A Phase ll, Randomized, Double-blind, Placebo-controlled Study of IMM-124E for Patients With Non-alcoholic Steatohepatitis.
Phase: PHASE2
Conditions: Non-alcoholic Steatohepatitis (NASH)
Sponsor: Immuron Ltd.

 
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Study Title: A phase II, randomized, double-blind, placebo-controlled study of    
IMM-124E for patients with non-alcoholic steatohepatitis 
  
Sponsor: Immuron Limited 
Unit 10,  25 – 37  Chapman Street,  
Blackburn North VIC 3130,  
Southbank VIC 3006 
Australia 
 
Phone: +61 3 8648 4530  
Fax: +61 3 8677 9390 
  
IND No.: 14933 
  
Protocol ID: IMM-124E-2001 
  
Medical Monitor: Professor Yaron Ilan 
 
Phone: +972-50-787-4551 
Email: ILAN@hadassah.org.il  
 
  
Protocol Version/Date: Version 1.3 
 
Date: 08 May 2016 
  
 
 
CONFIDENTIALITY STATEMENT 
This document contains the confidential information of Immuron Limited. 
The information contained in this document, particularly unpublished data, is the property of, 
or under the control of Immuron Limited (“Immuron”), and is provided to you in confidence 
as an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Institutional Review Board or Independent Ethics Committee. 
The information is only to be used by you in connection with authorized clinical studies of 
the investigational drug described in the protocol.  
Disclosure of any of the information to others requires written authorization from Immuron, 
except to the extent necessary to obtain informed consent from those persons to whom the 
investigational product(s) may be administered. 

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IMMURON LIMITED 
Level 1, 18 Kavanagh Street, Southbank, Victoria, Australia, 3006 
 
STUDY ACKNOWLEDGEMENT 
 
A phase II, randomized, double-blind, placebo-controlled study of IMM-124E for patients with 
non-alcoholic steatohepatitis. 
  
IMM-124E-2001, Version 1.3 (incorporating amendment 3), 08 May 2016 
 
This protocol has been approved by the Sponsor. The following signature documents this 
approval. 
  
  
 
 
                            
 
 
Name (Printed) 
 
Signature 
 
 
 
 
 
 
Date (dd mmm yyyy) 
 
 
 
INVESTIGATOR STATEMENT 
 
I have read the protocol entitled “A phase II, randomized, double-blind, placebo-controlled 
study of IMM-124E for patients with non-alcoholic steatohepatitis” dated 24 June 2015.  
 
I will conduct this study in accordance with this protocol and will make all reasonable efforts 
to complete the study within the time designated. I agree to disclose the financial interests of 
all investigators or sub-investigators who are directly involved in the treatment or evaluation 
of research subjects.  
 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Immuron. I will provide all study personnel under my supervision 
copies of the protocol and access to all information provided by Immuron. I will discuss this 
material with them to ensure that they are fully informed about the investigational product(s) 
and the study. 
 
 
 
 
 
 
Principal Investigator’s Name 
(Printed) 
 
 
Signature 
 
 
 
 
 
Date (dd mmm yyyy) 
 
 
 
Dan Peres,MD Head of Medical
9 May 2016

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1. STUDY SYNOPSIS 
 
Protocol No.: IMM-124E-2001 
Study Title: A phase II, randomized, double-blind, placebo-controlled dosing 
study of IMM-124E (bovine colostrum) for patients with non-alcoholic 
steatohepatitis (NASH). 
 
Investigational 
Product: 
IMM-124E: hyperimmune bovine colostrum containing polyclonal 
antibodies to bacterial lipopolysaccharide (LPS) and matching 
placebo. 
 
Indication: NASH 
 
Development 
Phase: 
2 
 
Primary 
objectives: 
To evaluate the safety and preliminary efficacy of two dose levels of 
IMM-124E in reducing liver fat  evaluated by MRI compared with 
placebo.  
Secondary 
objectives: 
Determine the pharmacokinetic profile of IMM-124E. 
 
Assess the impact of treatment with IMM-124E on markers of 
glucose metabolism and serum lipid profile.   
 
Assess the impact of treatment on liver function over 24 weeks. 
 
Establish the recommended dose. 
 
Exploratory 
objectives 
Investigate the impact of treatment on potentially relevant immune 
and metabolic biomarkers associated with NASH. 
 
Primary 
outcomes 
measures: 
Safety: Incidence and severity of adverse events and changes in vital 
signs and clinical laboratory tests. 
 
Efficacy:        
 
Mean change from Baseline in the percentage fat content of 
the liver measured by Magnetic Resonance Imaging (MRI) at 
Week 24. 
Secondary 
outcome 
measures: 
Pharmacokinetics:  
 
Serum concentration of IMM-124E bovine antibodies over 
time (if measurable) including, but not limited to, maximum 
observed concentration (Cmax), minimum observed 
concentration (Cmin) and area under the concentration-time 
curve (AUC), and, if feasible, elimination half-life (t1/2) 
 
Metabolic markers: 
 
Body Mass Index (BMI), waist circumference and waist:hip 
ratio, Hemoglobin(HB)A1C and the homeostatic model 
assessment of insulin resistance (HOMA-IR) 
 
Serum lipid profile: total cholesterol, triglycerides, low density 
lipoprotein (LDL) and high density lipoprotein (HDL) fractions 
Liver function: 

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 
Mean serum ALT, aspartate aminotransaminase (AST), 
bilirubin, albumin and gamma-glutamyl transpeptidase (GGT) 
at Weeks 4, 8, 12, 16, 20 and 24  
 
Proportion of subjects whose ALT at Week 24 is within the 
normal reference range defined a <19IU/L for women and 
<30IU/L for men. 
 
