatment) 
HbA1C was decreased by >1.0% in sub-groups with elevated HbA1C at baseline, at least 
comparable to most common antihyperglycemic agents after 26 to 52 weeks treatment. 
Additionally, HbA1C lowering was dose-dependent with no evidence of a plateau in treatment at 
week 16 suggesting that further decreases may be observed at a higher dose and over a longer 
treatment duration. Similar, dose-dependent decreases were observed for fasting plasma glucose, 
insulin resistance indices and markers of inflammation and endothelial dysfunction.  
 
These data suggest Epeleuton may have substantial therapeutic potential for cardiovascular risk 
reduction by simultaneously targeting hypertriglyceridemia, hyperglycaemia and inflammation.  
 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 39 of 90 
 
Figure 5. DS102A-02 study - Mean Change in HbA1C from Baseline to Week 16 (End-of-treatment) 
 
 
NS denotes non-significant p-values (>0.05) compared to placebo. 
 
The dose selection in this trial is based on the safety, PK and efficacy data from Phase I and Phase 
II trials and the intention to characterise the safety and efficacy of Epeleuton at up to 4000mg per 
day given in divided doses (BID) with or after food to patients with hypertriglyceridemia and 
concomitant type 2 diabetes.


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 40 of 90 
 
7 
PATIENTS AND SCREENING 
In order to participate in this study, patients must meet all inclusion criteria and must not meet 
any of the exclusion criteria. Inclusion in the trial starts with the informed consent signature. The 
inclusion and exclusion criteria are to be verified at the first Screening Visit (Visit #1), confirmed 
at the second Screening Visit (Visit #2) and again at Baseline (visit #3).  
 
7.1 
Source of Patients 
The study population will consist of male and female patients diagnosed with hypertriglyceridemia 
and type 2 diabetes, aged 18 years and over. 
 
7.2 
Inclusion Criteria 
 
1. Patients diagnosed with type 2 diabetes mellitus at least 90 days prior to the first screening 
visit. 
 
2. Patients with a HbA1C (glycosylated haemoglobin) between 7.0 - 10.0% (53-86 mmol/mol)  
(both inclusive) 
 
3. Patients with a fasting triglyceride level ≥200 mg/dL (2.26 mmol/L) and <750mg/dL (8.46 
mmol/L) at both screening visits. 
 
Note: If the triglyceride level is outside the required range at the second screening visit, an 
additional measurement can be obtained 1 week later, to confirm eligibility. 
 
Note: If a large difference in triglyceride level (>15%) is observed between screening 1 and 
screening 2, an additional measurement may be requested or patient may be deemed not 
eligible.  
 
4. Patients who have been educated regarding diet and exercise at or before visit 1 (screening 
1) and are willing to maintain and not alter a stable diet and activity routine throughout the 
study. 
 
5. Patients who have been on a stable statin therapy at doses that are likely to achieve optimal 
LDL cholesterol and who are willing to continue this treatment throughout the study. 
 
Note: Stable statin therapy may consist of a statin with or without ezetimibe.  
 
6. Patients with an LDL cholesterol level <130mg/dL (3.34 mmol/L) at both screening visits. 
 
7. Patients who have a body mass index (BMI) ≥ 25kg/m2 and <50kg/m2. 
 
8. Patients who have been on a stable daily dose of metformin (at least 1500mg or maximum 
tolerated dose for metformin monotherapy as documented in the subject medical record) 
and/or a sulfonylurea and/or a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or a sodium-
glucose transport protein 2 inhibitor (SGLT2i) and/or a GLP1-RA and/or basal insulin for at 
least 90 days prior to the day of first screening visit. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 41 of 90 
 
 
Note: Dose of GLP1-RA must be stable for 6 months prior to baseline with no weight change 
>2kg for 3 months prior to baseline.  
 
Note: Dose of basal insulin must be stable for 4 months prior to baseline. All types of basal 
insulin are permitted, including insulin glargine, insulin degludec, insulin detemir, NPH insulin 
and pre-mixed insulin. 
 
9. Female patients and male patients with female partners of childbearing potential must use 
highly effective contraceptive methods or have a sterilised partner for the duration of the 
study. Highly effective contraceptive methods are defined as methods that can achieve a 
failure rate of less than 1% per year when used consistently and correctly. Such methods 
include hormonal contraception, intrauterine device or sexual abstinence. 
 
Note: A woman is considered of childbearing potential (WOCBP), i.e. fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. Permanent 
sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. 
 
Note: Hormonal contraceptives must be on a stable dose for at least one month before 
baseline. 
 
Note: Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
 
10. Patients whose pre-study or screening clinical laboratory findings do not interfere with their 
participation in the study, in the opinion of the Investigator, and do not violate any inclusion 
or exclusion criteria 
 
11. Male or female patients aged 18 years and older on the day of signing the informed consent 
form (ICF). 
 
12. 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 
prior to initiation of any study specific activities or procedures. 
 
7.3 
Exclusion Criteria  
 
1. Patients who have a history of intolerance or hypersensitivity to any substance in epeleuton 
capsules, placebo capsules or statins.  
 
2. Patients with uncontrolled hypertension defined as a systolic blood pressure ≥160 mmHg or a 
diastolic blood pressure ≥100mmHg. 
 
3. Patients who have a body mass index (BMI) <25kg/m2 or ≥ 50kg/m2. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 42 of 90 
 
4. Patients who have a weight change >2kg from the first screening visit to the baseline visit. 
 
5. Patients who have type 1 diabetes mellitus. 
 
6. Patients who have thyroid stimulating hormone (TSH) levels >1.5 times the upper limit of 
normal. 
 
7. Patients with known familial lipoprotein lipase deficiency (Fredriksen type I), apolipoprotein 
C-II deficiency or familial dysbetaliproteinemia (Fredriksen type III). 
 
8. Patients with significant liver disease or liver function impairment defined as any of the 
following; cirrhosis, hepatitis, biliary obstruction with hyperbilirubinemia (total bilirubin >2 
times the upper limit of normal) and aspartate aminotransferase (AST) or alanine 
aminotransferase levels (ALT) >3 times the upper limit of normal. 
 
9. Patients with renal impairment defined as an estimated glomerular filtration rate 
<50mL/min/1.73m2 as per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
formula. 
 
10. Patients with a history of malignancies within the past 5 years other than curatively treated 
non-melanoma skin cancer (basal cell or squamous cell carcinomas). 
 
11. Patients who have been treated with any investigational product within 60 days prior to visit 
1 (Screening 1), or 5 half-lives (whichever is longer). Patients cannot participate in any other 
investigational medication or medical device trial while participating in this study. 
 
12. Patients who have used dietary supplements or prescription products rich in omega-3 or 
omega-6 fatty acids in the four weeks prior to baseline. 
 
13. Patients who have been treated with any medication for diabetes or obesity in the four weeks 
before the baseline visit, except for metformin, sulfonylureas, DPP-4 inhibitors, SGLT2 
inhibitors, basal insulin, GLP1-RAs (must be on a stable dose for at least  6 months) and short-
term insulin treatment for acute illness for a total of below or equal to 14 days. 
 
14. Patients who have been treated with fibrates, proprotein convertase subtilisin/kexin type 9 
(PCSK9) inhibitors, bile acid sequestrants, niacin, niacin analogues or dietary supplements for 
the purpose of lowering triglycerides or cholesterol in the six weeks prior to baseline. 
 
15. Patients who have a family or personal history of multiple endocrine neoplasia type 2 or 
medullary thyroid carcinomas. 
 
16. Patients who have a history of acute or chronic pancreatitis. 
 
17. Patients who have a history of major surgical procedures involving the stomach potentially 
affecting absorption of investigational medicinal product (e.g. subtotal and total gastrectomy, 
sleeve gastrectomy, gastric bypass surgery) 
 
18. Patients who have planned major surgical procedures, coronary intervention (such as stent 
placement or heart bypass), carotid or peripheral revascularisation. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 43 of 90 
 
 
19. Patients who have a history of myocardial infarction, stroke, coronary revascularisation or 
hospitalisation for unstable angina in the 3 months prior to screening. 
 
20. Patients with creatine kinase concentrations > 10 times the upper limit of normal or creatine 
kinase elevation due to known muscle disease at visit 1 (screening 1) 
 
21. Patients who are classified as being in New York Heart Association (NYHA) Class IV heart 
failure. 
 
22. Patients who have a history of diabetic ketoacidosis. 
 
23. Patients with known proliferative retinopathy or maculopathy requiring acute treatment. 
 
24. Patients with significant systemic or major illnesses that, in the opinion of the Investigator, 
would preclude or interfere with treatment with Epeleuton, adequate follow up and/or 
compliance with the protocol. 
 
25. Patients who are pregnant, planning pregnancy, breastfeeding and/or are unwilling to use 
adequate contraception (as specified in Inclusion Criterion 9) during the trial. 
 
26. Patients with active infectious diseases or chronic infectious disease (e.g. human 
immunodeficiency virus or tuberculosis). 
 
27. Patients who have recently received a vaccination or for whom a vaccination is planned (apart 
from flu, SARS-COV2 and pneumococcal vaccines which are permitted at any time). 
 
28. Patients who have previously been randomised into the study. 
 
29. 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 risks/benefits 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 ICF. The patients will then receive a copy 
of the signed and dated patient information sheet (PIS)/ICF. The original signed ICF will be filed in 
the Investigator Site File (ISF). The PIS will contain site contact information in case of any questions 
or medical emergency.  
 
If 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 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 44 of 90 
 
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 
repercussions. 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, every effort should be made to minimize the 
withdrawal of patients. Should a patient decide to withdraw, all efforts will be made to complete 
and report the observations from assessments conducted during study visits, particularly the 
follow-up examination, as thoroughly as possible. 
 
In the event of patient withdrawal, the Investigator or one of his or her staff members should talk 
to the patient either by telephone or through a personal visit to determine as completely as 
possible the reason for the withdrawal, and record the reason in the patient’s source document 
and case report form (CRF). A complete final early termination evaluation at the time of the 
patient’s withdrawal should be made with an explanation of why the patient is withdrawing from 
the study. If the reason for removal of a patient is an AE or an abnormal laboratory test result, the 
principal specific event or test will be recorded. 
 
Standard reasons for withdrawing from further participation in the study may be: 
• 
Unacceptable AEs 
• 
Patient’s decision 
• 
Investigator’s discretion 
• 
Intercurrent illness 
• 
Pregnancy 
• 
Patient lost to follow-up 
 
Note: the patient is allowed not to give a reason for withdrawal. If this is the case, this must be 
recorded as well. 
 
Patients who discontinue the study treatment before week 26 (visit #9) will be asked to come for 
an early termination visit as soon as possible and have the assessments listed at week 26 (visit #9) 
performed.  
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 45 of 90 
 
7.6 
Patient Replacement 
Patients who are withdrawn from the study due to an AE or lack of efficacy will not be replaced. 
 
Patients who do not meet the eligibility criteria or are withdrawn due to loss to follow up may be 
replaced. 
 
 
 
 
7.7 
Protocol Deviations 
 
All protocol deviations will be reviewed by the medical monitor as and when each deviation 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. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 46 of 90 
 
8 
STUDY CONDUCT 
 
8.1 
Study Schedule 
During the study, 10 visits to the clinic are scheduled: two Screening Visits (Visit 1 and Visit 2), one 
visit at the start of the comparative treatment period (Baseline/Visit 3), six visits in the 
comparative treatment period (Visit 4/Week 4, Visit 5/Week 8, Visit 6/Week 12, Visit 7/Week 16, 
Visit 8/Week 20 and Visit 9/Week 26 or Early Termination) and one final safety follow-up visit 
(Visit 10/Week 28). 
 
Patients who discontinue the study early before Week 26, for whatever reason, will be asked to 
attend the investigative site as soon as possible so that assessments scheduled for the early 
termination visit (Visit 9) will be performed.  
 
8.2 
Clinic Visits 
 
A tabulated flow chart of the study is presented in Appendix 1. 
 
8.2.1 
Screening Visit 1 (Visit 1) 
 
The patient must sign and date the ICF for inclusion in the screening phase before any study-
specific procedures are conducted. 
 
Once informed consent has been obtained, the Investigator will assign a patient number.  
 
The following screening assessments/sample collections will be performed: 
 
• 
Obtain Informed consent. 
• 
Verification of inclusion/exclusion criteria (Sections 7.2 & 7.3) 
• 
Serum pregnancy test (only female patients of childbearing potential) (as detailed in 
Section 9.2.1) 
• 
Counselling on contraception (as detailed in Section 9.2.1) 
• 
Demographic data 
• 
Medical history (including history of diabetes, cardiovascular disease (CVD), liver disease 
and smoking) (as detailed in Section 9.2.3) 
• 
Concomitant medication assessment (as detailed in Section 9.2.4)  
• 
Physical examination (weight, height, BMI, waist circumference) (as detailed in Section 
9.2.6) 
• 
Vital signs (blood pressure, heart rate and body temperature) (as detailed in Section 9.2.7) 
• 
Counselling on healthy lifestyle (see below) 
• 
Blood sampling for laboratory tests #1 (clinical haematology, serum biochemistry, 
coagulation) (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #2 (triglycerides, LDL-C (calculated), HbA1c) (as 
detailed in Section 9.1.3) 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 47 of 90 
 
• 
Serum blood sample for TSH testing 
 
All procedures that are medically necessary should be followed. 
 
Counselling on healthy lifestyle should be performed during this visit according to step 6 of the 
National Cholesterol Education Program Adult Treatment Panel III guidelines (NIH Publication No. 
01–3305). The assessment should include consultation on: 
• 
Diet: saturated fat <7% of calories, cholesterol <200mg/day, increase soluble fibre intake 
(10-25g/day) and plants stanols/sterols (2g/day) 
• 
Weight management 
• 
Increased physical activity 
 
 
8.2.2 
Screening Visit 2 (Visit 2) 
 
Screening visit 2 will be conducted one week prior to the baseline visit. 
 
• 
Concomitant Medication Assessment (as detailed in Section 9.2.4) 
• 
Physical examination (as detailed in Section 9.2.6) 
• 
Vital signs (blood pressure, heart rate and body temperature) (as detailed in Section 9.2.7) 
• 
Blood sampling for laboratory tests #2 (as detailed in Section 9.1.3) 
• 
Review of inclusion/exclusion criteria (Sections 7.2 & 7.3) 
 
8.2.3 
Treatment Period 
Following completion of a successful screening period, patients will begin the comparative 
treatment period (26 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 in a 1:1:1 ratio. 
 
Patients will take the allocated investigational medicinal product (IMP) twice daily, in the morning 
and in the evening, with or after food (within 30 minutes after a meal), throughout the 26 weeks 
study treatment period. Patients will attend the study visits fasting but will receive their morning 
IMP dose (Epeleuton or placebo) at site with or after food (within 30 minutes after a meal) after 
blood samples have been collected. 
 
Each administration of IMP will be recorded by the patient in an electronic diary. The record will 
include date, time and value. If the patient is unable to access the electronic diary, a paper diary 
back up will be provided and the data will be transcribed during the next site visit into the IRT by 
the Investigator or designee.  
 
Patients who discontinue the study early will have all study procedures scheduled for Visit 9 (see 
Section 8.2.10) performed as soon as possible after patient withdrawal so that all study-related 
information can be recorded. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 48 of 90 
 
In-study and post- discharge referral and intervention will be provided as needed. 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 49 of 90 
 
8.2.4 
Baseline (Visit 3) 
The following assessments/sample collections will be performed at Baseline/Visit 3: 
 
• 
Verification of inclusion/exclusion criteria (as detailed in Sections 7.2 & 7.3) 
• 
Serum and Urine Pregnancy test (as detailed in Section 9.2.1); female patients of 
childbearing potential only 
• 
Counselling on contraception (as detailed in Section 9.2.1) 
• 
Medical history (as detailed in Section 9.2.3) 
• 
Concomitant medication assessment (as detailed in Section 9.2.4) 
• 
ECG (as detailed in Section 9.2.5) 
• 
Physical examination (as detailed in Section 9.2.6) 
• 
Vital signs (blood pressure, heart rate and body temperature) (as detailed in Section 9.2.7) 
• 
Counselling on healthy lifestyle (see below) 
• 
Assessment of hypoglycaemic episodes (as detailed in Section 9.2.8.1) 
• 
PK sampling (sample will be taken pre-dose) (as detailed in Section 9.3) 
• 
Exploratory blood sampling (as detailed in Section 9.4) 
• 
Blood sampling for laboratory tests #1 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #2 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #3 (VLDL-C, non-HDL-C, total cholesterol, glucose, 
HDL-C, RLP-C) (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #4 (LDL-C (preparative ultracentrifugation), ApoA1, 
ApoB, ApoCIII, Lp(a), insulin, hsCRP, HOMA-IR, HOMA-β, nMR lipid profile) (as detailed in 
Section 9.1.3) 
• 
Blood sampling for laboratory tests #5 (IL-6, IL-1β, PAI-1, VCAM-1, ICAM-1, MCP-1, serum 
biomarker) (as detailed in Section 9.1.3) 
• 
Urinalysis (dipstick) (as detailed in Section 9.2.10) 
• 
Urinary sample for urinary albumin-to-creatinine ratio (as detailed in Section 9.1.4) 
• 
Self-monitoring of blood glucose (SMBG) (as detailed in Section 9.2.8) 
• 
Patient randomisation (see below) 
• 
IMP administration (see below) 
 
If all study eligibility criteria are satisfied, the Investigator will randomise the patient and provide 
the patient with the designated IMP or placebo from one of the patient treatments packs available 
at the site. 
 
Counselling on healthy lifestyle should be performed during this visit according to step 6 of the 
National Cholesterol Education Program Adult Treatment Panel III guidelines (NIH Publication No. 
01–3305). The assessment should include consultation on: 
• 
Diet: saturated fat <7% of calories, cholesterol <200mg/day, increase soluble fibre intake 
(10-25g/day) and plants stanols/sterols (2g/day) 
• 
Weight management 
• 
Increased physical activity 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 50 of 90 
 
All patients will be instructed on how to use their blood glucose meter device and test strips, and 
educated regarding hypoglycaemia. SMBG profiles will be recorded daily from Baseline (Visit 3) to 
Week 4 (Visit 4). 
 
The first dose of IMP (Epeleuton or placebo) will be administered at site only after all baseline 
assessments have been completed, with food or within 30 minutes after a meal. The patient will 
take their second dose of IMP in the evening of the day of the baseline visit (visit #3). Patients will 
be instructed how to store study medication (in the fridge) and to continue taking the capsules 
twice daily, starting with the next day. Patients will also be instructed to take medication with 
food, or within 30 minutes after a meal. 
 
8.2.5 
Week 2 Telephone Call 
 
Patients will receive a telephone call from site staff at Week 2. 
 
A review of SMBG (as detailed in Section 9.2.8) and assessment of hypoglycaemic episodes (as 
detailed in Section 9.2.8.1) will be conducted. 
 
IMP compliance and administration will be discussed to ensure correct dosing. Patients will also 
be asked to discuss the patient logs for confirmation of compliance.  
 
The following procedures/assessments will also occur: 
 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.4) 
 
8.2.6 
Visit 4/Week 4 
The following assessments will be performed: 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.4) 
• 
Physical examination (as detailed in Section 9.2.6) 
• 
Vital signs (blood pressure, heart rate and body temperature) (as detailed in Section 9.2.7) 
• 
Assessment of hypoglycaemic episodes (as detailed in Section 9.2.8.1) 
• 
PK sampling (as detailed in Section 9.3) 
• 
Blood sampling for laboratory tests #1 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #2 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #3 (as detailed in Section 9.1.3) 
• 
Self-monitoring of blood glucose (SMBG) (as detailed in Section 9.2.8) 
• 
IMP reconciliation and supply of new IMP pack to patient 
 
Patients will return their used IMP (Epeleuton or placebo) and further IMP will be supplied to the 
patient. The patient should take their next dose of IMP as soon as all visit assessments have been 
completed, with food or within 30 minutes after a meal. The IMP will continue to be taken twice- 
daily. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 51 of 90 
 
After Week 4 (Visit 4), at the investigator’s discretion, patients who have experienced 
hypoglycaemia may be asked to continue SMBG. 
 
8.2.7 
Visit 5/Week 8 
The following assessments will be performed: 
 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.4) 
• 
Physical examination (as detailed in Section 9.2.6) 
• 
Vital signs (blood pressure, heart rate and body temperature) (as detailed in Section 9.2.7) 
• 
Assessment of hypoglycaemic episodes (as detailed in Section 9.2.8.1) 
• 
PK sampling (as detailed in Section 9.3) 
• 
Blood sampling for laboratory tests #1 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #2 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #3 (as detailed in Section 9.1.3) 
• 
Self-monitoring of blood glucose (SMBG) (as detailed in Section 9.2.8) 
• 
IMP reconciliation and supply of new IMP pack to patient 
 
Patients will return their used IMP (Epeleuton or placebo) and further IMP will be supplied to the 
patient. The patient should take their next dose of IMP as soon as all visit assessments have been 
completed, with food or within 30 minutes after a meal. The IMP will continue to be taken twice-
daily. 
 
At the investigator’s discretion, patients who have experienced hypoglycaemia may be asked to 
continue SMBG. 
 
8.2.8 
Visit 6/Week 12 
The following assessments will be performed: 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.4) 
• 
Urinary pregnancy test (as detailed in Section 9.2.1); female patients of childbearing 
potential only 
• 
Counselling on contraception (as detailed in Section 9.2.1) 
• 
Physical examination (as detailed in Section 9.2.6) 
• 
Vital signs (blood pressure, heart rate and body temperature) (as detailed in Section 9.2.7) 
• 
Assessment of hypoglycaemic episodes (as detailed in Section 9.2.8.1) 
• 
Blood sampling for laboratory tests #1 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #2 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #3 (as detailed in Section 9.1.3) 
• 
Self-monitoring of blood glucose (SMBG) (as detailed in Section 9.2.8) 
• 
IMP reconciliation and supply of new IMP pack to patient 
 
Patients will return their used IMP (Epeleuton or placebo) and further IMP will be supplied to the 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 52 of 90 
 
patient. The patient should take their next dose of IMP as soon as all visit assessments have been 
completed, with food or within 30 minutes after a meal. The IMP will continue to be taken twice-
daily. 
 
At the investigator’s discretion, patients who have experienced hypoglycaemia may be asked to 
continue SMBG. 
 
8.2.9 
Visit 7/Week 16  
The following assessments will be performed: 
 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.4) 
• 
Physical examination (as detailed in Section 9.2.6) 
• 
Vital signs (blood pressure, heart rate and body temperature) (as detailed in Section 9.2.7) 
• 
Assessment of hypoglycaemic episodes (as detailed in Section 9.2.8.1) 
• 
PK sampling (as detailed in Section 9.3) 
• 
Blood sampling for laboratory tests #1 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #2 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #3 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #4 (as detailed in Section 9.1.3) 
• 
Self-monitoring of blood glucose (SMBG) (as detailed in Section 9.2.8) 
• 
IMP reconciliation and administration of new IMP packs 
 
Patients will return their used IMP (Epeleuton or placebo) and further IMP will be supplied to the 
patient. The patient should take their next dose of IMP as soon as all visit assessments have been 
completed, with food or within 30 minutes after a meal. The IMP will continue to be taken twice-
daily. 
 
At the investigator’s discretion, patients who have experienced hypoglycaemia may be asked to 
continue SMBG. 
 
8.2.10 Visit 8/Week 20 
The following assessments will be performed: 
 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.4) 
• 
Physical examination (as detailed in Section 9.2.6) 
• 
Vital signs (blood pressure, heart rate and body temperature) (as detailed in Section 9.2.7) 
• 
Assessment of hypoglycaemic episodes (as detailed in Section 9.2.8.1) 
• 
Blood sampling for laboratory tests #1 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #2 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #3 (as detailed in Section 9.1.3) 
• 
Self-monitoring of blood glucose (SMBG) (as detailed in Section 9.2.8) 
• 
IMP reconciliation and supply of new IMP packs to patient 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 53 of 90 
 
 
Patients will return their used IMP (Epeleuton or placebo) and further IMP will be supplied to the 
patient. The patient should take their next dose of IMP as soon as all visit assessments have been 
completed, with food or within 30 minutes after a meal. The IMP will continue to be taken twice-
daily. 
 
At the investigator’s discretion, patients who have experienced hypoglycaemia may be asked to 
continue SMBG. 
 
8.2.11 Visit 9/Week 26/ Early Termination 
The following assessments will be performed: 
 
• 
AE assessment (as detailed in Section 11) 
• 
Concomitant medication assessment (as detailed in Section 9.2.4) 
• 
Serum pregnancy test (as detailed in Section 9.2.1); female patients of childbearing 
potential only 
• 
Counselling on contraception (as detailed in Section 9.2.1) 
• 
ECG (as detailed in Section 9.2.5) 
• 
Physical examination (as detailed in Section 9.2.6) 
• 
Vital signs (blood pressure, heart rate and body temperature) (as detailed in Section 9.2.7) 
• 
Assessment of hypoglycaemic episodes (as detailed in Section 9.2.8.1) 
• 
PK sampling (as detailed in Section 9.3) 
• 
Exploratory blood sampling (as detailed in Section 9.4) 
• 
Blood sampling for laboratory tests #1 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #2 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #3 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #4 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #5 (as detailed in Section 9.1.3) 
• 
Urinalysis (dipstick) (as detailed in Section 9.2.10) 
• 
Urinary sample for urinary albumin-to-creatinine ratio (as detailed in Section 9.1.4) 
• 
IMP reconciliation 
 
The IMP (Epeleuton or placebo) will be returned by the patient. Further IMP will not be supplied 
to the patient. 
 
On completion of this visit, patients will be advised that they will be required to return to the 
investigational site in two weeks at Visit 10 for a final assessment. 
 
8.2.12 Visit 10/Week 28/ Follow up 
The following assessments will be performed: 
 
• 
AE Assessment (as detailed in Section 11) 
• 
Concomitant medication Assessment (as detailed in Section 9.2.4) 
• 
Physical examination (as detailed in Section 9.2.6) 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 54 of 90 
 
• 
Vital signs (blood pressure, heart rate and body temperature) (as detailed in Section 9.2.7) 
• 
Assessment of hypoglycaemic episodes (as detailed in Section 9.2.8.1) 
• 
Blood sampling for laboratory tests #1 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #2 (as detailed in Section 9.1.3) 
• 
Blood sampling for laboratory tests #3 (as detailed in Section 9.1.3) 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 55 of 90 
 
9 
ASSESSMENTS 
 
9.1 
Efficacy Assessments 
The efficacy assessments in this study consist of laboratory tests to assess the status of the 
underlying hypertriglyceridemia and type 2 diabetes and additional cardiovascular risk factors, as 
well as body weight, waist circumference and blood pressure. 
 
For a list of all laboratory tests in this study see Section 15.2(Appendix 2). 
 
9.1.1 
Body weight, waist circumference, BMI 
Body weight (kg), waist circumference (cm), and BMI are assessed as part of physical examination 
procedures at all visits (see Section 9.2.6. 
 
9.1.2 
Blood pressure 
Systolic and diastolic blood pressure is taken as part of the vital sign assessments at all visits (see 
Section 9.2.7).  
 
9.1.3 
Blood samples 
 
Blood samples will be collected according to the study flow chart (see Appendix 1) and will be 
analysed at the central laboratory to determine concentrations of the efficacy laboratory 
parameters. 
 
All patients must be fasted for a minimum of eight hours prior to blood sampling. If patients have 
not fasted for a minimum of eight hours, the duration of fasting should be recorded, and patient 
encouraged to fast appropriately for the next clinical visit. 
 
Different assessments will be organised in laboratory test panels as following: 
 
• 
Laboratory test panel 1 samples will be collected as per the study flow chart (Appendix 1) at 
Visit 1/Screening 1, Visit 3/Baseline, Visit 4/Week 4, Visit 5/Week 8, Visit 6/Week 12, Visit 
7/Week 16, Visit 8/Week 20, Visit 9/Week 26/Early Termination and Visit 10/Week 28/Follow 
up. 
 
The test panel will include safety parameters (clinical haematology, biochemistry and 
coagulation, see Section 9.2.9). 
 
• 
Laboratory test panel 2 samples will be collected as per the study flow chart (Appendix 1) at 
Visit 1/Screening 1, Visit 2/Screening 2, Visit 3/Baseline, Visit 4/Week 4, Visit 5/Week 8, Visit 
6/Week 12, Visit 7/Week 16, Visit 8/Week 20, Visit 9/Week 26/Early Termination and Visit 
10/Week 28/Follow up. 
 
The test panel will include the following efficacy laboratory parameters: 
triglycerides, LDL-C (calculated), HbA1C 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 56 of 90 
 
 
• 
Laboratory test panel 3 will be collected as per the study flow chart (Appendix 1) at Visit 
3/Baseline, Visit 4/Week 4, Visit 5/Week 8, Visit 6/Week 12, Visit 7/Week 16, Visit 8/Week 
20, Visit 9/Week 26/Early Termination and Visit 10/Week 28/Follow up. 
 
The test panel will include the following efficacy laboratory parameters: 
VLDL-C, non-HDL-C, total cholesterol, glucose, HDL-C, RLP-C.  
 
• 
Laboratory test panel 4 will be collected as per the study flow chart (Appendix 1) at Visit 
3/Baseline, Visit 7/Week 16 and Visit 9/Week 26/Early Termination. 
 
The test panel will include the following efficacy laboratory parameters: 
LDL-C (preparative ultracentrifugation), ApoA1, ApoB, ApoCIII, Lp(a), insulin, hsCRP, HOMA-
IR, HOMA-β, nMR lipid profile. 
 
The nMR lipid profile will include measurement of lipoprotein particle concentration and 
size; HDL-P, small LDL-P, large LDL-P, LDL-size, VLDL-size, HDL-size. 
 
• 
Laboratory test panel 5 will be collected as per the study flow chart (Appendix 1) at Visit 
3/Baseline and Visit 9/Week 26/Early Termination. 
 
The test panel will include the following efficacy laboratory parameters: 
IL-6, IL-1β, PAI-1, VCAM-1, ICAM-1, MCP-1, serum biomarker. 
 
 
The following efficacy assessments will be calculated from laboratory test results:  
 
• 
LDL cholesterol (calculated) will be calculated at Visit 1/Screening 1, Visit 2/Screening 2, Visit 
3/Baseline, Visit 4/Week 4, Visit 5/Week 8, Visit 6/Week 12, Visit 7/Week 16, Visit 8/Week 
20, Visit 9/Week 26/Early Termination and Visit 10/Week 28/Follow up. 
 
The LDL-C (calculated) value will be obtained using the Friedewald calculation. 
 
• 
Non-HDL Cholesterol (non-HDL-C) will be calculated at Visit 3/Baseline, Visit 4/Week 4, Visit 
5/Week 8, Visit 6/Week 12, Visit 7/Week 16, Visit 8/Week 20, Visit 9/Week 26/Early 
Termination and Visit 10/Week 28/Follow up. 
 
The non-HDL-C value will be obtained by subtracting the HLD-C value from the total 
cholesterol value.  
 
• 
RLP Cholesterol (RLP-C) will be calculated at Visit 3/Baseline, Visit 4/Week 4, Visit 5/Week 8, 
Visit 6/Week 12, Visit 7/Week 16, Visit 8/Week 20, Visit 9/Week 26/Early Termination and 
Visit 10/Week 28/Follow up. 
 
The RLP-C value will be obtained by subtracting LDL-C (calculated) from non-HDL-C. 
 
• 
HOMA-IR and HOMA-β.  
HOMA-IR and homeostatic model assessment for ß-cell function (HOMA-ß) will be calculated 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 57 of 90 
 
at Visit 3/Baseline, Visit7/Week 16 and Visit 9/Week 26/Early termination. HOMA-IR and 
HOMA-β are methods for assessing insulin resistance and β cell function from fasting glucose 
and insulin. 
 
The calculations for HOMA-IR and HOMA-β will use the following formulas: 
 
− 
HOMA-IR is calculated by multiplying fasting plasma insulin (μU/mL) by fasting plasma 
glucose (mg/dL), then dividing by the constant 405.  
 
− 
HOMA-ß is calculated as follows: 360 x fasting plasma insulin (μU/mL) / (fasting 
plasma glucose (mg/dL) - 63).  
 
9.1.4 
Urinary albumin-to-creatinine ratio 
 
Urinary samples will be collected according to the study flow chart (see Appendix 1) at 
Visit3/Baseline and Visit 9/Week 26/ Early Termination. They will be analysed at the central 
laboratory to determine albuminuria, assessed by urinary albumin-to-creatinine ratio (UACR) . 
 
 
9.2 
Safety Assessments 
 
9.2.1 
Pregnancy test and Contraception Counselling 
For female patients of childbearing potential only, a pregnancy test will be carried out as per the 
study flow chart (Appendix 1) at Visit 1/Screening 1, Visit 3/Baseline, Visit 6/Week 12 and Visit 
9/Week 26. 
 
Female patients and male patients with female partners of childbearing potential must use 
highly effective contraceptive methods or have a sterilised partner for the duration of the study 
and this must be continued post study for at least 30 days for WOCBP and 90 days for men. This 
should be discussed with the patient as per the study flow chart (Appendix 1) at Visit 
1/Screening 1, Visit 3/Baseline, Visit 6/Week 12 and Visit 9/Week 26.  
Highly effective contraceptive methods are defined as methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly. Such methods include hormonal 
contraception, intrauterine device or sexual abstinence.  
 
Note: A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
 
Note: Hormonal contraceptives must be on a stable dose for at least one month before baseline. 
 
Note: Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 58 of 90 
 
trial and the preferred and usual lifestyle of the patient. 
 
9.2.2 
Adverse Events Assessment 
See Section 11. 
 
9.2.3 
Medical History 
A complete review of the patient’s medical history will be undertaken by the Investigator or 
designee at the Visit 1/Screening 1 and Visit 3/Baseline to ensure that no exclusion criteria have 
been met.  
Any concomitant disease, whether considered relevant for the study or not by the Investigator, 
must be reported in the eCRF. The date of diagnosis or duration of the condition should be noted 
where possible. 
 
The following will be recorded in the eCRF at Visit 3/Baseline: 
 
• 
Diabetes history and complications: date of diagnosis, diabetic nephropathy, diabetic 
retinopathy, diabetic neuropathy 
 
• 
History of CVD: ischaemic heart disease, myocardial infarction, heart failure, NYHA class, 
hypertension, atrial fibrillation, stroke, peripheral arterial disease 
 
• 
History of liver disease: NAFLD, NASH, liver biopsy 
 
• 
Hypercholesterolaemia 
 
• 
Smoking history: including smoking status 
 
9.2.4 
Concomitant medication 
 
All administered concomitant medications should be recorded throughout the study. 
 
For the pre-trial background medications; antihyperglycemic (antidiabetic) medication, statins 
and ezetimibe, the following information must be collected at Visit 3/Baseline: 
• 
Generic name 
• 
Start date 
• 
Total daily dose 
 
The dose of pre-trial background medications should remain stable throughout the study. 
 
Patients should avoid both during the study and for four weeks prior to baseline, ingesting food 
supplements rich in omega-3 or omega-6 fatty acids (e.g., cod liver oil capsules).  
 
Patients should also avoid: 
• 
Any medication for diabetes or obesity (except for metformin, sulfonylureas, DPP-4 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 59 of 90 
 
inhibitors, SGLT2 inhibitors, GLP1-RAs and short-term insulin treatment for acute illness), 
both during the study and for four weeks prior to baseline, as well as 
 
• 
Fibrates, PCSK9 inhibitors, bile acid sequestrants, niacin, niacin analogues or dietary 
supplements for the purpose of lowering cholesterol, both during the study and for six 
weeks prior to baseline   
 
9.2.5 
Electrocardiogram 
 
A 12-lead electrocardiogram (ECG) 10 mm/1 mV, 25 mm/s with a 10 second lead II rhythm strip 
will be recorded. Patients will be rested quietly in a fully supine position for five minutes before 
the ECG is taken. Recordings will be made at Visit 3/Baseline and at Visit 9/Week 26/Early 
Termination. 
 
9.2.6 
Physical Examination 
A physical examination, including height (Visit 1/Screening 1 only), weight, BMI and waist 
circumference measurement, will be performed by the Investigator as per the study flow chart 
(Appendix 1) at Visit 1/Screening 1, Visit 2/Screening 2, Visit 3/Baseline, Visit 4/Week 4, Visit 
5/Week 8, Visit 6/Week 12, Visit 7/Week 16, Visit 8/Week 20, Visit 9/Week 26/Early Termination 
and Visit 10/Week 28/Follow up, in accordance with local practices. 
 
BMI should be calculated according to the following formula: BMI (kg/m2) = body weight 
(kg)/(Height (m) x Height (m)) or (kg/m2 = [lb/in2 x 703]). 
 
The waist circumference is the circumference located midway between the lower rib margin and 
the iliac crest. Waist circumference should be measured according to the following procedure: 
• 
Waist circumference is measured in the horizontal plane and rounded up or down to the 
nearest 0.5 cm using non-stretchable measuring tape. 
• 
The same measuring tape should be used throughout the study. 
• 
The circumference should be measured when the patient is in a standing position, with an 
empty bladder, with feet together, arms down and waist accessible. 
• 
The tape should touch the skin but not compress soft tissue. 
• 
Twists in the tape should be avoided. 
 
9.2.7 
Vital Signs 
 
Vital signs measurements will be performed as per the study flow chart (Appendix 1) at Visit 
1/Screening 1, Visit 2/Screening 2, Visit 3/Baseline, Visit 4/Week 4, Visit 5/Week 8, Visit 6/Week 
12, Visit 7/Week 16, Visit 8/Week 20, Visit 9/Week 26/Early Termination and Visit 10/Week 
28/Follow up, in accordance with local practices. 
  
Measurements to be taken include (see references for full guidelines): 
 
• BP which will be assessed according to American Heart Association (AHA) guidelines 
(Whelton et al, 2018): 
o Make sure that the device is properly validated and calibrated. 
o Instruct the patient to avoid coffee, exercise and smoking 30 minutes before the 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 60 of 90 
 
assessment. 
o The patient should be seated and resting for five minutes before the BP is 
measured. 
o Choose the correct cuff size and measure the BP by positioning it on the bare arm 
at the level of the right atrium. 
o Record systolic and diastolic BP (in mmHg) and use an average of two sequential 
readings obtained at least 5 minutes apart to estimate the patient’s BP. 
• 
Heart rate: taken at rest (in bpm). 
• 
Temperature: will be taken as per clinic practice. Temperature and route will be 
recorded in the eCRF. 
 
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 eCRF as an 
AE if made after the patient has received their first dose of IMP. Clinically significant findings made 
prior to the patient receiving the first dose if IMP will be recorded as medical history. 
 
9.2.8 
Self-monitoring of blood glucose (SMBG) and hypoglycaemia assessment 
 
All patients will be instructed or re-educated on how to use their blood glucose meter device and 
test strips at the baseline visit. The instruction will be repeated as necessary during the trial. 
 
SMBG profiles will be recorded daily from Visit 3/Baseline to Visit 4/Week 4. After Visit 4/Week, 
at the investigator’s discretion, patients who have experienced hypoglycaemia may be asked to 
continue SMBG.  
 
Patients will be asked to record SMBG daily before meals and before bedtime. Patients will also 
be asked to record SMBG before exercise and if they suspect low blood glucose, as described in 
Section 9.2.8.1 Hypoglycaemia assessment. 
 
Patients will record the results of the SMBG values in an electronic diary. The record of each SMBG 
value will include date, time and value. Any SMBG values <70 mg/dL (3.9 mmol/L) entered into 
the electronic diary will be automatically alerted to the investigator and medical monitor for 
follow-up. If the patient is unable to access the electronic diary, a paper diary back up will be 
provided and the data will be transcribed during the next site visit into the IRT by the Investigator 
or designee.  
 
 
 
9.2.8.1 Hypoglycaemia assessment 
 
Assessment of hypoglycaemic episodes will be conducted as per the study flow chart (Appendix 
1) at Visit 3/Baseline, Week 2 Telephone Call, Visit 4/ Week 4, Visit 5/Week 8, Visit 6/ Week 12, 
Visit 7/ Week 16, Visit 8/Week 20, Visit 9/Week 26/Early Termination and Visit 10/Week 
28/Follow-up. 
 
Hypoglycaemia is classified by the American Diabetes Association (ADA) and the European 
Association for the Study of Diabetes (EASD) as outlined in Table 1. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 61 of 90 
 
Table 1. ADA/EASD classification of hypoglycaemia 
 
Level 1 
Glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 mmol/L) 
Level 2 
Glucose <54 mg/dL (3.0 mmol/L), with or without symptoms 
Level 3 
A severe event characterised by altered mental and/or physical status 
requiring assistance for treatment of hypoglycaemia. 
 
Level 2 hypoglycaemia with or without symptoms and Level 3 hypoglycaemia should be recorded 
and warrant further investigation. 
 
Hypoglycaemic symptoms include hunger, headache, nausea, light-headedness, palpitations, 
sweating, confusion, drowsiness, speech difficulty and incoordination. Severe hypoglycaemia may 
lead to loss of consciousness (McAulay et al, 2001). Patients will be educated regarding 
hypoglycaemia at Baseline/Visit 3. 
 
When a hypoglycaemic episode is suspected, plasma glucose should be self-measured and all 
values, hypoglycaemic symptoms and details of the event should be reported in the provided form 
(Section 15.3, Appendix 3) by the patient, according to the instructions. The patient is required to: 
• 
Self-measure plasma glucose every 15 minutes until the value is > 3.9mmol/L (70mg/dL) 
or symptoms have been resolved. This will be considered as one hypoglycaemic episode. 
• 
In a case of several low glucose values within the hypoglycaemic episode, the lowest 
value will be reported (the remaining values will be kept as source data). 
• 
The start time of the episode will correspond to the first glucose measurement and or/ 
hypoglycaemic symptom. 
• 
If the hypoglycaemic episode fulfils the criteria for an SAE, it must be reported as 
described in Section 11. 
 
 
9.2.9 
Clinical Laboratory Safety Tests: Haematology, Serum Biochemistry, and Coagulation 
 
Blood samples will be taken as part of the laboratory test panel #1 (see Section 9.1.3), as per the 
study flow chart (Appendix 1). All samples will be analysed in the central laboratory. 
 
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 tests. 
 