Exploratory 
outcome 
measures 
 
Mean serum concentrations of: lipopolysaccharide (LPS), C-
reactive protein (CRP), cytokeratin (CK)-18 fragments, 
glucogon-like peptide (GLP)-1 and adiponectin and subsets of 
inflammatory cytokines: interleukin (IL)-6, IL-1α, IL1β, IL-2, IL-
3, IL-4 IL-10, IL-13, IL-12, IL-17α, IL-23 interferon gamma 
(IFNγ), Transforming Growth Factor Beta (TGF-β) and  tumor 
necrosis factor alpha (TNFα) 
 
Serum metabolomics 
 
Relative levels of regulatory T cells in peripheral blood 
mononuclear cells (PBMC) samples, including CD4, CD8, 
CD25, FoxP3, NKT, CD62 and CD69 T cells; 
 
Characterization of the gut microbiome 
 
Explore a dose effect  
Study design: This is a randomized, double blind, placebo controlled, 3-arm parallel 
group, multi-dose, multi-center study.  
 
Study duration / 
participant: 
Up to 45 days for Screening and 24 weeks of treatment.   
 
Subjects terminating study drug will be followed-up post-treatment for 
28 days. 
 
Number of 
participants: 
At least 120, randomized 1:1:1 
 
Treatment allocation will be stratified by the following: 
 
Baseline MRI Liver Fat, according to the following scale: 
≤10%, 10%<X≤20%, 20%<X<30% and ≥30% 
 
Diabetic status defined as being normal (HBA1C <6.0) or 
diabetic (having a diagnosis of Type II diabetes and/or 
HBA1C >6.0 and < 9.0 whether or not receiving allowable 
medication). 
 
Study drug: IMM-124E 600mg tablet 
 
Control group: Placebo to match 
 
Dose Regimens 
 
Arm A: IMM-124E 600mg three times daily; 
Arm B: IMM-124E 1200mg three times daily; 
Arm C: Matching placebo three times daily.  
 
All treatment dose regimens are administered per orally 
 
Inclusion criteria: 
1. Age ≥ 18 years  
2. Provision of written informed consent 
3. Diagnosis of NASH, histologically proven within 12 months of 
Screening with all of the following criteria met:  
• 
NASH activity score (NAS) of 4 or more 

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• 
Cytologic ballooning score of at least 1  
• 
10% or more macrovesicular steatosis  
• 
Hematoxylin & Eosin (H&E) stained slides and/or 
paraffin block available for independent assessment  
4. HBA1C of <9.0  
5. Agree to the use of effective contraceptive measures if either 
male or female of child bearing potential 
 
Exclusion 
criteria: 
1. Presence of vascular liver disease or cirrhosis   
2. Presence of liver disease with other cause (autoimmune, 
metabolic, medication induced) 
3. BMI <25kg/m2 
4. Alcohol use >30g/day 
5. Type 1 diabetes 
6. History of major bariatric surgery (not including balloon / 
sleeve gastrectomy) 
7. Weight loss or gain of 5kg or more in the past 6 months or 
>10% change in bodyweight in the past 12 months  
8. Contraindication for MRI 
9. Inadequate venous access 
10. Lactating/breastfeeding/pregnant at Screening or Baseline 
11. HIV antibody positive, hepatitis B surface antigen positive 
(HBsAg) or Hepatitis C virus (HCV)-RNA positive 
12. Receiving an elemental diet or parenteral nutrition 
13. Concurrent conditions: 
 
Inflammatory bowel disease 
 
Unstable angina, myocardial infarction, transient 
ischemic events, or stroke within 24 weeks of 
Screening 
 
Ongoing infectious disease 
 
Ongoing multi-systemic immune-mediated disease  
 
Concurrent or past malignant disease  
 
Any other concurrent condition which, in the opinion of 
the investigator, could impact adversely on the subject 
participating or on the interpretation of the study data 

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14. Concurrent medications including: 
 
Anti-NASH therapy(s) taken for more than 10 
continuous days in the last 3 months. These include S-
adenosyl methionine (SAM-e), betaine, milk thistle, 
probiotic supplements (other than yoghurt), vitamin E 
and gemfibrozil. 
 
NOTE: If determinant biopsy is performed 
while on stable treatment – subject is eligible 
 
Wash out for any of the anti-NASH therapies is 
as follows: under 10 days no washout required, 
more than 10 days and up to 3 months 
treatment requires 6 weeks washout. Any 
treatment of over 3 months would require to re-
biopsy to ensure histological eligibility 
 
Thiazolidinediones (glitazones), dipeptidyl peptidase 4 
inhibitors (gliptins) or glucagon-like peptide-1 analogs 
in the last 6 months. 
 
NOTE: If determinant biopsy is performed 
while on stable treatment of at least 6 months, 
subject is eligible  
 
NOTE: Allowable anti-diabetic treatment 
includes metformin and/or sulfonylureas 
administered at constant dose for at least 2 
months prior to study entry    
 
NOTE: Subjects treated with Insulin are eligible 
if clinically stable on insulin treatment (i.e. no 
recurrent acute hypo-/hyperglycemic episodes 
diagnosed clinically and by Glucose serum 
levels of <50 mg/dL and >200 mg/dL 
respectively) for at least 2 months prior to 
study entry 
o immune modulatory agents including: 
 
Within 3 months of study entry: 
 
systemic steroids for more than 7 days 
 
daily treatment with multiple non-
steroidal anti-inflammatory drugs (such 
as aspirin (>100mg/day), ibuprofen, 
naproxen, meloxicam, celecoxib) for 
more than 1 month 
 
In the last 12 months: 
 
azathioprine, 6-mercaptopurine, 
methotrexate, cyclosporin, anti-TNFα 
therapies (infliximab, adalimumab, 
etanercept) or anti-integrin therapies 
(namixilab) 
 
More than 10 consecutive days oral or parenteral 
antibiotics within 4 weeks prior to study entry NOTE: 
subjects administered with antibiotics for more the 5 
days prior to study entry would not be included in the 
stool and PBMC analysis) 
 
Variable dose of antilipidemic agents (3-hydroxy-3-
methyl-glutaryl (HMG)-Co-A reductase inhibitors – 
“statins”) in the 3 months prior to study entry  
15. The following laboratory abnormalities:  

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o Neutrophil count ≤1.0 x 109/L 
o Platelets <100 x 109/L 
o Hemoglobin <10g/dL  
o Albumin <3.5g/dL 
o International Normalized Ratio (INR) >1.5 
o Total bilirubin >1.5 x upper limit of reference range 
(unless Gilbert’s syndrome or extrahepatic source as 
denoted by increased indirect bilirubin fraction) 
o Either creatinine clearance ≤60mL/minute calculated 
by Cockroft-Gault or creatinine >1.5x upper limit of 
reference range  
16. Known substance abuse, including inhaled or injected drugs 
in the year prior to Screening 
17. Cow milk allergy, lactose intolerance or any known or 
suspected hypersensitivity to study products  
 
Study 
procedures: 
Refer to Table 1 for the schedule of study procedures. 
 