 
Haematology: 
Full blood count to include red cell count, haemoglobin, haematocrit, 
white cell count, differential white cell count, platelet count, 
reticulocyte count and red cell distribution width (RDW). 
Serum biochemistry:  
Urea (blood urea nitrogen (BUN)), creatinine, uric acid, total bilirubin, 
indirect and direct bilirubin, sodium, bicarbonate potassium, 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 62 of 90 
 
phosphorus, calcium chloride, alkaline phosphatase (ALP), AST, ALT, 
AST:ALT ratio, gamma-glutamyl transferase (GGT), albumin, total 
protein and TSH (screening only). 
Coagulation: 
PT (prothrombin time), International normalised ratio (INR) and APTT 
(activated partial prothrombin time) 
 
 
9.2.10 Urinalysis 
 
Urinalysis assessment will be conducted as per Flow Chart (Appendix 1) at Visit3/Baseline and Visit 
9/Week 26/Early Termination. 
 
pH, protein, glucose, blood, ketones, leukocytes, leukocyte esterase, bilirubin, specific gravity, 
urobilinogen and nitrate will be assessed. Reflex microbiology to be done locally if blood, protein, 
leukocyte esterase or nitrate/nitrite are present. 
 
 
9.3 
Pharmacokinetic sampling 
Plasma samples will be obtained prior to the first daily dose at Visit 3/Baseline, Visit 4/Week 4, 
Visit 5/Week 8, and Visit 7/Week 16 and Visit 9/Week 26/Early Termination for the measurement 
of trough plasma concentrations of total and unesterified 15-HEPE, and total EPA. 
 
A 1mL blood sample will be taken at each time point. Following centrifugation, plasma samples 
will be split in two and a back-up sample will be handled as specified in Section 9.5 and described 
in the laboratory manual. 
 
9.4 
Exploratory Blood Sampling 
Blood for exploratory biomarkers will be collected as per the Study Flow Chart (Appendix 1) at 
Visit 3/Baseline and Visit 9/Week 26/Early Termination and will be stored for later biomarker 
analysis. 
 
Details of the volume of blood to be taken, sample preparation and handling are contained in a 
separate laboratory procedures manual. 
 
9.5 
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. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 63 of 90 
 
10 
INVESTIGATIONAL PRODUCT/INVESTIGATIONAL DRUG 
 
10.1 Investigational Medicinal Product (IMP) 
 
The following medication supplies will be used in the study: 
 
Epeleuton Capsule: 
Description: 
Green hard-shelled capsule (size 0) containing 500mg of 15(S)-HEPE EE with 2.5% w/w of colloidal 
silicon dioxide as viscosity modifier. 
 
Epeleuton Placebo (Liquid Paraffin): 
Description: 
Green hard-shelled capsule (size 0) containing equivalent fill weight of liquid paraffin with 1% w/w 
of colloidal silicon dioxide as viscosity modifier. 
 
Liquid paraffin is selected as placebo to mimic the colour and consistency of epeleuton (15(S)-
HEPE EE). Liquid paraffin at high doses (15-30g/day) has been used as a laxative for over 100 years, 
in adults and children with good tolerability and limited AEs. 
 
10.2 Supply, Packaging, Labelling, Handling and Storage 
The study treatment is capsules of Epeleuton (15(S)-HEPE EE) or placebo. Epeleuton and placebo 
will be provided by Afimmune. 
 
Epeleuton and placebo capsules will be stored at 2 – 8°C in a secure area (e.g. a locked refrigerator 
or drug storage room), protected from unintended use. 
 
The study treatment will be identified by batch numbers and expiry date with each patient kit 
(sufficient for two weeks dosing) assigned a unique medication number. 
 
Labelling, packaging and release will be in accordance with the Clinical Trials Directive 2001/20/EC 
and Good Manufacturing Practice (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 detail the unique 
medication number for each kit which is traceable back to the dose. In addition, Epeleuton (15(S)-
HEPE EE) and placebo capsules will be labelled with information according to local regulations. 
 
10.3 Dosage and Administration 
Patients who fulfil all inclusion and no exclusion criteria may be accepted in the study. Each 
patient must read and sign an ICF prior to any screening procedures being performed. This study 
involves a comparison of Epeleuton with placebo, administered orally with or after food (within 
30 minutes after a meal) twice daily for a total duration of 26 weeks. Patients will also receive 
standard of care therapy in addition to their assigned IMP throughout the treatment period of 
the study. The last study drug administration should occur on the day preceding Visit 9/Week 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 64 of 90 
 
26/Early Termination. 
 
Patients will be randomised to one of the three treatment groups in a 1:1:1 ratio: 
 
• Treatment Group A (placebo): Four x placebo 500mg capsules orally administered BID 
(eight capsules daily) for 26 weeks. 
 
• Treatment Group B (Epeleuton 2g): Two x placebo 500 mg capsules + two x Epeleuton 
(DS102) 500mg capsules orally administered BID (eight capsules daily) for 26 weeks. 
 
• Treatment Group C (Epeleuton 4g): four x Epeleuton (DS102) 500mg capsules orally 
administered BID (eight capsules daily) for 26 weeks. 
 
 
Patients will be required to take the capsules with or after food (within 30 minutes after a meal). 
Medication(s) for other conditions that are permitted in the study can be taken as usual. 
 
Morning and Evening walleted blister packs will each consist of seven days of four capsules. Each 
patient kit containing four wallets, sufficient for two weeks dosing. Patients will be instructed to 
take the four capsules in the morning and four capsules in the evening from Morning and 
Evening wallets, on the relevant day, as shown below: 
 
Figure 6: Walleted Blister Packs 
 
     
 
 
 
(Morning walleted blister packs) 
 
 
(Evening walleted blister packs) 
 
 
10.4 Duration of Treatment 
Patients will take assigned medication for 182 consecutive days (26 weeks). 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 65 of 90 
 
10.5 Method for Assigning Patients to Treatment 
 
Approximately 240 patients will be randomized into double-blind treatment groups in a 1:1:1 ratio 
by an Interactive Web Response System (IWRS) as follows:  
 
• 4g Epeleuton: four x Epeleuton (DS102) 500mg capsules orally administered BID (eight 
capsules daily) for 26 weeks   
 
• 
2g Epeleuton: two x placebo 500mg capsules + two x Epeleuton (DS102) 500mg capsules orally 
administered BID (eight capsules daily) for 26 weeks   
 
• Placebo: four x placebo 500mg capsules orally administered BID (eight capsules daily) for 26 
weeks  
 
A randomization list permuted by blocks and stratified by site will be generated by the Sponsor or 
its designee. The randomization schedule with study drug assignments will be generated prior to 
the start of the study and will be known only to the individuals responsible for labelling the study 
drug, the statisticians generating the schedule and the IWRS team responsible for implementing 
the schedule. The IWRS will assign a medication kit number to each patient and the contents will 
be based on the randomization code.  
 
At the investigational site, each patient will be assigned a patient identifier number during 
screening that will be used on all patient documentation. The patient identifier number will 
contain the site number and the patient number assigned in numerical order at the screening visit 
(e.g.: 102-10 for the tenth patient screened at the site number 102). Patient numbers will be 
assigned in ascending order starting with 01. 
 
10.6 Drug Accountability 
The Investigator is responsible for maintaining accurate records of the study medication received 
initially, the study drug dispensed/used, the returned medication by patients (in the case of 
patients discharged prior to week 26) and the medication returned to the Sponsor or designee for 
destruction. All study drug accountability forms and treatment logs must be retained in the 
Investigator Site File (ISF). These records must be available for inspection by the Sponsor, its 
designees or by regulatory agencies at any time. 
 
Used drug boxes/blister packs will be stored safely in a secure ambient location 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 need to be accounted for. Any 
discrepancies between amounts dispensed and returned will need to be explained. 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 66 of 90 
 
11 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
11.1 Definitions and Reporting of Adverse Events 
 
11.1.1 Definitions 
 
Adverse Event (AE): 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered an IMP and which does not necessarily have a causal relationship with this 
treatment. All AEs must be recorded in the eCRF, defining relationship to IMP and severity. AEs 
should also be recorded by the Investigator in the patient file/notes. 
 
Examples of AEs include one of the following or a combination of two or more of these factors: 
• Any unfavourable and unintended sign, symptom, illness, or syndrome 
• Abnormal laboratory values, if judged clinically significant in the opinion of the Investigator 
• Worsening (change in nature, severity or frequency) of a concomitant or pre-existing illness 
• An AE of the IMP, including comparator or concomitant medication 
• Drug interactions 
• An AE of an invasive procedure required by the protocol 
• An accident or injury 
 
Of note: 
• Surgical procedures or other therapeutic interventions themselves are not AEs, but the 
condition for which the surgery/intervention is required is an AE and should be documented 
accordingly. 
• Planned surgical measures and the condition(s) leading to these measures are not AEs, if the 
condition(s) was (were) known before the period of observation and did not worsen during 
study. 
In the latter case the condition should be reported as medical history. 
 
Serious Adverse Event (SAE): 
A SAE (experience) or reaction is any untoward medical occurrence that at any dose: 
• 
results in death, or 
• 
is life-threatening, or 
Note: “Life-threatening” means that the patient was at immediate risk of death at the time of 
the SAE; it does not refer to a SAE that hypothetically might have caused death if it were more 
severe. 
• 
requires in-patient hospitalisation or prolongation of existing hospitalisation, or 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 67 of 90 
 
Note: This means that hospital inpatient admission or prolongation of hospital stay were 
required for the treatment of the AE, or that they occurred as a consequence of the event. 
Visits to a hospital by ambulance or to the emergency room without admission will not be 
regarded as hospitalisation unless the event fulfils any other of the serious criteria. 
• 
results in persistent or significant disability/incapacity, or 
Note: “Persistent or significant disability or incapacity” means a permanent or significant 
and substantial disruption of a person’s ability to carry out normal life functions. 
• 
is a congenital anomaly/birth defect, or 
• 
is an important medical event 
Note: Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalisation but may jeopardise the 
patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, 
or development of drug dependency or drug abuse. 
 
Unexpected Adverse Event (UAE): 
Expectedness will be determined by the Sponsor according to the designated Reference Safety 
Information. The Reference Safety Information for the IMP is contained in the Investigator’s 
Brochure (IB). 
 
Unexpected: An AE or suspected adverse reaction is considered unexpected if it is not listed in the 
Reference Safety Information or is not listed with the specificity or severity that has been 
observed. Unexpected, as used in this definition, also refers to AEs or suspected adverse reactions 
that are mentioned in the Reference Safety Information as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug but are not specifically mentioned as 
occurring with the particular drug under investigation. 
 
11.1.2 Severity 
The intensity of an AE is an estimate of the relative severity of the event made by the Investigator 
based on his or her clinical experience. The following definitions are to be used to rate the severity 
of an AE: 
 
− 
Mild: the AE is transient and easily tolerated. 
− 
Moderate: the AE causes the patient discomfort and interrupts the patient’s usual 
activities. 
− 
Severe: the AE causes considerable interference with the patient’s usual activities and 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 68 of 90 
 
may be incapacitating or life-threatening. 
 
Clarification of the difference in meaning between “severe” and “serious”: 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). 
 
This is not the same as “serious”, which is based on the outcome or action criteria usually 
associated with events that pose a threat to life or functioning. 
 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
 
11.1.3     Causality 
The term “causality” describes the degree of attributability (causality) between an IMP and an 
event.  
 
Causality assessment of AEs is the structured and standardised assessment of individual 
patients/case reports for the likelihood of involvement of a suspected drug in causing a particular 
event in a given patient. 
 
To assess whether there is a reasonable possibility that the AEs are associated with the IMP, 
temporal relationship between administration of the IMP and the event, de-challenge/re-
challenge, association with underlying disease or concomitant medication, and the presence of a 
more likely cause and physiological/pathological plausibility are considered.  
 
The Investigator should use medical judgment to determine whether he/she assumes a 
reasonable causal relationship, including into his/her evaluation all relevant factors and factual 
evidence such as 
• 
temporal course and latency 
• 
results from de-challenge or re-challenge 
• 
pattern of the reaction 
• 
known pharmacological properties of the product 
• 
and alternative explanations (e.g. other drugs, medical history, concomitant diseases). 
 
The expression “reasonable causal relationship” means to convey in general that there is evidence 
or argument to suggest a causal relationship. 
 
Assessment will be documented on the AE and SAE form. 
 
The following definitions will be used to determine causality of an AE: 
• If reasonable causal relationship, either: 
- 
Definitely 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 69 of 90 
 
- 
Probable 
- 
Possible 
• If no reasonable causal relationship, either: 
- 
Unlikely 
- 
Unrelated 
 
11.1.4 Reporting of AEs and SAEs 
All AEs must be recorded in the eCRF, defining relationship to IMP and severity. 
 
Every SAE must be reported to the pharmacovigilance contract research organisation (spm²) by e-
mail or fax within 24 hours of the investigator/site becoming aware of it. In case of questions 
regarding an SAE that will be reported, the Investigator or authorised study personnel can contact 
spm² by phone. The contact information is provided in the ISF. 
 
At the time of the call, the Investigator must provide, as a minimum requirement, the patient 
number, birth year, nature of the SAE and a preliminary assessment of causality. The Investigator 
should follow-up the initial notification of the potential SAE by faxing/e-mailing a copy of the SAE 
reporting form to spm² at the number provided in the ISF. The faxed/e-mailed SAE reporting form 
should be sent to the spm² within 24 hours of knowledge of such a case. 
 
Every attempt should be made to describe all AEs in terms of a diagnosis. If a clear diagnosis has 
been made, individual signs and symptoms should not be recorded unless they represent atypical 
or extreme manifestations of the diagnosis, in which case they should be reported as separate 
events. If a clear diagnosis cannot be established, each sign and symptom must be recorded 
individually.  
 
The “initial SAE report” should be as complete as possible, including details of the current illness 
and (serious) adverse event, the reason why the event was considered serious, date of onset and 
stop date (if applicable), diagnostic procedures and treatment of the event, relevant medical 
history and concomitant medication and action taken with study medication. 
 
Follow-up information on an existing SAE that is fatal or life-threatening should be reported by 
the Investigator to spm² within five days after the initial report. Upon request from spm², 
hospitalisation or autopsy reports should be made available. 
 
The TEAE reporting period begins from signing of the consent form and continues until the end of 
the follow-up visit. 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.  
 
All AEs that occur in the course of the study regardless of the causal relationship should be 
monitored and followed up until the outcome is known or it is evident that no further information 
can be obtained. There must be documented reasonable attempts to obtain follow-up 
information and outcome.  It is the responsibility of the Investigator to ensure that any necessary 
additional therapeutic measures and follow-up procedures are performed. 
 
11.1.5 Follow-up of Missing Information/Response to Sponsor Queries 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 70 of 90 
 
Information not available at the time of the initial SAE report (e.g. an end date for the AE or 
laboratory values received after the report) must be documented on a “Serious Adverse Event” 
form, with the box “Follow-up” checked under “Report type”. 
 
All patients who have AEs, whether considered associated with the use of the investigational 
products or not, must be monitored to determine the outcome. The clinical course of the AE will 
be followed up according to accepted standards of medical practice, even after the end of the 
period of observation, until a satisfactory explanation is found or the Investigator considers it 
medically justifiable to terminate follow-up. Should the AE result in death, a full pathologist’s 
report should be supplied, if possible. 
 
The Sponsor or pharmacovigilance contract research organisation (CRO) (spm²) will identify 
missing information for each SAE report. Requests for follow-up will be sent to the Investigator 
until all queries are resolved or no further information can be reasonably expected. All responses 
to queries and supply of additional information by the Investigator should follow the same 
reporting route and timelines as the initial report.  
 
11.2 Serious Adverse Reactions and Unexpected Adverse Reactions 
 
11.2.1 Definitions 
Adverse Reaction: 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions. 
 
The phrase “responses to a medicinal product” means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility, i.e. the relationship cannot be 
ruled out. 
 
For marketed medicinal products, an adverse reaction is a response to a drug which is noxious 
and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for modification of physiological function. 
 
Unexpected Adverse Reaction: 
An unexpected adverse reaction is defined as an adverse reaction, the nature or severity of which 
is not consistent with the applicable product information (e.g. IB for an unauthorised IMP or 
similar product information sheet such as the summary of product characteristics (SPC)). 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR): 
A SUSAR is defined as any serious adverse reaction that might be related to the IMP and is 
unexpected according to the definition above. 
 
11.2.2 Reporting of suspected unexpected serious adverse reactions (SUSARs) 
The Sponsor will report all serious and unexpected AEs, which are judged by either the 
Investigator or the Sponsor as having a reasonable suspected causal relationship (suspected 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 71 of 90 
 
unexpected serious adverse reaction - SUSAR), to the competent authorities and the concerned 
ethics committee (EC) according to applicable law. 
 
SUSARs will be reported by spm² according to appropriate competent authority and EC 
requirements. SUSARs will be reported to Investigators according to ICH Good Clinical Practice 
(GCP) and to local regulations. SUSAR reporting to competent authorities and ECs will be 
performed according to local regulations in an unblinded manner. Competent Authorities within 
the EU will be notified of all SUSARs through the EudraVigilance database. An electronic common 
technical document (eCTD) submission will be performed by a local representative to the FDA. 
 
Fatal and life-threatening SUSARs should be reported by spm² as soon as possible to the 
competent authorities and ECs according to local regulations, and, in any case, no later than seven 
calendar days after knowledge by spm² of such a case. Relevant follow-up information on the case 
will be subsequently communicated within an additional eight days. All other SUSARs shall be 
reported to the competent authorities and ECs according to local regulations as soon as possible 
but within a maximum of fifteen days of first knowledge by the Sponsor. 
 
 
11.3 Pregnancy Reporting 
If a patient or a patient’s partner becomes pregnant during the study, study staff must be informed 
as soon as possible. Upon confirmation of the pregnancy, the patient must be withdrawn from the 
study but closely followed-up during the entire course of the pregnancy and postpartum period. 
All recommendations described in the IB regarding pregnancy and lactation have to be carefully 
considered. 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. 
 
Parental and neonatal outcomes must be recorded even if they are completely normal and without 
AEs. Offspring should be followed up for at least eight weeks after delivery. Longer observation 
periods may be determined by the Sponsor if an adverse outcome of the pregnancy was observed. 
For documentation and follow-up, the Sponsor will collect all information on a specific pregnancy 
form which will be provided by spm2. 
 
11.4 Unblinding for Regulatory Reporting or Medical Necessity 
 
The study medication blind shall not be broken by the Investigator unless information concerning 
the study medication is necessary for the medical treatment of the patient. If possible, the Sponsor 
should be notified before the study medication blind is broken. If a medical emergency requiring 
unblinding occurs, the Investigator (or designee) will break the blind immediately. In the event 
unblinding is necessary for a patient, the site must notify the Sponsor’s medical monitor 
immediately after the unblinding. The date, time, and reason the blind was broken must be 
recorded in the source documents and on the appropriate eCRF. 
 
Note: If the unblinding is performed by the Investigator due to a medical requirement, the patient 
will discontinue trial participation. 
 
The method of unblinding is specified in Section 12.4 of the protocol. The study team will be kept 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 72 of 90 
 
blinded regarding treatment assignment.  
 
11.4.1 
Unblinding for studies conducted in the EU 
If applicable and required, treatment codes will be unblinded prior to submission to authorities 
and concerned ECs, by the Sponsor’s safety group, which is an independent entity within the 
Sponsor or by the pharmacovigilance CRO. 
 
The Sponsor will also inform all Investigators in a blinded fashion (EU only), unless otherwise 
required by local regulations. Reporting obligations to the local EC of the Investigator will be 
fulfilled by the Investigator, unless otherwise specified. 
 
11.4.2 
Unblinding for studies conducted in the US 
The blind will be broken for investigational new drug (IND) safety reports submitted to FDA and all 
participating Investigators. 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 73 of 90 
 
12 
STATISTICAL METHODOLOGY AND DATA MANAGEMENT 
 
12.1 Study Design 
This clinical trial employs a randomised, double-blind, placebo-controlled, 3-arm, 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 
the evaluation of safety and efficacy data. The use of placebo as a comparator is justified as a 
reasonable design to assess safety and efficacy in patients based on the fact that Epeleuton is 
administered as an add-on treatment to stable background treatment for hypertriglyceridemia 
and type 2 diabetes. A full description of the study design is presented in Section 6 above. 
 
12.2 Randomisation 
All patients will be screened, and the inclusion and exclusion criteria will be assessed during the 
screening period (Visit 1 and Visit 2).  
 
At the baseline visit (Visit 3), approximately 240 Patients will be randomised (1:1:1) into the 
following treatment groups: 
 
• 
Treatment Group A (placebo): Four x placebo capsules orally administered twice a 
day, i.e. eight capsules daily for 26 weeks 
 
• 
Treatment Group B (Epeleuton 2g): Two Epeleuton (DS102) 500mg capsules and 
two placebo capsules orally administered twice a day, i.e. eight capsules daily for 
26 weeks 
 
• 
Treatment Group C (Epeleuton 4g): Four Epeleuton (DS102) 500mg capsules 
orally administered twice a day, i.e. eight capsules daily for 26 weeks 
 
A randomisation list permuted by blocks and stratified by site and a corresponding medication 
number list linking each patient kit to dose group will be generated by the Sponsor or its designee. 
The randomisation schedule and medication number list will be generated prior to the start of the 
study and will be known only to the individuals responsible for labelling the study drug, the 
statisticians generating the schedule and the interactive web response system (IWRS) team 
responsible for implementing the schedule. The IWRS will assign a medication kit number to each 
patient and the contents will be based on the randomisation code.  
 
At the investigational site, each patient will be assigned a patient identifier number during 
screening that will be used on all patient documentation. The patient identifier number will 
contain the site number and the patient number assigned in numerical order at the screening visit 
(e.g.: 102-10 for the tenth patient screened at the site number 02 in country designated by the 
number 1). Patient numbers will be assigned in ascending order starting with 01. 
 
  


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 74 of 90 
 
12.3 Estimation of Sample Size 
 
Table 2. Sample size estimation using effect size (Cohen's d from -0.02 to -0.75) 
 
d 
Total Sample 
Size 
Sample size per 
group 
-0.2 
1180.2 
393.4 
-0.25 
756.5 
252.2 
-0.3 
526.2 
175.4 
-0.35 
387.3 
129.1 
-0.4 
297.3 
99.1 
-0.45 
235.5 
78.5 
-0.5 
191.3 
63.8 
-0.55 
158.6 
52.9 
-0.6 
133.8 
44.6 
-0.65 
114.5 
38.2 
-0.7 
99.0 
33.0 
-0.75 
86.7 
28.9 
 
The sample size was estimated based on results of a post hoc analysis of triglycerides and HbA1C 
from a Phase IIa trial of Epeleuton in patients with NAFLD. Changes in triglycerides and HbA1C at 
the highest tested dose (2g/day) at week 16 (end-of-treatment) were used to estimate relative 
effect sizes (Cohen’s D). Cohen’s D or the standardised relative effect size is the difference 
between the group means divided by the pooled standard deviation. 
 
To discover a conservative relative effect size (Cohen’s d) between epeleuton and placebo of 0.6 
in triglyceride change from baseline with 80% power, 45 patients per group are necessary under 
ideal assumptions using the t-test for independent samples (alpha=0.05, two-sided). 
 
To discover a conservative relative effect size (Cohen’s d) between epeleuton and placebo of 0.48 
in HbA1C change from baseline with 80% power, 70 patients per group are necessary under ideal 
assumptions using the t-test for independent samples (alpha=0.05, two-sided). 
 
To power the study for both primary endpoints and take deviations from ideal parametric 
conditions and drop-outs into account, randomisation of 80 patients per group is recommended. 
 
12.4 Blinding and Code Breaking Instructions 
All study site personnel, as well as the personnel involved in the monitoring or conduct of the 
study, will be blinded to the individual patient treatment assignments. Randomisation details will 
be kept strictly confidential, accessible only in an emergency to authorised persons, until the time 
of formal unblinding. The blinded code for the trial will be broken only after all patient data has 
been recorded and verified and the database locked. 
 
Emergency unblinding will be performed via the IWRS, with relevant site personnel and 
pharmacovigilance monitors provided with the required system access to carry out unblinding. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 75 of 90 
 
 
12.5 Data Analysis 
Data analysis will be performed at a data management CRO. All computations will be completed 
using SAS® Version 9.1.3 or later. Graphical summaries will be produced using SAS®. A detailed 
description of the analyses to be performed will be provided in the Statistical Analysis Plan (SAP). 
 
12.6 Analysis Populations 
Full Analysis Set (FAS): 
Patients will be included in the FAS, a modified intention-to-treat population, if they are 
randomised to the study, received at least one dose of study medication and have at least one 
post-baseline measurement. Analysis will be done according to treatment as randomised. 
 
Safety Analysis Set (SAS) 
The SAS consists of all patients who received at least one dose of the study medication. SAS is the 
analysis population for all safety endpoints. Analysis will be done according to the actual treatment 
patients received. 
 
Per Protocol Set (PPS): 
In order to qualify for the PPS, the patients must have followed the study protocol without any 
major protocol violations. Protocol violations will be assessed for each patient in a blinded fashion 
prior to database lock at a Blind Data Review Meeting (BDRM), and the PPS will also be finalised 
during this meeting. PPS is a supportive analysis population for the primary efficacy endpoint. 
Analysis will be done according to the treatment that patients were randomised to. 
 
12.7 Safety Analysis 
Demographic information, medical history and physical examination data will be listed for each 
patient and summarised descriptively. 
 
All AEs recorded during the study will be coded to system organ class and preferred terms using 
the current version of the Medical Dictionary for Regulatory Activities (MedDRA). TEAEs will be 
tabulated and summarised by treatment, relationship to treatment, seriousness and severity. 
Non-TEAEs will be listed separately. 
 
Clinical laboratory values (haematology, biochemistry, and coagulation) will be listed for each 
patient by treatment and day. Values outside the laboratory normal ranges will be listed 
separately with associated comments as to their clinical significance, with potentially clinically 
significant abnormalities highlighted and summarised by treatment. Clinical laboratory values 
obtained prior to dosing will be defined as baseline values. 
 
Individual values of vital signs will be listed and summarised descriptively for each treatment and 
day. 
 
ECG assessments will be listed for each patient with all associated comments and summarised by 
treatment and day. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 76 of 90 
 
 
Concomitant medications (if any), categorised by medication group and subgroup according to 
the latest version of the World Health Organisation drug dictionary (WHODD), will be listed and 
summarised by treatment. 
 
In general, appropriate descriptive statistics, according to the nature of the variable, will be 
applied. Categorical variables will be presented using counts and percentage, whilst continuous 
variables will be presented using mean, standard deviation, median, minimum, maximum, 
coefficient of variation and number of patients. 
 
 
12.8 Statistical Analysis Plan 
In addition to the summarised analysis outlined below, a separate SAP will detail all analyses to 
be performed. 
 
For continuous variables, descriptive statistics will include: the number of patients reflected in the 
calculation (n), mean, median, standard deviation, interquartile range, minimum, and maximum. 
 
For categorical data, frequencies and percentages will be displayed for each category. 
 
 
12.8.1 Primary Variables 
The primary efficacy endpoints are: 
• 
Percent change in triglycerides from baseline to week 16. 
 
• 
Change in HbA1c from baseline to week 26. 
 
Each of the independent primary endpoints will be analysed separately. Success in either of the 
primary endpoints will support a conclusion of effectiveness.  
 
The primary analysis will be based on the FAS and repeated for the PPS as a supportive analysis. 
 
Analysis of changes and percentage changes of triglycerides will be performed using a Wilcoxon 
rank sum test with the Hodges Lehmann median and 95% confidence intervals estimates. For 
analysis of triglycerides, baseline will be defined as the mean of the Baseline (Visit 3) and 
Screening 2/Week -1 (Visit 2) measurements. 
 
Changes from baseline of HbA1c at each visit will be analysed using mixed model analysis of 
covariance (ANCOVA) with baseline value as a covariate. 
 
12.8.2 Secondary variables 
Secondary and exploratory endpoints will be analysed by either an ANCOVA mixed model, if the 
data for that endpoint are normally distributed, or a Wilcoxon-rank-sum test, if the data are not 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 77 of 90 
 
normally distributed. 
 
Logistic regression with baseline HbA1C as a covariate will be used to analyse the percentage of 
patients with HbA1c < 7.0% and the percentage of patients with HbA1c < 6.5% at week 16. 
 
Exploratory analyses pooling the two doses vs. placebo for all pre-specified endpoints will be 
performed. 
 
12.8.3 Missing data and sensitivity analyses 
Missing data will be accounted for using a multiple imputation approach. 
 
Sensitivity analyses will be conducted for the primary endpoints using a last observation carried 
forward (LOCF) missing data handling approach. 
 
A two-sided p-value less than 0.05 is considered statistically significant for all comparisons. 
 
 
12.9 Interim Analysis 
An interim analysis may be conducted after at least 50% of planned enrolled patients have 
completed their Week 16 assessments or an early termination visit. The interim analysis will be 
conducted in accordance with sponsor standard operating procedure (SOP) “Interim Analysis of 
Clinical Studies”. 
 
An unblinded interim analysis will be performed by an unblinded independent statistician. Interim 
data and the results of interim analyses will not be accessible by anyone other than the unblinded 
statistician and an Independent Data Monitoring Committee (IDMC). 
 
The sponsor trial team will remain blinded with procedures in place to ensure the confidentiality 
of the interim data in accordance with sponsor SOP “Interim Analysis of Clinical Studies”. 
 
The IDMC will make one of the following recommendations to the sponsor based upon the 
primary efficacy endpoints:  
 
• 
Increase the sample size to a defined number 
 
• 
Continue the study as originally planned 
 
• 
Stop the study due to futility 
 
The IDMC may also make further recommendations to the sponsor including changes to study 
design and conduct. Further interim analyses may be conducted if recommended by the IDMC. 
 
Further details will be described in an interim statistical analysis plan. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 78 of 90 
 
12.10 Data Collection/Electronic Case Report Forms 
Data will be collected using a validated electronic data capture (EDC) solution. eCRFs will be 
utilised for recording data from each patient meeting the eligibility criteria and being randomised 
in the study, and a limited amount of data will be completed for patients who fail to meet eligibility 
criteria (i.e. screen failures). Electronic access to the eCRF will be available to all investigator sites. 
All study staff responsible for entering data into the eCRF system will be trained prior to the start-
up of the study. A personal log-in will be provided for all responsible personnel to allow for an 
audit trail relating to the study data to be maintained. 
 
All evaluations performed shall be entered in a timely manner into the eCRF by a member of the 
site staff delegated responsibility for this specific task by the Principal Investigator (PI) 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 information will be verified against the individual patient records. Any 
inconsistencies will be presented as queries, either as automatically generated queries, if raised 
by the logical data checks of the eCRF system, or by manually generated queries if raised by the 
data validation checks or the SDV performed by the data manager (DM) or the clinical research 
associate (CRA), respectively. Queries shall be resolved in a timely manner by a trained member 
of the site staff. 
 
12.11 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 data management CRO 
standard operating procedures (SOPs). The handling of data, including data quality control, will 
comply with all applicable regulatory guidelines. 
 
12.12 Protocol Deviations 
Protocol deviations will be captured through site self-reporting, CRA SDV and data management 
edit checks, and will be recorded by the CRA throughout the study in both monitoring visit reports 
and in a centralised log in the eCRF. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 79 of 90 
 
13 
REGULATORY AND ADMINISTRATIVE PROCEDURES 
 
13.1 Institutional Review 
Investigators will agree that the study will be conducted according to the principles of the ICH E6 
Guideline on GCP and the ethical principles that have their origins in the World Medical 
Association Declaration of Helsinki. The Investigator will conduct all aspects of this study in 
accordance with all national, state and local laws or regulations. 
 
The protocol and the patient information sheet (PIS)/ICF will be approved by the relevant 
competent authorities and ECs, and possibly other public bodies according to local requirements, 
before commencement of the study. If a protocol amendment is necessary, this will be prepared 
with the agreement of the national co-ordinating Investigator and signed by the relevant parties. 
If the amendment is considered to be substantial, it will be submitted to the competent authorities 
and ECs, and possibly other public bodies according to local requirements, for review and 
approval. The protocol amendment will not be implemented before such approvals are obtained, 
if required. Minor amendments which do not affect the safety or physical or mental integrity of 
the clinical trial participants or the scientific value of the trial (i.e. non-substantial amendments) 
do not need to be submitted to competent authorities 
 
SUSAR reports and periodic safety reports will be sent to competent authorities and ECs, 
according to local regulations. 
 
13.2 Good Clinical Practice 
The study will be managed and conducted according to the latest ICH GCP and applicable 
regulatory requirement(s) (specifically the principles of GCP in ICH topic E6, as laid down by the 
Commission Directive 2005/28/EC and in accordance with applicable local laws and guidelines). A 
copy of the ICH guidelines can be found in the ISF. 
 
13.3 Essential Documents 
The ICH guideline for GCP lists a number of essential GCP documents required prior to, during, 
and after the conduct of the study. It is the responsibility of the monitor to ensure that the 
Investigator is always provided with a copy of such documents prepared by the study 
management, and it is likewise the responsibility of the Investigator to provide the monitor with 
essential documents prepared by the Investigator or the local EC. A complete list of essential GCP 
documents can be found in the ISF. 
 
13.4 Record Retention 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These records include, but 
are not limited to, the identity of all participating patients, all original signed informed consent 
documents, copies of all eCRFs, safety reporting forms, source documents, and detailed records 
of treatment disposition and adequate documentation of relevant correspondence. 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 80 of 90 
 
The records should be retained by the Investigator according to ICH, local regulations, or as 
specified in the clinical trial agreement (CTA), whichever is longest. 
 
13.5 Monitoring/Quality Control 
Monitoring visits will be conducted during the study at regular intervals. Monitoring visits will be 
conducted to ensure protocol adherence, quality of data, accuracy of entries in the eCRF, drug 
accountability, compliance with regulatory requirements and continued adequacy of the 
investigational site and its facilities. 
 
Incorrect or missing entries in the eCRFs will be queried and will be corrected appropriately. 
 
All clinical data will undergo quality control checks prior to clinical database lock. Edit checks will 
then be performed for appropriate databases as a validation routine using SAS® to check for 
missing data, data inconsistencies, data ranges, etc. Each eCRF will be reviewed and signed by the 
PI. 
 
13.6 Quality Assurance 
Investigational sites may be audited during or after the study is completed by Sponsor 
representatives, or regulatory authorities may conduct an inspection. The Investigator(s) will be 
expected to cooperate with such a visit and to provide assistance and documentation (including 
all study documentation, and patient source data), as requested. 
 
13.7 Insurance and Liability 
Insurance and liability for the study is the responsibility of the Sponsor, Afimmune. Patient 
insurance is taken out for study participants in accordance with legal requirements. 
 
13.8 End of Trial 
The end of trial is defined as ‘last patient last visit (LPLV)’. LPLV is defined as the date the 
Investigator reviews the last patient’s safety data and determines that no further evaluation is 
required for the patient to complete the trial. 
 
13.9 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. 
 
13.10 Data Protection 
All information collected for this study will be kept strictly confidential. The Sponsor undertakes 
to comply with applicable data protection regulations, which are further detailed in the written 
information provided to the patient. In case of data security breach, this will be reported to the 
relevant supervisory authority where the breach presents a risk to the affected individuals. This 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 81 of 90 
 
will be reported within 72 hours of becoming aware of the breach. Where a breach is likely to 
result in a high risk to the affected individuals, the Sponsor will also inform those individuals 
without undue delay. 
 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the regulatory agency(ies), and 
the IRB/IEC direct access to review the patient’s original medical records for verification of study-
related procedures and data. For further information, the Sponsor data protection officer can be 
contacted at dataprotection@afimmune.com.  
 
13.11 Report and Publication 
Production of a clinical study report (CSR) in accordance with the ICH guidelines will be the 
responsibility of the CRO. No information from the study will be published without the prior 
written consent of the Sponsor. 
 
 
13.12  COVID-19 Contingency 
Due to the unprecedented worldwide COVID-19 pandemic, the Sponsor is implementing 
measures to assure the safety of trial participants, to maintain compliance with GCP and to 
minimise risk to trial integrity. 
Among these measures are modifications to the protocol to ensure that, if difficulties in adhering 
to protocol-specific procedures or protocol-mandated visits are encountered by patients, 
investigators or study sites, adequate and appropriate contingencies are in place. 
COVID-19 contingency measures do not replace the existing protocol procedures and visit 
schedule.  
The following contingencies and actions will be implemented in response to the evolving COVID-
19 pandemic: 
1. An interim analysis may be conducted after at least 50% of patients have completed their 
week 16 visits as described in Section 12.9 Interim Analysis. Due to the rapidly evolving 
COVID-19 situation at both a global and country level, a modification to the prospectively 
planned sample size may be necessary if patient recruitment is not feasible and must be 
stopped. The interim analysis will safeguard the integrity of the trial and inform whether 
further patient recruitment is required when conditions at participating sites are 
amenable to re-initiation of patient recruitment. 
2. In a worst-case scenario where a patient is unable to attend the study site for protocol-
mandated visits, due to patient considerations (such as COVID-19 infection or quarantine) 
or study site restrictions; 
A. The investigator will complete all possible assessments via phone for all impacted 
study visits as described in Appendix 4. COVID-19 Contingency Investigator 
Assessment Phone Visits. 
• 
Phone visit assessments must include assessment of adverse events, patient-
reported endpoints and compliance. 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 82 of 90 
 
• 
The patient will be reminded that IMP will continue to be administered with food 
or within 30 minutes after a meal at the same time twice daily and compliance 
should be recorded in the electronic diary or paper backup as appropriate.  
• 
On completion of this visit, patients will be advised that they will be required to 
return to the investigational site at the next scheduled visit and to bring with 
them the used epeleuton/placebo patient packs, and the patient compliance log. 
B. IMP will be couriered directly to the patient. 
Investigators must make every effort possible to ensure that patients adhere to the protocol 
procedures and attend all scheduled visits. COVID-19 contingency measures regarding IMP 
delivery and phone visits must only be used if absolutely necessary and after every effort to 
follow the protocol visit schedule has been exhausted. Investigator responsibilities as 
prescribed by ICH GCP, including oversight of patient safety must continue to be observed in all 
cases whether or not contingency actions relating to COVID-19 are required. 
This contingency will facilitate the conduct of appropriate safety monitoring and will preserve the 
investigational product supply chain. 
 
 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 83 of 90 
 
14 
REFERENCES 
 
• 
American Diabetes Association, 2019a. 10. Cardiovascular Disease and Risk Management: 
Standards of Medical Care in Diabetes—2019. Diabetes Care 42, S103–S123. 
https://doi.org/10.2337/dc19-S010. 
 
• 
American Diabetes Association, 2019b. Statistics About Diabetes [WWW Document], n.d. 
URL https://www.diabetes.org/resources/statistics/statistics-about-diabetes (accessed 
8.30.19). 
 
• 
American Diabetes Association, 2019c. Introduction: Standards of Medical Care in 
Diabetes—2019. Diabetes Care 42, S1–S2. https://doi.org/10.2337/dc19-Sint01. 
 
• 
American Diabetes Association, 2019d. 9. Pharmacologic Approaches to Glycemic 
Treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care 42, S90–S102. 
https://doi.org/10.2337/dc19-S009. 
 
• 
Bhatt, D.L., Steg, P.G., Miller, M., Brinton, E.A., Jacobson, T.A., Ketchum, S.B., Doyle, R.T., 
Juliano, R.A., Jiao, L., Granowitz, C., Tardif, J.-C., Ballantyne, C.M., REDUCE-IT Investigators, 
2019. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N. 
Engl. J. Med. 380, 11–22. https://doi.org/10.1056/NEJMoa1812792 
 
• 
Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and 
guidelines of good manufacturing practice in respect of medicinal products for human use 
and investigational medicinal products for human use.  OJ L 262, 14.10.2003, p. 22–26 
 
• 
Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed 
guidelines for good clinical practice as regards investigational medicinal products for 
human use, as well as the requirements for authorisation of the manufacturing or 
importation of such products. OJ L 91, 9.4.2005, p. 13–19  
 
• 
CRL Study 509554 (2020). A 26 week study of 15(S)-HEPE EE by oral (gavage) in rats with a 
4 week recovery period. 
 
• 
CRL Study 527545 (2014). A 7 Day Dose Range Finding Study of 15 (S)-HEPE EE by Oral 
(Gavage) in Rats.  
 
• 
CRL Study 527550 (2014). A Maximum Tolerated Dose followed by a Fixed Dose Phase 
Study of 15 (S)-HEPE EE by Oral (Gavage) in Dogs. 
 
• 
CRL-527943 (2015). A 4 week study of 15(S)-HEPE EE by oral (gavage) in rats with a 2 week 
recovery period. 
 
• 
CRL-527959 (2015). A 4 week study of 15(S)-HEPE EE by oral (gavage) in dogs with a 2 
week recovery period. 
 
• 
CRL-529139 (2015). A 39 week study of 15(S)-HEPE EE by oral (gavage) in dogs with a 4 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 84 of 90 
 
week recovery period. 
 
• 
CRL-529123 (2016). A 26 week study of 15(S)-HEPE EE by oral (gavage) in rats with a 4 
week recovery period. 
 
• 
Directive 2001/20/EC of the European parliament and of the council of 4 April 2001 on 
the approximation of the laws, regulations and administrative provisions of the Member 
States relating to the implementation of good clinical practice in the conduct of clinical 
trials on medicinal products for human use. OJ L 121, 1.5.2001, p. 34 
 
• 
DS-PC-30 (2016). An efficacy study of novel therapeutics from ds biopharma in the 
treatment of bleomycin-induced pulmonary fibrosis’. 
 
• 
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). 
 
• 
FDA: Center for Drug Evaluation and Research (CDER): Draft Guidance for Industry: 
Multiple Endpoints in Clinical Trials (2017). 
 
• 
Grundy Scott M., Stone Neil J., Bailey Alison L., Beam Craig, Birtcher Kim K., Blumenthal 
Roger S., Braun Lynne T., de Ferranti Sarah, Faiella-Tommasino Joseph, Forman Daniel E., 
Goldberg Ronald, Heidenreich Paul A., Hlatky Mark A., Jones Daniel W., Lloyd-Jones 
Donald, Lopez-Pajares Nuria, Ndumele Chiadi E., Orringer Carl E., Peralta Carmen A., 
Saseen Joseph J., Smith Sidney C., Sperling Laurence, Virani Salim S., Yeboah Joseph, 2018. 
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the 
Management of Blood Cholesterol: A Report of the American College of 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 
Circulation 139, e1082–e1143. https://doi.org/10.1161/CIR.0000000000000625 
 
• 
Guideline on multiplicity issues in clinical trials, EMA/CHMP/44762/2017. 
 