Subjects who provide voluntary written informed consent will be 
screened for eligibility. Subjects meeting all of the inclusion and none 
of the exclusion criteria will be eligible to participate. 
 
Eligible subjects will be randomized at the Baseline visit to receive 
one of the three study treatments three times daily for a period of 24 
weeks. Each subject will return to the study clinic for assessment and 
required study procedures on Day 7, 14 and 28 and every 4 weeks 
thereafter until Week 24. A final follow-up visit will be conducted at 
Week 28 if the subject ceases treatment at Week 24. Investigational 
product dispensing and accountability will be conducted on a 4 
weekly basis.  
 
Unscheduled or early withdrawal visits may be necessary with study 
related procedures defined.  
 
Safety 
parameters: 
Adverse events, vital signs, electrocardiogram (EKG) and safety 
laboratory assessments will be conducted at Screening, Baseline and 
4 weekly throughout the study. 
 

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Sample size 
determination: 
Fat Liver Content Change from Baseline: 
The current sample size of 40 subjects per group should yield 
approximately 85% power to detect a treatment effect of at least -5% 
with respect to the difference in the mean change from Baseline 
between one of the IMM-124E treatment groups and placebo 
assuming a standard deviation (SD) of 7.3% (α=0.05; two-tailed; 
unpaired t-test). The SD of 7.3% for the change from Baseline 
endpoint was derived assuming 1) SDs of 6% for each timepoint, 2) 
equal variances in each treatment group and 3) a low to moderate 
correlation of 0.25 between pre- and post-Baseline measurements.  
 
 
Sample size and power estimates have not been adjusted for 
multiple comparisons or multiple endpoints, dropouts or stratification.  
 
The analysis of each primary endpoint will be based on a linear 
model that incorporates the baseline measure as a covariate, the 
stratification factor and randomized treatment group. Pairwise 
comparisons of each active treatment group to control will be 
conducted via linear contrasts.  
Statistical 
analyses: 
The populations for analysis will be as follows: 
 
Full Analysis Set (FAS) for Efficacy: includes all subjects who 
received at least one dose of study medication. Only subjects with 
clear documentation that no study medication was received may be 
excluded. In the event of treatment allocation errors, subjects will be 
analyzed for efficacy according to the treatment to which they were 
randomized. 
 
Safety Analysis Set:  includes all subjects who received at least one 
dose of study medication.  Only subjects with clear documentation 
that no study medication was received may be excluded.  In the 
event of treatment errors, subjects will be analyzed for safety 
according to the treatment received. 
 
Per Protocol Analysis Set: includes all subjects in the FAS above 
who complete 24 weeks of study treatment and have MRI and ALT 
measured at Baseline and at Week 24 and no major protocol 
violations, determined prior to break of the treatment blind.  
 
Intention-To-Treat (ITT) Analysis Set: The ITT analysis set includes 
all patients randomized to treatment. An ITT analysis will only be 
implemented in the event that one or more patients are randomized 
but do not receive any treatment. 
 
When at least 30 subjects reach 24 weeks visit and have verified MRI 
results an interim analysis will be performed.  
The interim analysis will include the full analysis of all primary and 
secondary un-blinded outcomes and will be used to determine the 
following: 
1. Efficacy at time of analysis  
2. Dose effect to determine the most 
effective dose for treatment  

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3. Correct for the overall sample size for 
the primary endpoint 
4. Overall Safety  
 

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Table 1: Table of Assessments 
Visit 
Screening 
Baseline 
D3 
D7 
D14 
W4 
W8 
W12 
W16 
W20 
W24/WD 
W28 
U/S 
Visit Window (relative to Baseline) 
-45 to 0 
0 
+/- 1D  +/- 1D  +/- 1D +/- 1D +/- 3D +/- 3D +/- 3D +/- 3D 
+/- 3D 
+/- 3D  
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization to study treatment 8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight/ BMI 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X  
 
Waist circumference; waist hip ratio 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
  
 
HOMA-IR 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
MELD score 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Resting Pulse, Blood pressure, Resp., Temp. 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical examination 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 lead EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Diet and exercise counseling 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Diet and exercise diary card issue 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Diet and exercise diary card collection and review 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
AUDIT questionnaire administration 
 
X 
 
 
 
 
 
X 
 
 
X 
  
 
Concurrent Meds recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI of the liver7 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
HIV, HCV & HBV serology6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum alpha feto protein (AFP) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Chemistry 1 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid panel2 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology3 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
HBA1C 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
Samples for serum biomarkers4 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
 
Samples for PBMC (selected sites only)5 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Serum metabolomics  
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Urine safety 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Stool sample collection (selected sites only) 
 
X 
 
 
 
X 
  
X 
  
  
X 
 
 
Study Drug Dispensing and Accountability 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 

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1 Must be collected after subject has fasted for at least 8 hours (except for Screening and W28 assessment). Including: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatine phosphokinase, 
creatinine, total protein, albumin, serum amylase (fractionated if > greater than upper limited of reference range), serum lipase, phosphate, GGT, AST, ALT, alkaline phosphatase, total bilirubin, calcium, 
uric acid, glucose and insulin. In addition CRP and C-peptide will be included at the following visits: Baseline, W4, W12 and W24. 
2 Including: total cholesterol, triglycerides, HDL and LDL   
3Including: hemoglobin, hematocrit, red blood cell (RBC) and RBC morphology, white blood cell (WBC) and differential WBC count, platelet count, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin concentration (MCHC). 
4Serum biomarkers – CK-18, LPS, adiponectin, GLP-1 and cytokines (IL-1α, IL1β, IL-2, IL-3, IL-4, IL-6, IL-10, IL-13, IL-12, IL-17α, IL-23, IFNγ, TGF-β and TNFα) 
5 PBMC - FACS analysis for CD4 CD8 CD25 FoxP3 NKT CD62 CD69 T cells 
6 Serology (including HIV, HCV and HBV test) results will be acceptable for eligibility within range of 6 months prior to screening. 
7 MRI: Baseline MRI to be performed as soon as subject eligibility is determined. Week 24 MRI to be done within +/- 2 weeks week 24. 
8 Randomization is to be done within 2 weeks post baseline MRI, when the MRI result is available for stratification (hepatic fat fraction form – to be received by central imaging lab).  
 