• 
McAulay, V., Deary, I. J. and Frier, B. M. (2001), Symptoms of hypoglycaemia in people 
with diabetes. Diabetic Medicine, 18: 690-705.  
 
• 
SLMN063-1805-6 (2018). In Vivo Efficacy Study of DS102 in Bile Duct Ligation Model. 
 
• 
SLMC062-1805-5 (2018). In Vivo Efficacy Study of DS109 and DS102 in Unilateral Ureteral 
Obstruction induced Renal Interstitial Fibrosis. 
 
• 
SMCN013-1411-8 (2015). In Vivo Efficacy Study of 15-hetre and 15(S)-HEPE in STAM 
Model of Non-alcoholic Steatohepatitis. 
 
• 
NIH Publication No. 01–3305.The National Cholesterol education program guidelines. ATP 
III Guidelines At-A-Glance Quick Desk Reference. U.S. Department of Health and Human 
Services. 
https://www.nhlbi.nih.gov/files/docs/guidelines/atglance.pdf 
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                          
Page 85 of 90 
 
• 
The American Heart Association guidelines for blood pressure measurement 
https://www.heart.org/-/media/files/health-topics/high-blood-pressure/tylenol-
hbp/aha_toolkit_poster_final_102618.pdf?la=en&hash=99C0774B66645F9797360582E
56CEF35752737D5. 
 
• 
Toth, P.P., Granowitz, C., Hull, M., Liassou, D., Anderson, A., Philip, S. High Triglycerides 
Are Associated With Increased Cardiovascular Events, Medical Costs, and Resource Use: 
A Real‐World Administrative Claims Analysis of Statin‐Treated Patients With High Residual 
Cardiovascular Risk. J. Am. Heart Assoc. 2018; 7.  
 
• 
Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb 
C, DePalma 
SM, Gidding 
S, Jamerson 
KA, Jones 
DW, MacLaughlin 
EJ, Muntner 
P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA 
Sr, Williamson 
JD, Wright 
JT 
Jr. 
2017 
ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA 
Guideline 
for 
the 
Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A 
Report of the American College of Cardiology/American Heart Association Task Force on 
Clinical Practice Guidelines. Hypertension, 2018;71:e13–e115.  


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                           
Page 86 of 90  
 
15 
APPENDICES 
15.1 Appendix 1. Flow Chart 
 
 
Visit 
Visit 1  
Screening 1 
Visit 2  
Screening 2 
Visit 3  
Baseline 
Phone call 
Week 2 
Visit 4  
Week 4 
Visit 5  
Week 8 
Visit 6 
Week 12 
Visit 7 
Week 16 
Visit 8 
Week 20 
Visit 9 EoT 
Week 26 
Visit 10 EoS 
Week 28 
Day 
-42 
-7 
0 
14 
28 
56 
84 
112 
140 
182 
196 
Visit window 
+28 
±1 day 
0 
+/- 2 days 
+/- 2 days 
+/- 2 days 
+/- 2 days 
+/- 2 days 
+/- 2 days 
+/- 2 days 
+/- 2 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test1 
 
 
X 
 
 
 
X 
 
 
 
 
Serum pregnancy test1 
X 
 
X 
 
 
 
 
 
 
X 
 
Contraception counselling  
X 
 
X 
 
 
 
X 
 
 
X 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
 
X 
 
 
 
 
 
 
 
 
Concomitant medication assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead) 
 
 
X 
 
 
 
 
 
 
X 
 
Physical examination (incl. weight, BMI, waist 
circumference) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical examination (height) 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (incl. heart rate, blood pressure, temperature) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Counselling 
X 
 
X 
 
 
 
 
 
 
 
 
Assessment of hypoglycaemic episodes 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PK sampling (trough levels)2 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Exploratory blood sample 
 
 
X 
 
 
 
 
 
 
X 
 
Blood sampling for laboratory tests #1 (details below) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for laboratory tests #2 (details below) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for laboratory tests #3 (details below) 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for laboratory tests #4 (details below) 
 
 
X 
 
 
 
 
X 
 
X 
 
Blood sampling for laboratory tests #5 (details below) 
 
 
X 
 
 
 
 
 
 
X 
 
Urinary sampling for urinary albumin-to-creatinine ratio 
 
 
X 
 
 
 
 
 
 
X 
 
Urinalysis (dipstick) 
 
 
X 
 
 
 
 
 
 
X 
 
TSH sample 
X 
 
 
 
 
 
 
 
 
 
 
Self-monitoring of blood glucose3 
 
 
X…………………………..………………X3…………………………………………………………………………………………………………………....X 
 
Patient randomisation 
 
 
X 
 
 
 
 
 
 
 
 
IMP (Epeleuton/placebo) administration4 
 
 
X…………………………………..…… x……………………x…………………… x..…………..….……x…...……………… X 
 
 
IMP (Epeleuton/placebo) reconciliation 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
1 Female Patients of childbearing potential only 
3 SMBG is at the investigator’s discretion from visit 4/week 4  
2 Pharmacokinetics Ctrough only. Sample will be taken pre-dose 
4 To be taken with food at the same time each day  
 
Laboratory test panel #1 includes: Clinical haematology, clinical chemistry, coagulation. 
Laboratory test panel #2 includes: Triglycerides, LDL-C (calculated), HbA1c 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                           
Page 87 of 90  
 
Laboratory test panel #3 includes: VLDL-C, non-HDL-C, total cholesterol, glucose, HDL-C, RLP-C 
Laboratory test panel #4 includes: LDL-C (preparative ultracentrifugation), ApoA1, ApoB, ApoCIII, Lp(a), insulin, hsCRP, HOMA-IR, HOMA-β, nMR lipid profile 
Laboratory test panel #5 includes: IL-6, IL-1β, PAI-1, VCAM-1, ICAM-1, MCP-1, serum biomarker


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                           
Page 88 of 90  
 
15.2 Appendix 2. Table of Central Laboratory Assessments 
 
 
 
 
 
1 Including: Full blood count including red cell count, haemoglobin, haematocrit, white cell count, differential white cell count, platelet count, reticulocyte count and RDW 
2 Including: BUN, creatinine, uric acid, total bilirubin, indirect and direct bilirubin, sodium, bicarbonate potassium, phosphorus, calcium chloride, ALP, AST, ALT, AST:ALT ratio, GGT, albumin, total protein 
3 Including: PT, INR and APTT 
4 Including: pH, protein, glucose, blood, ketones, leukocytes, leukocyte esterase, bilirubin, specific gravity, urobilinogen and nitrate 
5 Including: HDL-P, small LDL-P, Large LDL-P, LDL-size, VLDL size, HDL-size
Analyte/Test 
Serum 
Plasma 
Urine 
Other 
Screening 1 
Week -6 to -2  
Screening 2  
Week -1 
Baseline 
Week 0 
Visit 4 
Week 4 
Visit 5 
Week 8 
Visit 6 
Week 12 
Visit 7  
Week 16 
Visit 8 
Week 20 
Visit 9 EoT 
Week 26 
Visit 10 
EoS 
Week 28 
Clinical haematology1  
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Serum biochemistry2  
x 
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation3  
  
  
  
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urinalysis4  
 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
Triglycerides 
x 
  
  
fasting 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
LDL-C (calculated) 
x 
  
  
fasting 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
LDL-C (preparative ultracentrifugation) 
x 
 
 
fasting 
 
 
x 
 
 
 
x 
 
x 
 
HbA1c 
  
x 
  
fasting 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
VLDL-C (calculated) 
x 
  
  
fasting 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HDL-C  
x 
  
  
fasting 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Non-HDL-C (calculated) 
x 
  
  
fasting 
x 
x 
x 
x 
x 
x  
x 
x  
x 
x 
RLP-C (calculated) 
x 
  
  
fasting 
x 
x 
x 
x 
x 
x  
x 
x  
x 
x 
Total cholesterol 
x 
  
  
fasting 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Glucose 
  
x 
  
fasting 
  
  
x 
x 
x 
x 
x 
x 
x 
x 
ApoA1  
x 
  
  
fasting 
  
  
x 
  
 
  
x 
  
x 
 
ApoB  
x 
  
  
fasting 
  
  
x 
 
x 
 
x 
 
ApoCIII  
x 
  
  
fasting 
  
  
x 
  
 
  
x 
  
x 
 
Lp(a) 
x 
  
  
fasting 
  
  
x 
  
 
  
x 
  
x 
 
Insulin 
  
x 
  
fasting 
  
  
x 
  
 
  
x 
  
x 
 
hsCRP  
x 
  
  
fasting 
  
  
x 
  
 
  
x 
  
x 
 
IL-6 
x 
  
  
fasting 
  
  
x 
  
 
  
 
  
x 
 
IL-1β 
x 
  
  
fasting 
  
  
x 
  
 
  
 
  
x 
 
PAI-1 
 
 x 
  
fasting 
  
  
x 
  
 
  
 
  
x 
 
VCAM-1 
x 
  
  
fasting 
  
  
x 
  
 
  
 
  
x 
 
ICAM-1 
x 
  
  
fasting 
  
  
x 
  
 
  
 
  
x 
 
MCP-1 (CCL2) 
x 
  
  
fasting 
  
  
x 
  
 
  
 
  
x 
 
HOMA-IR (calculated) 
 
x 
  
fasting 
  
  
x 
  
 
  
x 
  
x 
 
HOMA-β (calculated) 
 
x 
  
fasting 
  
  
x 
  
 
  
x 
  
x 
 
nMR lipid profile5 
x  
  
fasting 
  
  
x 
  
  
  
x 
  
x 
 
Urinary albumin-to-creatinine ratio 
 
 
x 
 
 
 
x 
 
 
 
 
 
x 
 
Trough 15-HEPE (15-hydoxy-eicasopentaenoic acid) 
  
x 
  
fasting 
  
  
x 
x 
x 
  
x 
  
x 
 
Trough EPA  
  
x 
  
fasting 
  
  
x 
x 
x 
  
x 
  
x 
 
Serum biomarker sample 
x 
  
  
fasting 
  
  
x 
  
  
  
  
  
x 
 
TSH  
x 
  
  
fasting 
x 
  
  
  
  
  
  
  
  
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                              
Page 89 of 90  
 
15.3 Appendix 3: Hypoglycaemic Episode Form 
 
 
Please record the following information regarding the 
hypoglycaemic episode: 
 
Answer 
Start date and time of the hypoglycaemic episode. 
 
Self-measured plasma glucose values  
 
Stop date and time of the hypoglycaemic episode 
(stop time is the first time the plasma glucose value is > 3.9 mmol/L 
(70 mg/dL) and/or symptoms have been resolved)1 
 
The plasma glucose level before treating the episode (if available) and 
any follow up measurements.  
 
Was the episode symptomatic? (Yes/No) 2 
 
Date, time and dose of last study drug administration and other anti-
diabetic treatments prior to the episode. 
 
Date and time of last main meal (not including snacks) prior to the 
episode. 
 
Did the episode occurred in relation to physical activity? 
 
Please report changes in any concomitant illness and any sign of fever 
or other acute disease 
 
Were you asleep when the episode occurred? 
 
Were you able to treat your-self alone (Yes/No)? 
If the answer is NO answer following questions3: 
The following questions should be completed at the study site by the 
investigator. 
 
a) Who assisted in the treatment of the hypoglycaemic episode 
(i.e. medical person or non-medical person) 
b) Where the treatment was administered (in clinic/emergency 
room/ hospital or other). If in clinic/ emergency room/ 
hospital, was the patient transported in ambulance? 
c) 
Type of treatment provided by other person (i.e. oral 
carbohydrates, glucagon, IV glucose or other) 
d) Were symptoms alleviated after administration of 
treatment? 
e) Did the patient experience a seizure? 
f) 
Was the patient unconscious/comatose? 
g) Did the patient experience any of the following symptoms: 
• 
Autonomic: sweating, trembling, hunger or palpitations 
(rapid or irregular heart beat) 
• 
Neuroglycopenic: confusion, drowsiness, speech difficulty, 
visual disturbances, odd behaviour, impaired balance or 
incoordination (reduced ability to coordinate movement) 
• 
General malaise: headache or malaise (feeling 
discomfort/unease) 
• 
Other symptoms? 
 
 
 
 
 
 
 
 
1 If a stop date and time is not reported a hypoglycaemic episode will cover a period of 60 minutes. 
2 A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the patient experiences symptoms later 
during the episode.  
3 The answer should be NO, if during the episode the patient needed assistance of another person to administer carbohydrate, 
glucagon or take other corrective actions. Oral carbohydrates should not be given if the patient is unconscious.  
 


Confidential/Clinical Study Protocol No. DS102A-07-CV1 Version 5.0 
                              
Page 90 of 90  
 
15.4 Appendix 4: COVID-19 Contingency Investigator Assessment Phone Visits 
 
 
Only to be used if a patient is unable to attend the Investigational Site due to COVID-19. Every effort 
should be made to complete the Study Visit at the Investigational Site.  
 
Please conduct all of the following: 
 
• 
Phone call to be completed by PI/Sub-Investigator  
• 
Please complete all assessments as listed in the flowchart below 
• 
Please document Phone Visit in Source Notes 
• 
Data to be entered into eCRF 
 
 
 
Visit 
Visit 4  
Week 4 
Visit 5  
Week 8 
Visit 6 
Week 12 
Visit 7 
Week 16 
Visit 8 
Week 20 
Visit 10 
EoS 
Week 28 
Day 
28 
56 
84 
112 
140 
196 
Visit window 
+/- 2 days 
+/- 2 days +/- 2 days 
+/- 2 days 
+/- 2 days +/- 2 days 
AE assessment 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Discuss hypoglycaemic episodes 
X 
X 
X 
X 
X 
X 
Discuss IMP compliance and 
diary compliance 
X 
X 
X 
X 
X 
 
Courier Study Drug 
X 
X 
X 
X 
X 
 
 

SAP_001.pdf: 
CONTRACT RESEARCH  
ORGANIZATION: 
SPONSOR: 
AMS Advanced Medical Services GmbH 
Afimmune Ltd. 
Am Exerzierplatz 2 
Trintech Building, South County Business Park, 
Leopardstown 
D-68167 Mannheim 
Dublin 18, Republic of Ireland. 
Phone: +49 (0)621 / 70095 100 
 
Fax:     +49 (0)621 / 70095 140 
 
 
Statistical Analysis Plan 
for Clinical Trial Protocol DS102A-07-CV1 
Study Title 
A Randomised, Double-Blind, Placebo-Controlled, Dose Finding 
Phase IIb Study to Assess the Efficacy and Safety of Orally 
Administered Epeleuton in Patients with Hypertriglyceridemia 
and Type 2 Diabetes. 
Test product 
Epeleuton 2g and Epeleuton 4g 
Type of Study 
Randomised, double-blind, placebo controlled, 3-arm, multi-
centre Phase IIb study 
Objectives of Study 
To assess the efficacy and safety of orally administered Epeleuton 
capsules versus placebo, in the treatment of adult patients with 
hypertriglyceridemia and type 2 diabetes. 
Sponsor Study No.  
DS102A-07-CV1 
EudraCT-No.: 
2020-000065-16 
SAP Author  
 
Responsible 
Biostatistician 
Sandra Roldan 
AMS Advanced Medical Services GmbH 
 
Florian Schelz 
AMS Advanced Medical Services GmbH 
 
Date 
June 09, 2022 
Status of Document 
Final Version 2.0 
Pages 
38 
 
 
CONFIDENTIAL 
 
 
 




Maud Hennion 
(Signature)
Digitally signed by Maud Hennion 
(Signature) 
Date: 2022.06.14 08:34:49 +02'00'




Afimmune Ltd.
AMS Advanced Medical Services GmbH
Statistical Analysis Plan DS 1024-07-CV1
Version history
I have thoroughly read and reviewed the Statistical Analysis Plan for the above
mentioned study and approve its content:
Sponsor Signature(s)
Version
Date
Author
Description of chanses
0.3
May 27,2020
Frank Scherer
Third Draft Version
0.4
November 23,2021
Florian Schelz
Fourth Draft Version
0.5
March L1,2022
Florian Schelz
Fifth Draft Version according to protocol
version 5.0
1.0
Mav 03.2022
Florian Schelz
Final Version
2.0
June09,2022
Sandra Roldan
Final Version
Markus Weissbach
(Chief Medical Officer, Afimmune)
Date
Maud Hennion
(Statistical Consultant, Pharmalex)
AMS Signature(s)
Date
Sandra Roldan, Biostatistician
(SAP Author)
Date
4,*LJU;
tt|/^:tltw
Frank Scherer, Director Biostatistics
(SAP Reviewer)
Date
Final Version 2.0, June 09,2022
Page 2 of38


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 3 of 38 
Contents 
List of Abbreviations and Definition of Terms 
5 
1 
Introduction 
8 
1.1 
Study Objectives 
8 
1.2 
General Study Design 
8 
1.3 
Study Population 
9 
1.4 
Study Medication 
9 
1.5 
Randomisation and Unblinding 
10 
1.5.1 
Emergency unblinding 
10 
1.5.2 
Unblinding for studies conducted in the EU 
11 
1.5.3 
Unblinding for studies conducted in the US 
11 
1.6 
Interim Analysis 
11 
1.7 
Time Schedule / Study Duration 
11 
2 
Sample Size 
15 
3 
Analysis Populations 
15 
4 
Blind Data Review Meeting 
15 
5 
Data Handling 
17 
5.1 
General 
17 
5.1.1 
Data sources 
17 
5.1.2 
Coding 
17 
5.1.3 
Visits 
17 
5.1.4 
Baseline value 
17 
5.1.5 
Units for laboratory tests 
18 
5.2 
Handling of missing values 
18 
5.2.1 
Handling of missing dates 
18 
5.3 
Algorithms for data calculations and modifications 
18 
5.3.1 
Study Day 
18 
5.3.2 
Age 
18 
5.3.3 
Time since diagnosis 
18 
5.3.4 
BMI 
19 
5.3.5 
Treatment duration 
19 
5.3.6 
Previous vs. concomitant medication 
19 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 4 of 38 
6 
General Methodology 
19 
6.1 
Primary Endpoint Evaluation 
19 
6.2 
Descriptive Analyses, Exploratory Tests 
20 
6.3 
Subgroup analyses 
20 
7 
Final analysis 
21 
7.1 
Demographic and other baseline data 
21 
7.2 
Efficacy - Primary Endpoint Evaluation  
21 
7.3 
Efficacy - Secondary Endpoints Evaluation 
21 
7.4 
Exploratory Endpoints 
22 
7.5 
Safety Evaluation 
24 
7.5.1 
Adverse Events 
24 
7.5.2 
Hypoglycaemia assessment 
25 
7.5.3 
Self-monitoring of blood glucose (SMBG) 
26 
7.5.4 
Vital signs 
26 
7.5.5 
ECG 
26 
7.5.6 
Physical Examination 
26 
7.5.7 
Safety Laboratory data 
27 
7.5.8 
Urinalysis 
27 
7.5.9 
Further safety endpoints 
27 
7.6 
Further Analyses 
28 
7.6.1 
Previous and concomitant medication 
28 
7.6.2 
Study medication 
28 
7.6.3 
Patients’ study termination status 
28 
7.6.4 
Study duration and analysis sets 
28 
7.6.5 
Protocol deviations 
29 
7.6.6 
Pharmacokinetic sampling 
29 
8 
Tables, Figures and Listings 
30 
9 
References 
38 
 
 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 5 of 38 
List of Abbreviations and Definition of Terms  
15(S)-HEPE 
15-Hydroxy-Eicosapentaenoic Acid 
15(S)-HEPE EE 
15-Hydroxy-Eicosapentaenoic Acid Ethyl Ester, Epeleuton 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase  
ALT 
Alanine transaminase 
AMS 
Advanced Medical Services GmbH (CRO) 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
ApoCIII 
Apolipoprotein CIII 
APTT 
Activated Partial Prothrombin Time 
AST 
Aspartate transaminase 
BDRM 
Blind Data Review Meeting 
BUN 
Blood Urea Nitrogen  
CRO 
Clinical Research Organisation 
ECG 
Electrocardiography 
eCRF 
electronic Case Report Form 
EPA 
Eicosapentanoic Acid 
ES 
Enrolled Set 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GGT 
Gamma-Glutamyl Transferase 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
IND 
Investigational new drug 
IWRS 
Interactive Web Response System 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 6 of 38 
HDL-C 
High Density Lipoprotein Cholesterol 
HDL-P 
High Density Lipoprotein Particle Concentration 
HOMA-β 
Homeostatic Model Assessment of β-cell Function 
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
hsCRP 
High-Sensitivity C-Reactive Protein 
ICAM-1 
Intercellular Adhesion Molecule 1 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IL- 
Interleukin- 
IMP 
Investigational Medicinal Product 
INR 
International Normalised Ratio  
LDL-C 
Low-Density Lipoprotein Cholesterol 
LDL-P 
Low-Density Lipoprotein Particle Concentration 
LOCF 
Last observation carried forward 
Lp(a) 
Lipoprotein (a) 
MCP-1 
Monocyte Chemoattractant Protein 1 
MedDRA 
Medical dictionary for Drug Regulatory Affairs 
nMR 
Nuclear Magnetic Resonance 
non-HDL-C 
Non-High-Density Lipoprotein Cholesterol 
PAI-1 
Plasminogen Activator Inhibitor 1 
PPS 
Per-Protocol Set 
PT 
Prothrombin Time 
RDW 
Red Cell Distribution Width 
RLP-C 
remnant lipoprotein cholesterol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 7 of 38 
SAS 
Safety Analysis Set 
SDV 
Source data verification 
SMBG 
Self-monitoring of Blood Glucose 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TSH 
Thyroid Stimulating Hormone 
UACR 
Urinary Albumin-to-Creatinine Ratio 
V 
Visit 
VCAM-1 
Vascular Cell Adhesion Molecule 1 
VLDL 
Very Low-Density Lipoprotein 
VLDL-C 
Very Low-Density Lipoprotein Cholesterol 
WHO 
World Health Organisation 
 
 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 8 of 38 
1 Introduction 
This Statistical Analysis Plan (SAP) refers to trial protocol DS102A-07-CV1, version 5.0 dated 
February 14, 2022. The SAP will be finalised before any analysis will be conducted. The 
specifications included in this SAP provide more detail to the analysis descriptions in the study 
protocol and are focussed to statistical methodologies. 
Additions or changes to the analysis planned in this SAP may be defined during the BDRM 
(Blind Data Review Meeting) and documented in the BDRM minutes which will be approved 
by the BDRM participants prior to database hard lock and unblinding. 
The document is written in compliance with ICH Guideline E9 and AMS SOP ST-02.01 
(Statistical Analysis Plan). 
 
1.1 Study Objectives 
Efficacy Objective: 
· To assess the efficacy of orally administered Epeleuton capsules versus placebo, in the 
treatment of adult patients with hypertriglyceridemia and type 2 diabetes. 
Safety Objective: 
· To assess the safety of orally administered Epeleuton capsules versus placebo, in the 
treatment of adult patients with hypertriglyceridemia and type 2 diabetes. 
 
The efficacy assessments in this study consist of laboratory tests to assess the status of the 
underlying hypertriglyceridemia and type 2 diabetes and additional cardiovascular risk factors, 
as well as body weight, waist circumference and blood pressure. 
For details on primary/secondary efficacy endpoints and safety endpoints see section 7. 
 
1.2 General Study Design 
This is a randomised, double-blind, placebo controlled, 3-arm, multi-centre Phase IIb study 
consisting of 26 weeks of active treatment and a 2-week post-treatment follow up period in 
adult patients with hypertriglyceridemia and concomitant type 2 diabetes. It is planned to 
perform this study in Germany, Switzerland, Latvia, Israel, US, UK and Georgia. 
The proposed study aims to investigate the triglyceride lowering, antihyperglycemic, 
triglyceride lowering and anti-inflammatory effects of Epeleuton as surrogate markers of its 
potential to improve diabetic control and cardiovascular outcomes. Lipid qualification 
eligibility criteria include a fasting triglyceride level ≥200 mg/dL (2.26 mmol/L) and 
<750mg/dL (8.46 mmol/L) (inclusion #3) and LDL cholesterol <130mg/dL (3.34 mmol/L) 
(inclusion #6). 
Blood samples will be analysed at the central laboratory to determine concentrations of the 
efficacy laboratory parameters. All patients must be fasted for a minimum of eight hours prior 
to blood sampling. If patients have not fasted for a minimum of eight hours, the duration of 
fasting should be recorded, and patients encouraged to fast appropriately for the next clinical 
visit. Safety laboratory parameters will be analysed at the central laboratory as well. 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 9 of 38 
In a Phase IIa trial in patients with non-alcoholic fatty liver disease, Epeleuton produced 
significant decreases of triglycerides, total cholesterol and multiple atherogenic lipids without 
raising LDL cholesterol. Notably, decreases were greater in the higher dose group; and greater 
at both 1g and 2g daily doses in sub-groups with elevated triglycerides at baseline, suggesting 
that further decreases may be seen in prospectively designed studies in patients with 
hypertriglyceridemia and at a higher daily dose. 
Additionally, Epeleuton significantly decreased HbA1c. Notably, at week 16 (end-of-
treatment) HbA1C was decreased by >1.0% in sub-groups with elevated HbA1C at baseline, at 
least comparable to most common antihyperglycemic agents after 26 to 52 weeks treatment. 
Additionally, HbA1C lowering was dose-dependent with no evidence of a plateau in treatment 
at week 16 suggesting that further decreases may be observed at a higher dose and over a longer 
treatment duration. Similar, dose-dependent decreases were observed for fasting plasma 
glucose, insulin resistance indices and markers of inflammation and endothelial dysfunction. 
 
1.3 Study Population 
The study population will consist of male and female patients diagnosed with 
hypertriglyceridemia and type 2 diabetes, aged 18 years and over. For a detailed list of the 
inclusion/exclusion criteria please refer to study protocol sections 7.2 and 7.3. 
Approximately 240 male or female patients, i.e. 80 patients per treatment group will be 
randomised. 
Patients who are withdrawn from the study due to an AE or lack of efficacy will not be replaced. 
Patients who do not meet the eligibility criteria or are withdrawn due to loss to follow up may 
be replaced. 
 
1.4 Study Medication 
The study treatment is capsules of Epeleuton (15(S)-HEPE EE) or placebo. Epeleuton and 
placebo will be provided by Afimmune. Epeleuton and corresponding placebo are provided as 
green hard-shelled capsules. 
A patient kit contains four wallets (two “Morning” and two “Evening” walleted blister packs) 
is sufficient for two weeks dosing. Each wallet holding 4 capsules for each of seven days (cf. 
Figure 6 in study protocol section 10.3). 
At the baseline visit, the first dose of IMP (Epeleuton or placebo) will be administered at site 
only after all baseline assessments have been completed. The patient will take their second dose 
of IMP in the evening of the day of the baseline visit (visit #3). Patients will be instructed how 
to store study medication (in the fridge) and to continue taking the capsules twice daily, 
throughout the 26 weeks study treatment period, starting with the next day. Patients will also 
be instructed to take medication with food, or within 30 minutes after a meal. 
Patients will attend the study visits fasting but will receive their morning IMP dose (Epeleuton 
or placebo) at site after blood samples have been collected. 
Each administration of IMP will be recorded by the patient in their eDiary or on a paper diary 
card which is then transcribed during the next site visit into the eDiary system by the 
Investigator or designee. 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 10 of 38 
At Visit 4 and subsequent visits, patients will return their used IMP (Epeleuton or placebo) and 
further IMP will be supplied to the patient. The patient should take their next dose of IMP as 
soon as all visit assessments have been completed, with food or within 30 minutes after a meal. 
The IMP will continue to be taken twice- daily. 
From Visit 9 on, further IMP will not be supplied to the patient. 
Patients will receive standard of care therapy in addition to their assigned IMP throughout the 
treatment period of the study. 
 
1.5 Randomisation and Unblinding 
A randomisation list permuted by blocks and stratified by site will be generated by the Sponsor 
or its designee. The randomisation schedule with study drug assignments will be generated prior 
to the start of the study and will be known only to the individuals responsible for labelling the 
study drug, the statisticians generating the schedule and the IWRS team responsible for 
implementing the schedule. The IWRS will assign a medication kit number to each patient and 
the contents will be based on the randomisation code. 
Patients will be randomised (1:1:1) at the baseline visit into the following treatment groups 
according to a computer-generated randomisation plan: 
· Treatment Group A (placebo): four placebo capsules orally administered twice a day, 
i.e. eight capsules daily for 26 weeks. 
· Treatment Group B (Epeleuton 2g): two Epeleuton 500mg capsules and two placebo 
capsules orally administered twice a day, i.e. eight capsules daily for 26 weeks. 
· Treatment Group C (Epeleuton 4g): four Epeleuton 500mg capsules orally administered 
twice a day, i.e. eight capsules daily for 26 weeks. 
To maintain the double-blind conditions, the Epeleuton capsules and placebo capsules will be 
identical in appearance. 
All study site personnel, as well as the personnel involved in the monitoring or conduct of the 
study, will be blinded to the individual patient treatment assignments. Randomisation details 
will be kept strictly confidential, accessible only in an emergency to authorised persons, until 
the time of formal unblinding. The blinded code for the trial will be broken only after all patient 
data has been recorded and verified and the database locked. 
 
1.5.1 Emergency unblinding 
The study medication blind shall not be broken by the Investigator unless information 
concerning the study medication is necessary for the medical treatment of the subject. The date, 
time, and reason the blind was broken must be recorded in the source documents and on the 
appropriate eCRF. 
If the unblinding is performed by the Investigator due to a medical requirement, the patient will 
discontinue trial participation. 
Emergency unblinding will be performed via the IWRS, with relevant site personnel and 
pharmacovigilance monitors provided with the required system access to carry out unblinding. 
The rest of the study team will be kept blinded regarding treatment assignment. 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 11 of 38 
1.5.2 Unblinding for studies conducted in the EU 
If applicable and required, treatment codes will be unblinded prior to submission to authorities 
and concerned ECs, by the Sponsor’s safety group, which is an independent entity within the 
Sponsor or by the pharmacovigilance CRO. 
The Sponsor will also inform all Investigators in a blinded fashion (EU only), unless otherwise 
required by local regulations. Reporting obligations to the local EC of the Investigator will be 
fulfilled by the Investigator, unless otherwise specified. 
 
1.5.3 Unblinding for studies conducted in the US 
The blind will be broken for investigational new drug (IND) safety reports submitted to FDA 
and all participating Investigators. 
 
1.6  Interim Analysis 
An interim analysis may be conducted after at least 50% of planned enrolled patients have 
completed their Week 16 assessments or an early termination visit. The interim analysis will be 
conducted in accordance with sponsor standard operating procedure (SOP) “Interim Analysis 
of Clinical Studies”. 
An unblinded interim analysis will be performed by an unblinded independent statistician. 
Interim data and the results of interim analyses will not be accessible by anyone other than the 
unblinded statistician and an Independent Data Monitoring Committee (IDMC).  
The sponsor trial team will remain blinded with procedures in place to ensure the confidentiality 
of the interim data in accordance with sponsor SOP “Interim Analysis of Clinical Studies”. 
The IDMC will make one of the following recommendations to the sponsor based upon the 
primary efficacy endpoints: 
· Increase the sample size to a defined number 
· Continue the study as originally planned 
· Stop the study due to futility 
The IDMC may also make further recommendations to the sponsor including changes to study 
design and conduct. Further interim analyses may be conducted if recommended by the IDMC. 
Further details will be described in an interim statistical analysis plan. 
 
1.7 Time Schedule / Study Duration 
During the study, 10 visits to the clinic are scheduled: two Screening Visits (Visit 1 and Visit 
2), one visit at the start of the comparative treatment period (Baseline/Visit 3), six visits in the 
comparative treatment period (Visit 4/Week 4, Visit 5/Week 8, Visit 6/Week 12, Visit 7/Week 
16, Visit 8/Week 20 and Visit 9/Week 26 or Early Termination) and one final safety follow-up 
visit (Visit 10/Week 28). 
The screening period will consist of up to 6-weeks lead-in during which all patients will 
undergo diet and lifestyle stabilisation, washout of disallowed medications and optimisation of 
statins. 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 12 of 38 
Patients who meet the inclusion criteria at both screening visits will be eligible to participate in 
the study. Eligible patients will be randomised at the baseline visit. 
Patients who discontinue the study early before Week 26, for whatever reason, will be asked to 
attend the investigative site as soon as possible so that assessments scheduled for the early 
termination visit (Visit 9) will be performed.  
The flowchart below details the timing of assessments up to Visit V10.  


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 13 of 38 
Flow chart 
Visit 
Visit 1 
Screening 1 
Visit 2 
Screening 2 
Visit 3 
Baseline 
Phone call 
Week 2 
Visit 4 
Week 4 
Visit 5 
Week 8 
Visit 6 
Week 12 
Visit 7 
Week 16 
Visit 8 
Week 20 
Visit 9 EoT 
Week 26 
Visit 10 EoS 
Week 28 
Day 
-42 
-7 
0 
14 
28 
56 
84 
112 
140 
182 
196 
Visit window 
+28 
±1 day 
0 
+/- 2 days +/- 2 days +/- 2 days 
+/- 2 days +/- 2 days +/- 2 days +/- 2 days 
+/- 2 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test1 
 
 
X 
 
 
 
X 
 
 
 
 
Serum pregnancy test1 
X 
 
X 
 
 
 
 
 
 
X 
 
Contraception counselling 
X 
 
X 
 
 
 
X 
 
 
X 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
 
X 
 
 
 
 
 
 
 
 
Concomitant medication assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead) 
 
 
X 
 
 
 
 
 
 
X 
 
Physical examination (incl. weight, BMI, waist 
circumference) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical examination (height) 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs (incl. heart rate, blood pressure, 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Counselling 
X 
 
X 
 
 
 
 
 
 
 
 
Assessment of symptomatic hypoglycaemic episodes 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma PK sampling (trough levels)2 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Exploratory blood sample 
 
 
X 
 
 
 
 
 
 
 
 
Blood sampling for laboratory tests #1 (details below) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for laboratory tests #2 (details below) 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for laboratory tests #3 (details below) 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Blood sampling for laboratory tests #4 (details below) 
 
 
X 
 
 
 
 
X 
 
X 
 
Blood sampling for laboratory tests #5 (details below) 
 
 
X 
 
 
 
 
 
 
X 
 
Urinary sampling for urinary albumin-to-creatinine ratio 
 
 
X 
 
 
 
 
 
 
X 
 
Urinalysis (dipstick) 
 
 
X 
 
 
 
 
 
 
X 
 
TSH sample 
X 
 
 
 
 
 
 
 
 
 
 
Self-monitoring of blood glucose3 
 
 
X………………………X3………………………………………………………………….X 
 
Patient randomisation 
 
 
X 
 
 
 
 
 
 
 
 
IMP (Epeleuton/placebo) administration4 
 
 
 
X 
 
IMP (Epeleuton/placebo) reconciliation 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
1 Female Patients of childbearing potential only 
2 Pharmacokinetics Ctrough only. Sample will be taken pre-dose  
3 SMBG is at the investigator’s discretion from visit 4/week 4  
4 To be taken with food at the same time each day 
 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 14 of 38 
Laboratory test panel #1: Clinical haematology, clinical chemistry, coagulation. 
Laboratory test panel #2: Triglycerides, LDL-C (calculated), HbA1c 
Laboratory test panel #3: VLDL-C, non-HDL-C, total cholesterol, glucose, HDL-C, RLP-C 
Laboratory test panel #4: LDL-C (preparative ultracentrifugation), ApoA1, ApoB, ApoCIII, Lp(a), insulin, hsCRP, HOMA-IR, HOMA-β, nMR lipid profile 
Laboratory test panel #5: IL-6, IL-1β, PAI-1, VCAM-1, ICAM-1, MCP-1, serum biomarker 
 
 
For a full list of the laboratory tests to be performed please refer to Appendix 2. “Table of Central Laboratory Assessments” in the study protocol. 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 15 of 38 
2 Sample Size 
The primary efficacy endpoints are the percent change in triglycerides from baseline to week 16 
and the change in HbA1c from baseline to week 26, which will be analysed separately. For details 
how the familywise error rate is preserved see section 6.1. 
The sample size was estimated based on results of a post hoc analysis of triglycerides and HbA1C 
from a Phase IIa trial of Epeleuton in patients with non-alcoholic fatty liver disease. Changes in 
triglycerides and HbA1C at the highest tested dose (2g/day) at week 16 (end-of-treatment) were 
used to estimate relative effect sizes (Cohen’s D). Cohen’s D or the standardised relative effect 
size is the difference between the group means divided by the pooled standard deviation. 
· To discover a conservative relative effect size (Cohen’s d) between Epeleuton and placebo 
of 0.6 in triglyceride change from baseline with 80% power, 45 patients per group are 
necessary under ideal assumptions using the t-test for independent samples (alpha=0.05, 
two-sided). 
· To discover a conservative relative effect size (Cohen’s d) between Epeleuton and placebo 
of 0.48 in HbA1C change from baseline with 80% power, 70 patients per group are 
necessary under ideal assumptions using the t-test for independent samples (alpha=0.05, 
two-sided). 
To power the study for both primary endpoints and take deviations from ideal parametric 
conditions and drop-outs into account, randomisation of 80 patients per group is recommended. 
 
3 
 Analysis Populations 
The following population will be defined: 
1. Enrolled Set (ES): All patients who provided informed consent will be included in the ES. 
2. Full Analysis Set (FAS): Patients will be included in the FAS, a modified intention-to-treat 
population, if they are randomised to the study, received at least one dose of study 
medication and have at least one post-baseline measurement. Analysis will be done 
according to treatment as randomised. 
3. Safety Analysis Set (SAS): The SAS consists of all patients who received at least one dose 
of the study medication. SAS is the analysis population for all safety endpoints. Analysis 
will be done according to the actual treatment patients received. 
4. Per Protocol Set (PPS): In order to qualify for the PPS, the patients must have followed the 
study protocol without any major protocol violations. Protocol violations will be assessed 
for each patient in a blinded fashion prior to database lock at a Blind Data Review Meeting 
(BDRM), and the PPS will also be finalised during this meeting. PPS is a supportive 
analysis population for the primary efficacy endpoint. Analysis will be done according to 
the treatment that patients were randomised to. 
 
4 Blind Data Review Meeting 
During the study conduct, protocol deviations will be captured through site self-reporting, source 
data verification (SDV) and data management edit checks, and will be recorded throughout the 
study in monitoring visit reports and in the eCRF. 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 16 of 38 
A BDRM will be held prior to database hard lock/unblinding where AMS and Sponsor 
representatives will assess protocol deviations as major or minor with regard to their influence on 
any of the efficacy variables. 
The AMS biostatistician will prepare blinded data review listings. Deviations not apparent in the 
clinical database (e.g. findings during monitoring of the investigational site) will be contributed 
by the clinical project leader. Additionally, data management may provide information to the 
discussions. 
The following criteria might be considered as major protocol violations: 
(1) Violation of inclusion or exclusion criteria 
(2) Assignment to incorrect treatment (i.e. actual treatment taken differs from the randomised 
treatment scheduled) 
(3) Non-adherence to the treatment schedule indicating insufficient treatment compliance  
(4) Intake of prohibited concomitant therapies (medication for diabetes or obesity except for 
metformin, sulfonylureas, DPP-4 inhibitors, SGLT2 inhibitors and short-term insulin 
treatment for acute illness / Fibrates, PCSK9 inhibitors, bile acid sequestrants, niacin, 
niacin analogues or dietary supplements for the purpose of lowering cholesterol / food 
supplements rich in omega-3 or omega-6 fatty acids) 
 
Listings for the criteria mentioned above and further listings relating to the following topics will 
be prepared for the discussion in the review meeting: 
· Identification of patients randomised but not treated 
· Eligibility of diary data including checks on the availability of diaries (especially regarding 
primary endpoint) 
· Patients without efficacy data 
· Patients where blind was broken prior to formal unblinding of the study 
· Procedural deviations at the trial sites which are not reflected in the clinical database 
· Premature patient discontinuations (reason and timing). 
· Visit window deviations 
· Further aspects deemed of interest 
Further outputs may be prepared for data exploration purposes, e.g. to check distribution 
assumptions, to check for outliers. 
 
The decision of findings being major or minor protocol deviations will be taken during the BDRM. 
The patients allocated to the PPS and the reasons for exclusion of patients from the PPS will be 
documented prior to database hard lock and unblinding.  
Full details on the reviews performed and the decisions made in the BDRM will be documented 
in writing in the BDRM protocol and will be approved by signature of the attendees. The decisions 
in the BDRM protocol may potentially amend/ overrule methodology/ analysis set definitions 
planned in this SAP. The BDRM protocol will be handled as an addendum to the SAP. 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 17 of 38 
5 Data Handling 
5.1 General 
5.1.1 Data sources 
Data will be collected using a validated, FDA CFR 21 Part 11compliant, electronic data capture 
(EDC) solution. eCRFs will be utilised for recording data from each patient meeting the eligibility 
criteria and being randomised in the study, and a limited amount of data will be completed for 
patients who fail to meet eligibility criteria (i.e. screen failures).  
Captured data will be monitored electronically and SDV will take place at the site, where 
information will be verified against the individual patient records. Details will be specified in a 
data validation plan, respectively monitoring plan. 
Any inconsistencies will be presented as queries, either as automatically generated queries, if 
raised by the logical data checks of the eCRF system, or by manually generated queries if raised 
by the data validation checks or the SDV performed by the data manager (DM) or the clinical 
research associate (CRA), respectively 
SAEs will be reported to the pharmacovigilance contract research organisation (spm²). Prior to 
data base lock an SAE reconciliation between the pharmacovigilance database and the clinical 
database will be performed. 
The biostatistical analysis will be based on the information recorded in the clinical database. 
 
5.1.2 Coding 
The process of coding will be performed according to the data management CRO standard 
operating procedures and will comply with applicable regulatory coding guidelines (e.g. 
‘MedDRA Points to consider’ / ‘Best Practices for the use of the WHO Drug Dictionaries’). 
Adverse events and medical history terms will be coded to system organ class and preferred terms 
using the current version of the Medical Dictionary for Regulatory Activities (MedDRA).  
The current version of the WHO Drug Dictionary (WHO-DD) Global version B3 dictionary will 
be used for the coding of concomitant medications. Coding will be performed indication-specific, 
such that each medication is assigned the ATC code corresponding to its reason for administration. 
 