 
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TABLE OF CONTENTS 
 
1. 
STUDY SYNOPSIS ..................................................................................................... 3 
2. 
STUDY CONTACTS ................................................................................................... 19 
3. 
INTRODUCTION ......................................................................................................... 20 
3.1 
Epidemiology of Non-alcoholic Fatty Liver Disease 
20 
3.2 
Clinical Presentation 
20 
3.3 
Diagnostic Tools 
21 
 
Current Treatment for NASH ........................................................................... 21 
3.4 
IMM-124E - Hyperimmune Bovine Colostrum 
21 
 
Hyperimmune Bovine Colostrum as a Therapeutic.......................................... 21 
 
IMM-124E Composition .................................................................................. 22 
 
Pharmacology ................................................................................................... 22 
 
Preclinical Safety .............................................................................................. 22 
 
Metabolism and Pharmacokinetics ................................................................... 23 
 
Clinical Trials of IMM-124E ............................................................................ 23 
3.5 
Rationale 
24 
 
Dose Rationale .................................................................................................. 25 
 
Discussion of Study Design and Choice of Control Group(s) .......................... 25 
4. 
OBJECTIVES AND ENDPOINTS ............................................................................... 26 
4.1 
Objectives 
26 
4.2 
Endpoints 
26 
5. 
STUDY DESIGN ......................................................................................................... 28 
5.1 
Study Design 
28 
5.2 
Dosing Regimens 
28 
5.3 
Study Sites 
28 
5.4 
Estimated Duration of the Study 
28 
6. 
SUBJECT POPULATION ........................................................................................... 29 
6.1 
Subject Selection and Numbers 
29 
6.2 
Inclusion Criteria 
29 
6.3 
Exclusion Criteria 
29 
6.4 
Other Study Eligibility Criteria Considerations 
31 
 
Contraception .................................................................................................... 31 
 
Renal Function .................................................................................................. 31 
6.5 
Subject Enrollment 
31 
7. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES ............................................ 33 
7.1 
Study Schedule of Evaluations 
33 
7.2 
Study Procedures and Assessment Periods 
33 
 
Screening Assessments ..................................................................................... 33 
 
Randomization Process ..................................................................................... 33 
 
Day 0: Baseline Evaluations and Study Medication Administration ............... 34 
 
Day 3 ................................................................................................................. 34 
 
Day 7 ................................................................................................................. 34 
 
Day 14 ............................................................................................................... 35 
 
Weeks 4, 8, 12, 16 and 20 ................................................................................. 35 
 
Unscheduled Visit ............................................................................................. 36 

 
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Week 24 (or early withdrawal from treatment) ................................................ 36 
 
Week 28 (Post-treatment Follow-up) ............................................................... 36 
7.3 
Details of Study Assessments and Data Collection 
37 
 
Demographic Data, Medical History, Medication History and Concurrent 
Medication ........................................................................................................ 37 
 
Physical Examination and Targeted Examination ............................................ 37 
 
Vital Signs ........................................................................................................ 37 
 
Electrocardiograms ........................................................................................... 37 
 
Diet and Exercise Counseling and Assessment ................................................ 38 
 
Safety Laboratory Assessments ........................................................................ 38 
 
Screening & Serology Laboratory Parameters ................................................. 39 
 
Blood Samples for Pharmacokinetics ............................................................... 39 
 
Biomarkers ........................................................................................................ 39 
 
Urine Pregnancy Test ....................................................................................... 39 
 
Fecal Samples for Microbiome Assessment (selected sites only) .................... 40 
 
Handling and Processing of Biological Specimens .......................................... 40 
 
Disease Assessment .......................................................................................... 40 
7.4 
Visit/Assessment Windows 
40 
8. 
STUDY DRUGS .......................................................................................................... 41 
8.1 
Randomization 
41 
8.2 
Blinding 
41 
8.3 
Unblinding Procedures 
41 
8.4 
Formulation 
41 
 
Investigational Products ................................................................................... 41 
 
Supply, Packaging and Labeling, Storage and Handling ................................. 42 
 
Dispensing and Accountability ......................................................................... 42 
 
Dosage and Administration of Study Drugs ..................................................... 43 
9. 
CONCURRENT MEDICATIONS AND TREATMENTS ............................................... 44 
9.1 
Special Dietary Requirements 
44 
9.2 
Concurrent Medications/Treatments Not Permitted 
44 
 
Prior to Study Entry .......................................................................................... 44 
 
During the Study Dosing Period ....................................................................... 44 
10. 
ADVERSE EVENT REPORTING AND MANAGEMENT ............................................. 45 
10.1 
Safety Parameters 
45 
10.2 
Adverse Events 
45 
 
Assessment of AEs ........................................................................................... 45 
 
Adverse Event Reporting Period ...................................................................... 46 
10.3 
Serious Adverse Events 
46 
 
Serious Adverse Event Definition .................................................................... 46 
 
Clarification of Serious Adverse Events .......................................................... 46 
 
Serious Adverse Event Reporting Requirements ............................................. 47 
 
Investigator Reporting Requirements for SAEs ............................................... 47 
10.4 
Follow up of Serious and Non-serious Adverse Events 
48 
10.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs or 
SAEs 
48 
10.6 
Guidance for Discontinuation of Treatment 
48 
10.7 
Warnings and Precautions 
49 
10.8 
Risks for Women of Childbearing Potential or During Pregnancy 
49 
10.9 
Procedures to be Followed in the Event of Pregnancy 
49 