5.1.3 Visits 
In the analysis, visits and points in time will be presented under the visit number as documented 
in the database. 
 
5.1.4 Baseline value 
For analysis of triglycerides, baseline will be defined as the mean of the Baseline (Visit 3) and 
Screening 2/Week -1 (Visit 2) measurements. 
For other parameters, the last non-missing value prior to first treatment will be referred to as 
baseline value and will be used for change from baseline calculations. Thus, depending on data 
availability, the baseline value could be a pre-dose value from Visit 3 (Baseline), a value from 
Visit 2 (Screening 2) or from Visit 1 (Screening 1). 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 18 of 38 
5.1.5 Units for laboratory tests 
All blood samples will be analysed at the central laboratory. In the biostatistical analysis, the 
laboratory tests will be displayed in the unit defined by the central laboratory. 
 
5.2 Handling of missing values 
Imputation of missing values will be performed for primary efficacy endpoints and secondary 
efficacy endpoints: A multiple imputation (MI) approach will be applied that uses the baseline 
value and all post-baseline values for a specific variable (e.g. triglycerides) as well as the treatment 
group. 
For the primary endpoints, a last observation carried forward (LOCF) missing data handling 
approach will be conducted as an alternative imputation approach. 
For exploratory endpoints, a last observation carried forward missing data handling approach will 
be conducted. 
Where mentioned there also will be a complete-case analysis, i.e. a data presentation without 
imputation. 
 
5.2.1 Handling of missing dates 
Where a complete date is required for calculations but an incomplete date is documented only, the 
following rules will be applied: 
If only the day is not known completely, for onset dates or start dates missing day information will 
be assumed as the 1st. If both day and month are missing, the 1st January will be used. For stop 
dates missing day information will be imputed as the last of the month, if both day and month are 
missing, the 31st December will be used. 
However, if for adverse events it is not clear whether the event started prior to or in the treatment 
period, the onset at day of first treatment will be assumed. 
Handling of incomplete stop dates for concomitant medications is described in section 5.3.6. 
 
5.3 Algorithms for data calculations and modifications 
5.3.1 Study Day 
Consistent with the study flowchart, the Study Day of an assessment or event will be defined as 
Study Day = Date of Assessment - Date of first treatment 
For patients without treatment, study day will not be calculated. 
 
5.3.2 Age 
The age of patients at screening as documented in the eCRF will be analysed.  
 
5.3.3 Time since diagnosis 
The time since diagnosis of diabetes will be given in months and will be rounded to one decimal. 
Further analyses will use the rounded value. Time since diagnosis will be calculated as: 
Time since diagnosis = (date of informed consent – date of diagnosis)/(365.25/12) 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 19 of 38 
If the date of diagnosis is incomplete it will be imputed assuming the first of the month or the first 
of January (cf. section 5.2.1). 
 
5.3.4 BMI 
If the Body Mass Index (BMI) is missing (e.g. weight not collected at a specific visit). BMI will 
be defined as weight [kg] / (height [cm]/100)2 using a patient’s last preceding non-missing weight 
value. 
 
5.3.5 Treatment duration 
The treatment duration of study medication [days] will be calculated as date of last dose 
administration minus the date of first dose (i.e. usually the baseline visit date Visit 3) plus one.  
 
5.3.6 Previous vs. concomitant medication 
Previous medications are those medications on the concomitant medication page that were stopped 
before the date of first study treatment of the patient. Concomitant medications are all other 
medications. In case of doubt (due to incomplete stop date) a medication will be assumed to be 
taken concomitantly. 
For concomitant medication, if for indication “primary diagnosis” is ticked, the coding on the 
TSG-level will be used to decide, if it is a medication for Type II Diabetes or for 
Hypertriglyceridemia. It will be filtered for TSG= A10 Drugs used in diabetes and TSG= C10- 
Lipid modifying agents. 
 
6 General Methodology 
All analyses will be performed using SAS Version 9.1.3 or higher. 
If not mentioned otherwise significance tests and confidence intervals will be two-sided using a 
Type I error rate of 0.05 / a confidence level of 95%. A two-sided p-value less than 0.05 is 
considered statistically significant for all comparisons. 
If not mentioned otherwise, analyses will be stratified by treatment group displaying the following 
treatment groups (in this ordering): Epeleuton 4g, Epeleuton 2g, Epeleuton Total (where 
mentioned), Placebo, Total. Therefore treatment will not be mentioned explicitly as stratification 
variable usually. 
At the investigational site, each patient will be assigned a patient identifier number during 
screening that will be used on all patient documentation. The patient identifier number will contain 
the site number and the patient number assigned in numerical order at the screening visit 
(e.g. 102-10 for the tenth patient screened at the site number 102). This patient identifier number 
will be used in listings. 
Usually listings will be sorted by treatment, patient number and (if applicable) visit/point in time.  
All eCRF data will be listed, therefore listings may not be mentioned explicitly in section 7. 
 
6.1 Primary Endpoint Evaluation  
The primary efficacy endpoints are: 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 20 of 38 
· Percent change in triglycerides from baseline to week 16. 
· Change in HbA1c from baseline to week 26. 
The primary analysis will be based on the FAS using values imputed via multiple-imputation.  
Pairwise comparisons of both Epeleuton doses vs Placebo will be performed. 
The primary analysis will be repeated for FAS using LOCF and for the PPS as supportive analyses. 
 
Analysis of the percentage change of triglycerides will be performed using a Wilcoxon rank sum 
test with the Hodges Lehmann median and 95% confidence intervals estimates (Test 1 and Test 
2).  
Changes from baseline of HbA1c will be analysed using mixed model analysis of covariance 
(ANCOVA) with baseline value as a covariate, patient as random effect and treatment regime as 
fixed effect using type III sum of squares and calculating the least squares means for treatment and 
treatment contrast including corresponding 95% confidence intervals (Test 3 and Test 4). 
 
6.2 Descriptive Analyses, Exploratory Tests 
Categorical variables will be displayed by absolute and relative frequencies (percentages). 
Percentages for categorical variables will be based on all non-missing values (=100%). 
Percentages will be rounded to one decimal place and therefore, there may be occasions when the 
total of the percentages does not exactly equal 100%. The number of missing values will be 
displayed. 
Continuous variables will be summarised with number of observations used, number of missing 
values, mean, standard deviation, median, minimum, maximum and the 25% and 75% quantiles. 
If other statistical tests than those described in section 6.1 will be performed, these will have 
exploratory character only and will be carried out using a two-sided significance level of 5% 
without adjustment for multiplicity. 
 
6.3 Subgroup analyses 
Where conducted, subgroup analyses may use one or several of the following stratification 
variables: 
· Gender (male, female) 
· Age group (<65, ≥65 years) 
· Country 
Subgroup definitions may be amended during the BDRM and further subgroups may be defined 
during the BDRM. 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 21 of 38 
7 Final analysis 
The final analysis will be conducted after end of patient observation, i.e. after the last patient 
completed Visit 10 (Week 28) assessments. 
The following sections summarise all analyses planned. 
 
7.1 Demographic and other baseline data 
All analyses described in this section will be performed as described in section 6.2 with the Safety 
Analysis Set.  
The analysis will be presented overall. The following variables will be analysed: 
· 
Age at Screening [years] 
· 
Age group (<65, ≥65 years) 
· 
Gender (male, female) 
· 
Ethnic origin (Caucasian, Black, Asian, other) 
· 
Smoking status (current smoker / ex-smoker / never smoked) 
 
For medical history, the number/percentage of patients will be displayed by MedDRA primary 
SOC and Preferred Term. 
Medical history data will be listed including its MedDRA coding information. 
The time since diagnosis of diabetes will be summarised descriptively. Further analyses may be 
considered (at latest in the BDRM) for other data on diabetes history and complications (diabetic 
nephropathy, diabetic retinopathy, diabetic neuropathy). 
 
7.2 Efficacy - Primary Endpoint Evaluation  
The primary efficacy endpoints (i.e. Percent change in triglycerides from baseline to week 16 and 
Change in HbA1c from baseline to week 26) will be tested as described in section 6.1. 
Triglyceride and HbA1c values and percentage change from baseline will be summarised 
descriptively (location and dispersion parameters) by visit as detailed in section 6.2 (displaying all 
visits).  
Descriptive summary statistics for the two Epeleuton doses pooled will be given as well and 
exploratory inference tests for the two Epeleuton doses pooled vs Placebo will be performed for 
both primary endpoints. 
Descriptive analyses for changes from baseline will generally include both absolute change and 
percentage change. 
 
7.3 Efficacy - Secondary Endpoints Evaluation  
The secondary efficacy endpoints are: 
· 
Percent change in triglycerides from baseline to weeks 4, 8, 12, 20 and 26. 
· 
Change in HbA1c from baseline to weeks 4, 8, 12, 16 and 20. 
· 
Proportion of patients achieving a HbA1c below 7.0% at weeks 4, 8, 12, 16, 20 and 26. 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 22 of 38 
· 
Percent change in very low-density lipoprotein cholesterol (VLDL-C) from baseline to 
weeks 4, 8, 12, 16, 20 and 26. 
· 
Percent change in non-high-density lipoprotein cholesterol (non-HDL-C) from baseline 
to weeks 4, 8, 12, 16, 20 and 26. 
· 
Percent change in total cholesterol from baseline to weeks 4, 8, 12, 16, 20 and 26. 
· 
Change in fasting plasma glucose from baseline to weeks 4, 8, 12, 16, 20 and 26. 
· 
Proportion of patients achieving a HbA1c below 6.5% at weeks 4, 8, 12, 16, 20 and 26. 
· 
Percent change in apolipoprotein B (ApoB) from baseline to weeks 16 and 26. 
· 
Percent change in remnant lipoprotein cholesterol (RLP-C) from baseline to weeks 8, 
16 and 26. 
· 
Percent change in high-density lipoprotein cholesterol (HDL-C) from baseline to weeks 
4, 8, 12, 16, 20 and 26. 
· 
Percent change in low-density lipoprotein cholesterol (LDL-C) (preparative 
ultracentrifugation) from baseline to weeks 16 and 26. 
· 
Change in body weight (kg) from baseline to weeks 4, 8, 12, 16, 20 and 26. 
· 
Change in high-sensitivity C-reactive protein (hsCRP) from baseline to weeks 8, 16 
and 26. 
· 
Change in systolic blood pressure from baseline to weeks 4, 8, 12, 16, 20 and 26. 
· 
Change in diastolic blood pressure from baseline to weeks 4, 8, 12, 16, 20 and 26. 
· 
Change in urinary albumin-to-creatinine ratio (UACR) from baseline to week 26 in the 
sub-group of patients with microalbuminuria at baseline. 
 
Logistic regression with baseline HbA1C as a covariate will be used to analyse the percentage of 
patients with HbA1c < 7.0% and the percentage of patients with HbA1c < 6.5% at week 16. 
All other secondary efficacy endpoints will be analysed using an ANCOVA mixed model, if the 
data for that endpoint are normally distributed, or a Wilcoxon-rank-sum test, if the data are not 
normally distributed. Significant departure from normality is defined as p-value of <0.01 for the 
Shapiro-Wilk test. The ANCOVA mixed model for each specific endpoint will use the baseline 
value of the specific endpoint variable as a covariate, patient as random effect and treatment regime 
as fixed effect, type III sum of squares and the least squares means for treatment and treatment 
contrast including corresponding 95% confidence intervals. 
All statistical tests will be performed in an exploratory manner, without adjustment for 
multiplicity. All tests will be repeated for the pooled Epeleuton dose vs Placebo. 
All analyses of secondary efficacy endpoints will be performed a) based on the FAS using values 
imputed via multiple-imputation b) using FAS with LOCF for endpoints related to triglycerides, 
change in HbA1c, and body weight. Endpoints related to Triglycerides and change in HbA1c will 
also be evaluated for PPS. 
 
7.4 Exploratory Endpoints  
Exploratory Endpoints are: 
· 
Change in waist circumference from baseline to weeks 8, 16 and 26. 
· 
Percent change in apolipoprotein CIII (ApoCIII) from baseline to weeks 16 and 26. 
· 
Percent change in apolipoprotein A1 (ApoA1) from baseline to weeks 16 and 26. 
· 
Percent change in lipoprotein (a) (Lp(a)) from baseline to weeks 16 and 26. 
· 
Percent change in high-density lipoprotein particle concentration (HDL-P) from 
baseline to weeks 16 and 26. 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 23 of 38 
· 
Percent change in small low-density lipoprotein particle concentration (Small LDL-P) 
from baseline to weeks 16 and 26. 
· 
Percent change in large low-density lipoprotein particle concentration (Large LDL-P) 
from baseline to weeks 16 and 26. 
· 
Percent change in low-density lipoprotein size (LDL size) from baseline to weeks 16 
and 26. 
· 
Percent change in very low-density lipoprotein size (VLDL size) from baseline to 
weeks 16 and 26. 
· 
Percent change in high-density lipoprotein size (HDL size) from baseline to weeks 16 
and 26. 
· 
Change in fasting plasma insulin from baseline to weeks 16 and 26. 
· 
Change in Homeostatic model assessment insulin resistance (HOMA-IR) from baseline 
to weeks 16 and 26. 
· 
Change in Homeostatic model assessment β-cell function (HOMA-β) from baseline to 
weeks 16 and 26. 
· 
Change in interleukin 6 (IL-6) from baseline to week 26. 
· 
Change in interleukin 1β (IL-1β) from baseline to week 26. 
· 
Change in plasminogen activator inhibitor 1 (PAI-1) from baseline to week 26. 
· 
Change in vascular cell adhesion molecule 1 (VCAM-1) from baseline to week 26. 
· 
Change in intercellular adhesion molecule 1 (ICAM-1) from baseline to week 26. 
· 
Change in monocyte chemoattractant protein 1 (MCP-1) from baseline to week 26. 
· 
Change in red cell distribution width (RDW) from baseline to weeks 16 and 26. 
· 
Change in haemoglobin from baseline to weeks 16 and 26. 
· 
Change in reticulocyte count from baseline to weeks 16 and 26. 
· 
Change in erythrocyte (red blood cell) count from baseline to weeks 16 and 26. 
 
All exploratory endpoints will be analysed using an ANCOVA mixed model, if the data for that 
endpoint are normally distributed, or a Wilcoxon-rank-sum test, if the data are not normally 
distributed. Significant departure from normality is defined as p-value of <0.01 for the Shapiro-
Wilk test. The ANCOVA mixed model for each specific endpoint will use the baseline value of 
the specific endpoint variable as a covariate, patient as random effect and treatment regime as fixed 
effect, type III sum of squares and the least squares means for treatment and treatment contrast 
including corresponding 95% confidence intervals. 
All statistical tests will be performed in an exploratory manner, without adjustment for 
multiplicity. All significance tests will be repeated for the pooled Epeleuton dose vs Placebo. 
All analyses of exploratory endpoints will be performed for FAS using LOCF imputation. 
Further exploratory endpoints are: 
· 
Trough plasma concentrations of total and unesterified 15-hydroxy eicosapentaenoic 
acid (15(S)-HEPE) in treated population compared to placebo population at 
Baseline/Day 0, Week 4, Week 8, Week 16 and Week 26. 
· 
Trough plasma concentrations of EPA in treated population compared to placebo 
population at Baseline/Day 0, Week 4, Week 8, Week 16 and Week 26. 
The analysis of these endpoints will be conducted by an independent pharmacokineticist. The 
analysis methods for these exploratory endpoints will be described in a separate document. The 
results and conclusions will be forwarded to the Medical Writer for incorporation into the Clinical 
Study Report. 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 24 of 38 
Blood for exploratory biomarkers will be collected as per the Study Flow Chart (Appendix 1) at 
Visit 3/Baseline and Visit 9/Week 26/Early Termination and will be stored for later biomarker 
analysis. The biostatistical evaluation therefore will be performed separately from the analyses 
described in this SAP. The sampling dates will be listed. 
 
7.5 Safety Evaluation  
Safety endpoints include 
· 
Incidence of treatment-emergent level 2 and level 3 hypoglycaemic episodes 
· 
Level 2 – Glucose <54 mg/dL (3.0 mmol/L), with or without symptoms  
· 
Level 3 – A severe event characterised by altered mental and/or physical status 
requiring assistance for treatment of hypoglycaemia. 
· 
AE and SAE frequency and severity. 
· 
Safety laboratory parameters (haematology, clinical chemistry, coagulation). 
· 
Urinalysis 
· 
ECGs 
· 
Vital signs (heart rate, temperature, blood pressure) 
· 
Physical examination 
 
Analyses generally use the Safety Analysis Set. 
 
7.5.1 Adverse Events 
The degree of attributability (causality) between an IMP and an AE is documented as Definitely / 
Probable / Possible / Unlikely / Unrelated. A reasonable causal relationship is assumed if the 
causality is at least “possible”. 
An AE will be considered “treatment emergent” if its onset is at or after the first dose of study 
drug at the baseline visit or if it worsened at or after the first dose of study drug. 
 
The analyses of adverse events with onset on or after first administration of study medication 
(“treatment-emergent AEs”) will be based on the Safety Analysis Set.  
Adverse events occurring before first application of study medication will be included in AE 
listings. Please note that Adverse Events with onset on study day of 0 or higher are treatment 
emergent AEs, while AEs with negative study day are those that occurred before first application 
of study medication.  
The number and percentage of patients with specific adverse events during the treatment period 
will be displayed by MedDRA primary SOC, Preferred Term and worst severity. The counts in 
these analyses will reflect numbers of patients reporting one or more AE that map to the MedDRA 
system organ class/preferred term, displaying patients who reported several AEs of one Preferred 
Term with differing severities under the worst severity reported. E.g. one patient with two reported 
headaches (mild and moderate) will be analysed with moderate. The percentage is a crude 
incidence rate, i.e. the number of patients with a specific adverse event divided by the total number 
of patients in the analysis population. 
The analysis of treatment-emergent adverse events will be repeated for the following AE 
categories: 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 25 of 38 
· 
All adverse events 
· 
Serious adverse events 
· 
Adverse events related to the study medication 
· 
Serious related adverse events 
· 
Adverse events leading to permanent discontinuation of study drug 
 
Furthermore, a summary table with the overall incidences of the above mentioned AEs will be 
created.  
Listings will be based on the Enrolled Set and will include study day of AE onset and AE stop as 
well as MedDRA information (i.e. SOC, Preferred Term, and Lowest Level Term).  
Listings will be created for the following topics: 
· 
All adverse events 
· 
Serious adverse events 
· 
Adverse events related to the study medication  
 
The number/percentage of patients with treatment-emergent adverse events will also be 
summarised by MedDRA primary SOC and Preferred Term for most frequent non-serious adverse 
events (incidence of preferred term ≥ 5%). In this table, the Totals overall or by SOC will consider 
only those preferred terms with an incidence >=5%. 
 
7.5.2 Hypoglycaemia assessment 
Assessment of symptomatic hypoglycaemic episodes will be conducted at Visit 3/Baseline, 
Week 2 Telephone Call, Visit 4/ Week 4, Visit 5/Week 8, Visit 6/ Week 12, Visit 7/ Week 16, 
Visit 8/Week 20, Visit 9/Week 26/Early Termination and Visit 10/Week 28/Follow-up. 
Hypoglycaemia is classified by the American Diabetes Association (ADA) and the European 
Association for the Study of Diabetes (EASD) into the following levels:  
· Level 1: Glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 mmol/L) 
· Level 2: Glucose <54 mg/dL (3.0 mmol/L), with or without symptoms 
· Level 3: A severe event characterized by altered mental and/or physical status requiring 
assistance for treatment of hypoglycaemia. 
Level 2 hypoglycaemia with or without symptoms and Level 3 hypoglycaemia should be recorded 
and warrant further investigation. 
When a hypoglycaemic episode is suspected, plasma glucose should be self-measured and all 
values, hypoglycaemic symptoms and details of the event should be reported in the 
Hypoglycaemic Episode Form (cf. study protocol section 15.3, Appendix 3) by the patient. 
Based on a blinded medical review the episodes will be classified into Level 1 to Level 3. 
Data on the Hypoglycaemic Episode Form will be listed. 
The number/percentage of patients with events (overall and per level) will be summarised. 
The number/percentage of events (with percentage based on the total number of events) will be 
summarised overall and per level. 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 26 of 38 
7.5.3 Self-monitoring of blood glucose (SMBG) 
All patients will be instructed or re-educated on how to use their blood glucose meter device and 
test strips at the baseline visit. The instruction will be repeated as necessary during the trial. 
SMBG profiles will be recorded daily from Visit 3/Baseline to Visit 4 / Week 4. After Visit 4 / 
Week, at the investigator’s discretion, patients who have experienced hypoglycaemia may be 
asked to continue SMBG. 
Patients will be asked to record SMBG daily before meals and before bedtime. Patients will also 
be asked to record SMBG before exercise and if they suspect low blood glucose, as described in 
Section 7.5.2 Hypoglycaemia assessment. 
Patients will record the results of the SMBG values in an electronic diary. The record of each 
SMBG value will include date, time and value. Any SMBG values <70 mg/dL (3.9 mmol/L) 
entered into the electronic diary will be automatically alerted to the investigator and medical 
monitor for follow-up. If the patient is unable to access the electronic diary, a paper diary back up 
will be provided and the data will be transcribed during the next site visit into the IRT by the 
Investigator or designee. 
The information if self-monitoring of blood glucose was completed and if the investigator does 
recommend that the patient continues to complete eDiary for self-monitoring of blood glucose will 
be listed. 
 