 
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11. 
SUBJECT COMPLETION/WITHDRAWAL ................................................................. 50 
11.1 
Subject Completion 
50 
11.2 
Criteria for Premature Withdrawal from Treatment or the Study 
50 
11.3 
Withdrawal of Subjects from Study drug 
50 
11.4 
Withdrawal of Subjects from the Study 
50 
11.5 
Replacement of Withdrawn Subjects 
51 
12. 
STATISTICAL ANALYSIS .......................................................................................... 52 
12.1 
Sample Size Determination 
52 
12.2 
Analysis Populations 
52 
 
Full Analysis Set (FAS) for Primary Assessment of Efficacy ......................... 52 
 
Safety Analysis Set ........................................................................................... 52 
 
Per Protocol Analysis Set ................................................................................. 53 
 
Intention-To-Treat (ITT) Analysis Set ............................................................. 53 
12.3 
Subject Disposition, Baseline Demographics and Disease Status 
53 
12.4 
Statistical Analysis Plan 
53 
12.5 
Efficacy Analyses 
53 
 
Other Efficacy Analyses ................................................................................... 53 
 
Exploratory Analyses ....................................................................................... 54 
 
Final Analysis ................................................................................................... 54 
12.6 
Analysis of Safety 
54 
 
Incidence of Adverse events ............................................................................. 54 
 
Clinical Laboratory Parameters ........................................................................ 54 
 
Vital Signs ........................................................................................................ 54 
12.7 
Analysis of Pharmacokinetics 
54 
12.8 
Interim Analysis 
54 
13. 
GENERAL STUDY ADMINISTRATION ...................................................................... 56 
13.1 
Ethical Aspects 
56 
 
Local Regulations/Declaration of Helsinki ...................................................... 56 
 
Informed Consent ............................................................................................. 56 
 
Institutional Review Boards/Ethics Committees .............................................. 56 
 
Conditions for Modifying the Protocol ............................................................ 56 
 
Conditions for Terminating the Study .............................................................. 57 
13.2 
Study Documentation, CRFs and Record Keeping 
57 
 
Investigator Files/Retention of Documents ...................................................... 57 
 
Background Data .............................................................................................. 58 
 
Audits and Inspections ...................................................................................... 58 
 
Case Report Forms ........................................................................................... 58 
13.3 
Monitoring the Study 
58 
13.4 
Confidentiality of Trial Documents and Subject Records 
59 
13.5 
Publication of Data and Protection of Trade Secrets 
59 
13.6 
Anticipated Subject Accrual and Duration of the Study 
59 
14. 
REFERENCES ............................................................................................................ 60 
15. 
APPENDICES ............................................................................................................. 64 
APPENDIX A 
ADVERSE EVENT TOXICITY GRADING SCALES .................................. 65 
Clinical abnormalities ..................................................................................................... 65 
APPENDIX A - Clinical abnormalities, continued 
66 
APPENDIX A - Laboratory Abnormalities 
67 
APPENDIX A – Laboratory Abnormalities, continued 
68 

 
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APPENDIX B 
MODEL PATIENT INFORMATION SHEET .............................................. 69 
APPENDIX C 
HOMEOSTATIC MODEL ASSESSMENT OF INSULIN RESISTANCE     
SCORE 
83 
APPENDIX D 
ALCOHOL USE DISORDERS IDENTIFICATION TEST (AUDIT) 
QUESTIONNAIRE ...................................................................................................... 84 
APPENDIX E 
STANDARDIZED DIET AND EXERCISE COUNSELING ......................... 86 
APPENDIX F 
DIET AND EXERCISE DIARY CARD ....................................................... 87 
APPENDIX G 
PROTOCOL AMENDMENT #3 – SUMMARY OF CHANGES .................. 88 
 

 
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LIST OF TABLES 
 
Table 1: 
Table of Assessments .......................................................................................................... 10 
Table 2:   IMM-124E daily dose levels ................................................................................................. 28 
Table 3: Safety Laboratory Parameters ................................................................................................. 38 
Table 4:  Screening tests - serum ........................................................................................................... 39 
Table 5:  Biomarkers for analysis .......................................................................................................... 39 
Table 6:  Visit/assessment windows ...................................................................................................... 40 
Table 7:  Investigational Products ......................................................................................................... 41 
Table 8:  Treatment regimen and tablet allocation ................................................................................ 42 
Table 9: Severity Grades ....................................................................................................................... 45 
Table 10: Adverse Event Causality Definitions .................................................................................... 46 

 
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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
Term 
Definition 
oC 
Degrees Celsius 
µg 
Microgram(s) 
AE 
Adverse Event 
ALT 
Alanine aminotransaminase 
AST 
Aspartate aminotransaminase 
AUC 
Area under the curve 
AUDIT 
Alcohol Use Disorders Identification Test 
BCP 
Bovine colostrum powder 
BMI 
Body mass index 
BP 
Blood pressure 
CFR 
CK 
Code of Federal Regulations 
Cytokeratin 
cm 
centimeter 
Cmax 
Cmin 
Maximum concentration 
Minimum concentration 
CRF 
CRP 
Case report form 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
D 
Day 
dL 
Deciliter 
EKG 
Electrocardiogram 
ELISA 
ETEC 
Enzyme-linked immunosorbent assay 
Enterotoxigenic Escherichia Coli  
FDA  
Food and Drug Administration, United States of America 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transpeptidase 
GLP 
GLP-1 
H&E 
HBA1C 
Good Laboratory Practice(s) 
Glucagon-like peptide-1 
Hematoxylin & Eosin 
Hemaglobin A1C 
HBV 
Hepatitis B virus 
HCV 
HDL 
Hepatitis C virus 
High density lipoprotein 
HIV 
HMG Co-A 
HOMA-IR 
Human immunodeficiency virus 
3-hydroxy 3-methyl glutaryl Co-A 
Homeostatic Model of Insulin Resistance 
HREC 
Human Research Ethics Committee 
IB 
Investigator’s Brochure 
ICH 
IEC 
International Conference on Harmonization 
Independent Ethics Committee 
IFNγ 
IgG 
Interferon gamma 
Immunoglobulin G 
IL 
IND 
Interleukin 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ITT 
Intention-to-treat 

 
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kg 
Kilograms 
L 
LDL 
LPS 
Liter 
Low density lipoprotein 
Lipopolysaccharide 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
mg 
Model of End-stage Liver Disease 
Milligram(s) 
min 
Minute(s) 
mL 
Milliliter(s) 
mmHg 
Millimeter of mercury 
MR 
MRI 
Magnetic Resonance 
Magnetic Resonance Imaging 
NAFL(D) 
NAS 
NASH 
Non-alcoholic fatty liver (disease) 
NASH activity score 
Non-alcoholic steatohepatitis  
PBMC 
Peripheral blood mononuclear cells 
PD 
Pharmacodynamic(s) 
pH 
Measure of acidity 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RBC 
Red blood cells 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
T1/2 
TGS 
Half-life 
Toxicity Grading Scale 
TNFα 
TK 
Tregs 
W 
Tumor Necrosis Factor alpha 
Toxicokinetic(s) 
Regulatory T cells 
Week 
WBC 
White blood cells 
 

 
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2. STUDY CONTACTS 
Please refer to the Study Reference Manual for full study contacts. 
 

 
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3. INTRODUCTION 
3.1 
Epidemiology of Non-alcoholic Fatty Liver Disease 
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in most 
of the Western world. Approximately 7.9% of the population in the United States has persistently 
elevated liver enzymes without any clear etiology [Clark et al., 2003] and it is hypothesized that over 
80% of these cases are due to NAFLD. In those who have concomitant features of metabolic 
syndrome, the likelihood of NAFLD exceeds 90%. Based on Magnetic Resonance Imaging (MRI), it 
has been estimated that the overall prevalence of NAFLD in the United States is approximately 30% 
[Browning JD, 2004].  
 
The more severe, progressive form of NAFLD, non-alcoholic steatohepatitis (NASH), is an 
increasingly common chronic liver disease with distribution that is closely associated with diabetes 
and obesity, which have both reached epidemic proportions. Approximately 6 million individuals in 
the USA are estimated to have progressed to NASH and some 600,000 to NASH-related cirrhosis 
[World Gastroenterology Organization Global Guidelines, Nonalcoholic Fatty Liver Disease, and 
Nonalcoholic Steatohepatitis, June 2012]. However, estimates of 5.7% of the general population [Ong 
et al., 2007] and in excess of 12% in a middle aged US population [Williams et al 2011] have been 
made. 
 
3.2 
Clinical Presentation 
NAFLD is the hepatic manifestation of the metabolic syndrome, a condition characterized by the 
presence of at least three of five co-morbidities: abdominal (central) obesity, elevated blood pressure, 
elevated fasting plasma glucose, high serum triglycerides and low high-density lipoprotein (HDL) 
levels [Kang et al, 2006].  
 
The probability of having NAFLD rises with increasing body mass index (BMI) with over 80% of 
subjects with a BMI > 35 having NAFLD. The histological spectrum of NAFLD includes: isolated 
hepatic steatosis, characterized by a fatty liver with no other histological abnormalities and also 
referred to as nonalcoholic fatty liver (NAFL); and steatohepatitis, characterized by steatosis 
associated with histological abnormalities that include cytological ballooning, Mallory’s hyaline, 
inflammation and pericellular fibrosis [Kleiner et al., 2005]. NASH is defined by the presence of 
predominantly macrovesicular hepatic steatosis or steatohepatitis in individuals who either do not 
consume alcohol or consume it in quantities that are not generally considered to be harmful to the liver 
[Sanyal, 2002]. There are currently no non-invasive ways to distinguish NAFLD from NASH. 
 
NAFLD is associated with a benign clinical course and the majority of cases remain asymptomatic and 
free of fibrosis or development of steatohepatitis over a 5 to 10 year time frame from diagnosis [Teli et 
al., 1995]. The development of steatohepatitis requires both accumulation of fat and additional 
injurious processes in the liver. It is believed that oxidative stress plays an important role in this 
process. The impact of the gut microbiome on weight gain, fat accumulation and development of 
NAFLD is being actively investigated [Compare et al., 2012, Manco et al., 2010]. 
 
The immune system plays a role in the pathogenesis of NAFLD and its complications. Metabolic 
syndrome, obesity and NASH are all associated with a state of chronic inflammation. The immune 
system and the inflammatory cascade are common to the development of these conditions. 
 
NASH progresses to cirrhosis in approximately 20% of cases [McCullough, 2002] and is also 
associated with an increased risk of cardiovascular mortality and type 2 diabetes mellitus. Cirrhosis 
due to NASH also increases the risk of hepatocellular carcinoma and NASH contributes substantially 
to the population burden of hepatocellular cancer [Vernon et al., 2011]. Twenty two to 33% of patients 
who have cirrhosis die of complications of liver failure or require liver transplantation [Ong et al., 
2007].  
 

 
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3.3 
Diagnostic Tools 
Currently, abnormal liver function tests are the primary method of identifying patients for further 
investigation for NAFLD and NASH. Population based studies have utilized imaging modalities such 
as ultrasound and MRI to diagnose NAFLD but are limited by the absence of histologic confirmation. 
Recently, changes on MRI have been correlated with hepatic lipid content [Yokoo et al 2008]. The 
presence of NAFLD can be diagnosed with relative confidence using MRI [Schwenzer et al., 2009]. 
MR spectroscopy and imaging techniques have been shown to have utility and greater sensitivity for 
fat quantification compared with histology-determined steatosis. [Noureddin et al 2013].  
 
NASH presents with variable presence of steatosis, inflammation and cytologic ballooning and is 
usually determined on an overall assessment of histologic findings on liver biopsy. In order to 
standardize the assessment, a NASH activity score (NAS) was developed by the National Institutes of 
Health (NIH) NASH Clinical Research Network [Kleiner et al 2005]. Steatohepatitis is diagnosed 
when scored 4 or more. MRI provides information about liver fat content but does not distinguish 
between NAFL and NASH [Saadeh et al., 2002].  
 