7.5.4 Vital signs 
Vital signs measurements will be performed at each visit, before any blood samples are taken. The 
following vital sign parameters are obtained: 
· 
Systolic blood pressure [mmHg] - seated and resting for five minutes  
· 
Diastolic blood pressure [mmHg - seated and resting for five minutes ] 
· 
Heart rate [beats per min] – taken at rest 
· 
Temperature [°C]: - taken as per clinic practice 
 
The analysis for systolic/diastolic blood pressure is described in section 7.3. The analysis for heart 
rate and temperature will be performed as described in section 6.2 by visit using the Safety 
Analysis Set considering values as well as changes from baseline. 
 
7.5.5 ECG 
A 12-lead electrocardiogram (ECG) 10 mm/1 mV, 25 mm/s with a 10 second lead II rhythm strip 
will be recorded. Patients will be rested quietly in a fully supine position for five minutes before 
the ECG is taken. Recordings will be made at Visit 3/Baseline and at Visit 9/Week 26/Early 
Termination. 
The number/percentage of patients with normal results, abnormal results with clinical significance 
and abnormal results without clinical significance will be summarised overall and by visit for the 
Safety Analysis Set (as described in section 6.2. 
 
7.5.6 Physical Examination 
A physical examination, including height (Visit 1/Screening 1 only), weight, BMI and waist 
circumference measurement, will be performed at Visit 1/Screening 1, Visit 2/Screening 2, 
Visit 3/Baseline, Visit 4/Week 4, Visit 5/Week 8, Visit 6/Week 12, Visit 7/Week 16, 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 27 of 38 
Visit 8/Week 20, Visit 9/Week 26/Early Termination and Visit 10/Week 28/Follow up, in 
accordance with local practices. 
The analysis for weight is described in section 7.3, the analysis for waist circumference is 
described in section 7.4. The analysis for BMI values and height values will be performed as 
described in section 6.2 by visit using the Safety Analysis Set. 
 
7.5.7 Safety Laboratory data 
Safety laboratory include haematology, serum biochemistry and coagulation: 
· Haematology: Full blood count to include red cell count, haemoglobin, haematocrit, white 
cell count, differential white cell count, platelet count, reticulocyte count and red cell 
distribution width (RDW). 
· Serum biochemistry: Urea (blood urea nitrogen (BUN)), creatinine, uric acid, total 
bilirubin, indirect and direct bilirubin, sodium, bicarbonate potassium, phosphorus, 
calcium chloride, alkaline phosphatase (ALP), AST, ALT, AST:ALT ratio, gamma-
glutamyl transferase (GGT), albumin, total protein and TSH (screening only). 
· Coagulation: PT (prothrombin time), International normalised ratio (INR) and APTT 
(activated partial prothrombin time) 
Those parameters are not evaluated as efficacy/exploratory endpoints. The value and change from 
baseline will be summarised descriptively by visit as described in section 6.2. 
For all parameters a summary will display the number/percentage of patients with normal results, 
abnormal results with clinical significance and abnormal results without clinical significance 
overall and by visit. 
Per parameter, a shift table will display the category (normal / abnormal, not clinically significant 
/ abnormal, clinically significant) of the patient’s baseline value vs. the worst category observed 
post-baseline. 
All analyses for the safety laboratory will be based on the Safety Analysis Set. 
Laboratory values outside the normal range will be listed separately in detail.  
 
7.5.8 Urinalysis 
Urinalysis assessment will be conducted as per Flow Chart (Appendix 1) at Visit3/Baseline and 
Visit 9/Week 26/Early Termination. pH, protein, glucose, blood, ketones, leukocytes, leukocyte 
esterase, bilirubin, specific gravity, urobilinogen and nitrate will be assessed. Reflex microbiology 
to be done locally if blood, protein, leukocyte esterase or nitrate/nitrite are present. 
Urinalysis assessment results will be summarised descriptively by visit as described in section 6.2 
as applicable. Reflex microbiology data will be listed only. 
 
7.5.9 Further safety endpoints 
For female patients of childbearing potential only, a pregnancy test will be carried out as per the 
study flow chart (Appendix 1) at Visit 1/Screening 1 and at Visit 3/Baseline, Visit 6/Week 12 and 
Visit 9/Week 26. 
Female patients and male patients with female partners of childbearing potential must use highly 
effective contraceptive methods or have a sterilised partner for the duration of the study and this 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 28 of 38 
must be continued post study for at least 30 days for WOCBP and 90 days for men. This should 
be discussed with the patient as per the study flow chart (Appendix 1) at Visit 1/Screening 1, Visit 
3/Baseline, Visit 6/Week 12 and Visit 9/Week 26. 
Pregnancy test data and counselling on contraception will be listed only. 
 
7.6 Further Analyses 
 
7.6.1 Previous and concomitant medication 
All administered concomitant medications should be recorded throughout the study. 
The incidence of previous and concomitant medication will be displayed by ATC classification 
(level 2 and preferred term). The analysis will be performed separately for previous medications 
and concomitant medications for the Safety Analysis Set (cf. section 5.3.6). 
 
7.6.2 Study medication 
Drug accountability 
If documented in the eCRF, the Drug Accountability data (i.e. amount of dispensed / returned 
medication and other related information) will be listed. 
Exposure data 
Treatment duration [days] will be summarised descriptively by visit as described in section 6.2 for 
the Safety Analysis Set. 
 
7.6.3 Patients’ study termination status 
Standard reasons for withdrawing from further participation in the study may be: 
· 
Unacceptable AEs 
· 
Patient’s decision (withdrawal of consent to participate) 
· 
Investigator’s discretion 
· 
Intercurrent illness 
· 
Pregnancy 
· 
Patient lost to follow-up 
· 
Reason not specified 
 
The number/percentage of patients completing the study will be given, the number/percentage of 
patients with premature study termination will be given overall and per main reason. The analysis 
will be performed separately for screening failures, i.e. non-randomised patients, and for all 
randomised patients. 
 
7.6.4 Study duration and analysis sets 
The date of the first patient in the study (i.e. the date of first informed consent) and the date of the 
last patient out of the study (i.e. the last date of a patient visit/patient assessment in the study) will 
be given for the Enrolled Set as well as for the Safety Set. 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 29 of 38 
The number of patients in each analysis set will be given overall and by centre nested in countries. 
All patients will be listed with their assignment to the analysis populations and if applicable the 
reason for exclusion from specific analysis sets. 
The patient’s visit dates will be listed including an indication of the corresponding study days. 
 
7.6.5 Protocol deviations 
Protocol deviations identified in the BDRM will be listed including the decision if these constitute 
a minor or major protocol violation. 
Based on the number of protocol deviations observed a summary may be considered during the 
BDRM. 
 
7.6.6 Pharmacokinetic sampling 
Pharmacokinetic sampling and associated biostatistical evaluation is described in section 7.4. 
 
 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 30 of 38 
8 Tables, Figures and Listings 
FAS MI: Full Analysis Set with multiple imputation data, FAS LOCF: Full Analysis Set with 
LOCF data, FAS: Full Analysis Set complete-case analysis 
Item No. 
Title  
Population 
Content Description 
14.1 
Demographic data, Baseline Characteristics, Patient disposition , 
concomitant medication 
 
Patient disposition 
14.1.1 
Study termination status 
Randomised 
patients 
Descriptive statistics 
14.1.2 
Study termination 
reasons for screening 
failures 
Non-
randomised 
patients 
Descriptive statistics 
14.1.3 
Duration of study 
ES, SAS 
Date of first patient in and 
last patient out 
14.1.4 
Number of patients in 
analysis sets by country, 
centre and overall 
ES 
Descriptive statistics 
14.1.5 
Treatment duration of 
study medication 
SAS 
Descriptive statistics of 
treatment duration 
 
Demographic data, Baseline characteristics, concomitant 
medication 
14.1.6 
Demographics / Smoking 
status 
SAS 
Descriptive statistics (incl. 
age, age group, gender, 
ethnic origin, smoking 
status) 
14.1.7 
Diabetes history and 
complications  
SAS 
Descriptive statistics for 
time since diagnosis and 
possibly other parameters 
14.1.8 
Medical History 
SAS 
Descriptive statistics by 
MedDRA SOC and 
preferred term 
14.1.9.1 
Previous medication 
SAS 
Descriptive statistics by 
ATC classification (level 
2) and preferred term  
14.1.9.2 
Concomitant medication  
SAS 
Descriptive statistics by 
ATC classification (level 
2) and preferred term  


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 31 of 38 
Item No. 
Title  
Population 
Content Description 
14.2 
Efficacy  
14.2.1 
Primary Endpoint 
14.2.1.1.1 to 
14.2.1.1.3 
Percent change in 
triglycerides from 
baseline to week 16: 
Wilcoxon Test with 
Hodges Lehmann median 
FAS MI, 
FAS LOCF, 
PPS 
Wilcoxon rank sum tests 
(per Epeleuton dose level 
and pooled Epeleuton 
dose) with the Hodges 
Lehmann median and 95% 
confidence intervals 
estimates 
14.2.1.1.4 to 
14.2.1.1.6 
Triglycerides values and 
changes by visit  
FAS MI, 
FAS LOCF, 
PPS 
Descriptive summaries 
incl. a pooled Epeleuton 
dose, absolute and 
percentage change 
14.2.1.2.1 to 
14.2.1.2.3 
Change in HbA1c from 
baseline to week 26: 
ANCOVA 
FAS MI, 
FAS LOCF, 
PPS 
Mixed model analysis of 
covariance (per Epeleuton 
dose level and pooled 
Epeleuton dose) with 
baseline value as a 
covariate 
14.2.1.2.4 to 
14.2.1.2.6 
HbA1c values and 
changes by visit  
FAS MI, 
FAS LOCF, 
PPS 
Descriptive summaries 
incl. a pooled Epeleuton 
dose, absolute and 
percentage change 
14.2.2 
Secondary Endpoints 
14.2.2.1.1 to 
14.2.2.1.3 
Percent change in 
triglycerides from 
baseline per visit: 
Wilcoxon Test with 
Hodges Lehmann median 
FAS MI, 
FAS LOCF, 
PPS 
Wilcoxon rank sum tests 
(per Epeleuton dose level 
and pooled Epeleuton 
dose) with the Hodges 
Lehmann median and 95% 
confidence intervals 
estimates, per visit 
14.2.2.2.1 to 
14.2.2.2.3 
Change in HbA1c from 
baseline per visit: 
ANCOVA 
FAS MI, 
FAS LOCF, 
PPS 
Mixed model analysis of 
covariance (per Epeleuton 
dose level and pooled 
Epeleuton dose)  with 
baseline value as a 
covariate, per visit 
14.2.2.3.1 
Proportion of patients 
with HbA1c below 7.0% 
per visit: Logistic 
regression 
FAS MI 
Logistic regression with 
baseline HbA1c as a 
covariate, per visit  


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 32 of 38 
Item No. 
Title  
Population 
Content Description 
14.2.2.4.1 
Proportion of patients 
with HbA1c below 6.5% 
per visit: Logistic 
regression  
FAS MI 
Logistic regression with 
baseline HbA1c as a 
covariate, per visit 
14.2.2.5.1 
Percent change in 
VLDL-C per visit: 
Significance Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.6.1 
Percent change in 
non-HDL-C per visit: 
Significance Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.7.1 
Percent change in total 
cholesterol per visit: 
Significance Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.8.1 
Change in fasting plasma 
glucose per visit: 
Significance Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.9.1 
Percent change in ApoB 
per visit: Significance 
Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.10.1 
Percent change in RLP-C 
per visit: Significance 
Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.11.1 
Percent change in 
HDL-C per visit: 
Significance Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.12.1 
Percent change in LDL-C 
per visit: Significance 
Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.13.1 to 
14.2.2.13.2 
Change in body weight 
per visit: Significance 
Test 
FAS MI, 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.14.1 
Change in hsCRP per 
visit: Significance Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.15.1 
Change in systolic blood 
pressure per visit: 
Significance Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.16.1 
Change in diastolic blood 
pressure per visit: 
Significance Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.2.17.1 
Change in UACR per 
visit: Significance Test 
FAS MI 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 33 of 38 
Item No. 
Title  
Population 
Content Description 
14.2.3 
Exploratory Analyses 
14.2.3.1.1 
Change in waist 
circumference per visit: 
Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.2.1 
Percent change in 
ApoCIII per visit: 
Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.3.1 
Percent change in ApoA1 
per visit: Significance 
Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.4.1 
Percent change in Lp(a) 
per visit: Significance 
Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.5.1 
Percent change in HDL-P 
per visit: Significance 
Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.6.1 
Percent change in LDL-P 
per visit: Significance 
Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.7.1 
Percent change in Large 
LDL-P per visit: 
Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.8.1 
Percent change in LDL 
size per visit: 
Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.9.1 
Percent change in VLDL 
size per visit: 
Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.10.1 
Percent change in HDL 
size per visit: 
Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.11.1 
Change in fasting plasma 
insulin per visit: 
Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.12.1 
Change in HOMA-IR per 
visit: Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.13.1 
Change in HOMA-β per 
visit: Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 34 of 38 
Item No. 
Title  
Population 
Content Description 
14.2.3.14.1 
Change in IL-6 per visit: 
Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.15.1 
Change in IL-1β per 
visit: Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.16.1 
Change in PAI-1 per 
visit: Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.17.1 
Change in VCAM-1 per 
visit: Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.18.1 
Change in ICAM-1 per 
visit: Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.19.1 
Change in MCP-1 per 
visit: Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.20.1 
Change in RDW per 
visit: Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.21.1 
Change in haemoglobin 
per visit: Significance 
Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.22.1 
Change in reticulocyte 
count per visit: 
Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.23.1 
Change in erythrocyte 
(red blood cell) count per 
visit: Significance Test 
FAS LOCF 
ANCOVA mixed model, if 
feasible, otherwise 
Wilcoxon-rank-sum test 
14.2.3.24 
Trough plasma 
concentrations of total 
and unesterified 
15(S)-HEPE: Descriptive 
summary by visit 
FAS LOCF 
Descriptive summary incl. 
a pooled Epeleuton dose 
14.2.3.25 
Trough plasma 
concentrations of EPA: 
Descriptive summary by 
visit 
FAS LOCF 
Descriptive summary incl. 
a pooled Epeleuton dose 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 35 of 38 
Item No. 
Title  
Population 
Content Description 
14.3 
Safety 
14.3.1 
Adverse events 
14.3.1.1 
Summary of adverse 
events  
SAS 
Overall incidences of 
specific adverse event 
types (AE, SAE, …) 
14.3.1.2 
Adverse events by 
MedDRA SOC, preferred 
term and worst severity 
SAS 
Descriptive statistics by 
MedDRA SOC, preferred 
term and worst severity 
14.3.1.3 
Serious adverse events 
by MedDRA SOC, 
preferred term and worst 
severity 
SAS 
Descriptive statistics by 
MedDRA SOC, preferred 
term and worst severity 
14.3.1.4 
Adverse events related to 
study medication by 
MedDRA SOC, preferred 
term and worst severity 
SAS 
Descriptive statistics by 
MedDRA SOC, preferred 
term and worst severity 
14.3.1.5 
Adverse events leading 
to permanent 
discontinuation of study 
drug by MedDRA SOC, 
preferred term and worst 
severity 
SAS 
Descriptive statistics by 
MedDRA SOC, preferred 
term and worst severity 
14.3.1.6 
Adverse events with at 
least 5% incidence, by 
MedDRA SOC, preferred 
term 
SAS 
Descriptive statistics by 
MedDRA SOC and 
preferred term 
14.3.1.7 
Hypoglycaemia: 
Incidence on patient level 
SAS 
Descriptive summary 
14.3.1.8 
Hypoglycaemia: 
Incidence on event level 
SAS 
Descriptive summary 
14.3.5 
Vital signs 
14.3.5.1 
Vital signs 
SAS 
Descriptive statistics of 
values and changes to 
baseline for heart 
rate+temperature 
14.3.6 
Laboratory values 
14.3.6.1 
Serum biochemistry: 
absolute values and 
change from baseline 
SAS 
Descriptive statistics of 
absolute values and 
changes to baseline for 
each parameter  


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 36 of 38 
Item No. 
Title  
Population 
Content Description 
14.3.6.2 
Serum biochemistry: 
number and percentage 
of normal and abnormal 
values 
SAS 
Descriptive statistics for 
each parameter (normal 
and abnormal values with 
and without clinical 
significance) 
14.3.6.3 
Serum biochemistry: 
Shift tables of normality 
SAS 
Shift table for change from 
baseline to the worst value 
post-baseline 
14.3.6.4 
Haematology: absolute 
values and change from 
baseline 
SAS 
Descriptive statistics of 
absolute values and 
changes to baseline for 
each parameter  
14.3.6.5 
Haematology: number 
and percentage of normal 
and abnormal values 
SAS 
Descriptive statistics for 
each parameter (normal 
and abnormal values with 
and without clinical 
significance) 
14.3.6.6 
Haematology: Shift 
tables of normality 
SAS 
Shift table for change from 
baseline to the worst value 
post-baseline 
14.3.6.7 
Coagulation: absolute 
values and change from 
baseline 
SAS 
Descriptive statistics of 
absolute values and 
changes to baseline for 
each parameter  
14.3.6.8 
Coagulation: number and 
percentage of normal and 
abnormal values 
SAS 
Descriptive statistics for 
each parameter (normal 
and abnormal values with 
and without clinical 
significance) 
14.3.6.9 
Coagulation: Shift tables 
of normality 
SAS 
Shift table for change from 
baseline to the worst value 
post-baseline 
14.3.6.10 
Urinalysis 
SAS 
Descriptive statistics for 
each parameter  
14.3.7 
ECG 
14.3.7.1 
ECG: number and 
percentage of normal and 
abnormal values 
SAS 
Descriptive statistics for 
each parameter (normal 
and abnormal values with 
and without clinical 
significance) by visit and 
overall 
14.3.8 
Physical Examination 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 37 of 38 
Item No. 
Title  
Population 
Content Description 
14.3.8.1 
Physical examination: 
Descriptive summary 
SAS 
Descriptive statistics for 
height and (by visit) BMI 
 
 
 
 
16 
Appendices 
16.2 
Patient data listings 
16.2.1.1 
Study termination 
Randomised 
patients  
Individual patient data 
listing of premature 
termination yes/no incl. 
reason for termination if 
applicable 
16.2.1.2 
Screening failures  
Non-
randomised 
patients 
Individual patient data 
listing incl. reason for 
screening failures, only 
non-randomised patients  
16.2.2 
Protocol deviations 
ES 
Individual patient data 
listing of protocol 
deviations incl. decision if 
minor or major 
16.2.3 
Listing of patient 
assignment to analysis 
sets 
ES 
Individual patient data 
listing incl. randomisation 
number, randomisation 
date, randomised 
treatment, reason for 
exclusions from analysis 
sets 
16.2.4.1 
Demographic data / 
Informed consent 
ES 
Individual patient data 
listing 
16.2.4.2 
Medical history 
ES 
Individual patient data 
listing incl. history of 
CVD, history of liver 
disease and 
Hypercholesterolaemia 
16.2.4.3 
Diabetes history and 
complications  
ES 
Individual patient data 
listing 
16.2.4.4 
Previous/ Concomitant 
medications 
ES 
Individual patient data 
listing 
16.2.5 
Study medication 
administration 
SAS 
Individual patient data 
listing of study medication 
data 
16.2.7 
Adverse Events Listings 
16.2.7.1 
Adverse events 
ES 
Individual patient data 
listing 


Afimmune Ltd. 
 
Statistical Analysis Plan DS102A-07-CV1 
AMS Advanced Medical Services GmbH 
 
 
Final Version 2.0, June 09, 2022 
 
 
Page 38 of 38 
Item No. 
Title  
Population 
Content Description 
16.2.7.2 
AEs related to study 
medication 
ES 
Individual patient data 
listing 
16.2.7.3 
Serious adverse events 
ES 
Individual patient data 
listing 
16.2.7.4 
Symptomatic 
hypoglycaemic episodes 
ES 
Individual patient data 
listing 
16.2.8 
Listing of individual laboratory measurements 
16.2.8.1 
Listing of laboratory 
values 
All 
Individual patient data 
listing of laboratory 
results, lab tests grouped 
by test panel (PK, Panel 1 
to 5, UACR, Urinalysis, 
TSH) 
16.2.8.2 
Listing of abnormal 
laboratory values 
All 
Individual patient data 
listing of laboratory 
results, lab tests grouped 
by test panel (PK, Panel 1 
to 5, UACR, Urinalysis, 
TSH) 
16.2.8.3 
Pregnancy test and 
Contraception 
All 
Individual patient data 
listing  
16.2.8.4 
Exploratory biomarker 
samples: Sampling dates 
All 
Individual patient data 
listing  
16.2.9 
Other Listings  
16.2.9.1 
Vital signs / Physical 
examination 
All 
Individual patient data 
listing 
16.2.9.2 
ECG 
All 
Individual patient data 
listing 
16.2.9.3 
Self-Monitoring of Blood 
Glucose 
All 
Individual patient data 
listing 
16.2.9.4 
Visit dates 
All 
Individual patient data 
listing incl. study days 
 
 
9 References 
FDA: Center for Drug Evaluation and Research (CDER): Draft Guidance for Industry: Multiple 
Endpoints in Clinical Trials (2017) 
Guideline on multiplicity issues in clinical trials, EMA/CHMP/44762/2017