 
Current Treatment for NASH  
Currently, there is no specific treatment for NASH [Dixon et al., 2004; Neuschwender-Tetri et al., 
2003]. Patients presenting with NASH are advised to reduce their weight (if obese or overweight), 
follow a balanced and healthy diet, increase physical activity, avoid alcohol and avoid unnecessary 
medications (http://digestive.niddk.nih.gov/ddiseases/pubs/nash/#treatment). Experimental approaches 
aimed at reducing oxidative stress have potential as treatments. It has been reported that vitamin E 
improved liver histology in 43% of patients with NASH compared with 19% in a placebo group 
[Sanyal et al., 2010].  
 
Most patients with NASH have insulin resistance. Treatments for type-2 diabetes including metformin, 
rosiglitazone, and pioglitazone may have utility in this condition although these have been associated 
with weight gain. The metabolic syndrome and NASH can be treated with bariatric surgery in obese 
individuals to reduce dietary intake.  
 
3.4 
IMM-124E - Hyperimmune Bovine Colostrum  
The following summarizes current information on IMM-124E. 
 
 
Hyperimmune Bovine Colostrum as a Therapeutic 
Mammals supply their newborn before birth, at birth or shortly after birth with antibodies, 
immunocytes and humoral constituents. This “borrowed immunity” is a form of passive immunization 
to protect the newborn against environmental pathogens until it establishes its own pathogen 
recognition and disposal systems. In cows, goats, horses and some other animal species, most 
immunoglobulins are obtained from the colostrum, the first milk after birth, via the gut but in humans 
the majority of immunoglobulins, and those of the Immunoglobulin(Ig)G-class in particular, are 
acquired from the mother by placental transport in the weeks prior to parturition [Struff & Sprotte].  
 
Ingested proteins are normally degraded by proteases in the stomach and small intestine to form small 
peptides and amino acids which are subsequently absorbed. The proteolytic enzymes involved include 
pepsin, trypsin, chymotrypsin, carboxy-peptidase and elastase which initially degrade antibodies of the 
IgG type into F(ab’)2, Fab and Fc fragments. The F(ab’)2 and Fab fragments, however, retain some of 
their antigen neutralizing activity locally in the gastrointestinal tract [Reilly et al. 1997]. In addition 
the colostrum contains adjuvants which alter the systemic immune system (Adar et al. 2012). 
 

 
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IMM-124E Composition 
IMM-124E is hyperimmune bovine colostrum that is lactose- and fat-reduced. IMM-124E is harvested 
from the colostrum of dairy cows which have been immunized against the outer antigens, mostly LPS, 
of the most common strains of Enterotoxigenic Escherichia coli (ETEC). This inoculation activates a 
generalized immune response in the host animal to produce antibody clones which recognize and bind 
with the bacterial cell-surface epitopes presented. These polyclonal antibodies can also cross-react 
with other similar bacterial cell surface antigens.  
 
IMM-124E contains approximately 40% IgG in the drug substance, mainly IgG1 and IgA, with small 
amounts of IgM and IgE. The non-specific nature of the immunoglobulins in IMM-124E and high 
binding activity against the LPS moiety of ETEC and non-ETEC gram-negative bacteria facilitates the 
potential for broad protective coverage against these infective agents.  
 
Immuron’s IMM-124E-based product, Travelan, has been sold in Australia over-the-counter (for use 
by adults and children over 6 years of age) at a dose 200 mg three times a day since September 2004. 
Approximately 140,000 packets (30 tablets each packet) have been sold and no treatment-related 
adverse events have been reported.  
 
For more information on IMM-124E, please refer to the current Investigator’s Brochure 
 
 
Pharmacology 
3.4.3.1 In vitro Pharmacology 
IMM-124E contains anti-LPS antibodies to both the O polysaccharide and lipid A core region of all 
the serotypes included in the ETEC vaccine. These anti-LPS antibodies also cross-react with both lipid 
A-core and O-polysaccharide regions of eight other Gram negative bacteria. IMM-124E was able to 
bind and agglutinate ETEC bacteria in vitro. Flagella-specific antibodies present in IMM-124E Drug 
Substance were able to reduce bacterial motility and adherence to host-cells. For further information, 
please refer to the Investigator’s Brochure.  
 
3.4.3.2 In vivo Pharmacology 
3.4.3.2.1 Effect of IMM-124E in Leptin Deficient Ob/Ob Mice 
In leptin deficient Ob/Ob mice, oral administration of 1mg IgG-enhanced fraction of ETEC colostrum 
significantly decreased alanine aminotransferase (ALT) (p<0.05) and serum and hepatic triglycerides 
(p<0.009 and p<0.05, respectively) compared with control animals. Oral administration of the IgG-
enhanced fraction of ETEC colostrum induced regulatory T cells and alleviated the chronic 
inflammatory state in the metabolic syndrome, alleviating insulin resistance and liver injury. For 
further details, please refer to the Investigator’s Brochure.  
 
 
Preclinical Safety 
3.4.4.1 In vitro Safety  
No cytotoxicity or mutagenesis was shown in a Good Laboratory Practice (GLP) AMES study. For 
further information, please refer to the Investigator’s Brochure.  
 
3.4.4.2 In vivo Safety 
Two short-term, non-GLP, repeat-dose dietary studies were conducted in mice with hyperimmune 
bovine colostrum powder. There was no indication of treatment-related toxicity in either study.  
 
Freeze-dried hyperimmune bovine colostrum powder (10% w/w, test diet) or milk whey powder (10% 
w/w, control diet) was added to ground commercial feed for laboratory mice. The test and control 
batches were pelleted and fed for the duration of the trial (10 days). Mice were divided randomly into 
four groups (5/sex/group). After a 3-day acclimatization period on the diets, individual mice were 

 
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weighed each day and average food consumption was determined. All mice survived and the weight of 
mice in all four groups increased. Clinical observations did not reveal any adverse effects. There was 
no significant effect of diet, sex or diet-sex interaction on body weight changes between Days 3 and 
10.  
 
A second study was conducted using hyperimmune bovine colostrum powder at the Department of 
Microbiology, The University of Melbourne, Australia. Five female and five male mice per test group 
were given a bottle containing either bovine colostrum powder (50mg/mL) or skim milk or water for a 
total of eight days. All mice showed a steady increase in weight over the eight-day period with no 
adverse effects on health or behavior between the test and control groups. For further information, 
please refer to the Investigator’s Brochure. 
 
 
Metabolism and Pharmacokinetics 
The pharmacokinetics (PK) and toxicokinetics (TK) of IMM-124E have not been established.  
 
 
Clinical Trials of IMM-124E  
IMM-124E has been studied for the prevention of traveler’s diarrhea in three double-blind, 
randomized, placebo-controlled clinical trials in Europe and the USA, conducted to Good Clinical 
Practice (GCP) standard. A Phase 1 open label study in NASH has also been conducted.  
 
3.4.6.1 Study 1: Central Public University Hospital, Warsaw, Poland 
This was a double-blind, randomized, placebo-controlled, challenge trial with 60 healthy volunteers 
divided randomly into 4 groups. Each group of 15 was given either one or two IMM-124E or matching 
placebo tablets 3 times a day (with or without bicarbonate) before meals for 7 days and were then 
challenged with a pathogenic dose of O78 ETEC (1-2 x 109 bacteria). IMM-124E resulted in 
significant protection of the volunteers against the development of diarrhea after challenge with 
pathogenic doses of ETEC, compared with placebo (p<0.01). ETEC O78 was detected in the feces of 
most volunteers after challenge, independent of treatment, suggesting that the mode of action was 
blocking the bacteria from binding to the gut epithelium, rather than a bactericidal effect. There were 
no treatment related adverse events reported. For further information, please refer to the Investigator’s 
Brochure. 
  
3.4.6.2 Study 2: Central Public University Hospital, Warsaw, Poland 
This was a double-blind, randomized, placebo-controlled, challenge trial with 30 healthy volunteers 
randomly assigned to either 400mg IMM-124E or matching placebo tablets 3 times a day before meals 
for 7 days, before challenge with 1-2 x 109 O78 ETEC. Continuing the results of study 1, IMM-124E 
was significantly more effective (p<0.001) than placebo treatment in protecting the volunteers against 
the development of diarrhea after challenge with pathogenic doses of ETEC. Bacterial output in stools 
was not significantly different between placebo and treatment groups. There were no treatment related 
adverse events reported. For further information, please refer to the Investigator’s Brochure. 
 
3.4.6.3 Study 3: Center for Vaccine Development, University of Maryland, Baltimore, 
Maryland  
This was a double-blind, randomized, two-group, placebo-controlled, challenge trial of 22 healthy 
volunteers. Subjects were treated with ten tablets of active immunoglobulin concentrate containing an 
equivalent of 1.4 g of colostral immunoglobulins, or equivalent placebo, taken 3 times a day, with 
bicarbonate solution. Participants were closely observed by clinical staff. IMM-124E reduced the 
incidence of diarrhea by 44% following experimental challenge with ETEC strain O78. No treatment 
related adverse events were reported (Tacket et al., 1988). 
 

 
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3.4.6.4 Phase 1 Clinical Trial of IMM-124E in Patients with NASH, Hadassah Medical 
Center, Jerusalem  
This was an open-label investigator-initiated trial comprising 10 subjects with biopsy proven NASH 
and insulin resistance; subjects were treated for 30 days with IMM-124E 1800mg daily per orally. 
Response was determined by changes in liver function tests and metabolic syndrome. Comparison 
between Day 30 and Day 0 was performed for each patient. 
 
Oral administration of IMM-124E was well tolerated and no treatment-related adverse events were 
reported. Improvement in markers of insulin resistance were observed though these changes were not 
statistically significant over 30 days of treatment. A downward trend in HbA1C was observed in a 
majority of patients. Increases in peripheral blood mononuclear cells (PBMCs) CD4+CD25+, 
CD4+CD25+Foxp3+ Tregs and in CD4+CD62+ and CD4+CD25+ HLA-DR were also observed.  
 
3.5 
Rationale 
A close interplay exists between the gut and liver. This is based on the evidence that more than 70% of 
the blood liver supply derives from the portal vein, the direct venous outflow of the intestine [Compare 
et al. 2012]. 
Disturbances in the homeostasis between bacteria- and host-derived signals at the epithelial level lead 
to a break in intestinal barrier function and may foster “bacterial translocation”, defined as the 
migration of bacteria or bacterial products from the intestinal lumen to mesenteric lymph nodes or 
other extraintestinal organs and sites. While the full repertoire of gut-derived microbial products that 
reach the liver in health and disease is yet to be explored, the levels of bacterial LPS are increased in 
the portal and/or systemic circulation in several types of chronic liver diseases, including NASH 
[Manco et al., 2010]. Derangement of the gut flora, particularly small intestinal bacterial overgrowth, 
occurs in a large percentage (20-75%) of patients with chronic liver disease. It has been suggested that 
fatty diets promote gut microbiota changes and endotoxins produced by gram negative bacteria 
promote the development of NASH [Compare et al. 2012].  
Hepatic steatosis is commonly associated with factors such as obesity and sub-clinical insulin 
resistance. Vulnerability to subsequent insults such as endogenous or exogenous toxins increases the 
production of pro-inflammatory cytokines. This further exacerbates insulin resistance, oxidative stress 
and organelle dysfunction within liver cells. In addition, circulating LPS has been found to trigger a 
molecular cascade which results in the release of pro-inflammatory cytokines. The latter eventually 
leads to hepatocyte death and the accumulation of inflammatory cells seen in NASH. In mice, LPS has 
also been associated in studies with increase in body weight and accumulated intrahepatic triglyceride 
[Manco et al 2010].  
Bovine colostrum contains increased concentrations of immunoglobulins (mainly IgG) compared with 
normal cow’s milk, presented with other physically protective milk proteins. IgGs are not absorbed 
into the blood and act in the lumen against bacterial antigens or interact at the mucosal surface with 
dendritic cells that sample antigens from gut contents, influencing populations of T regulatory 
lymphocytes. 
 
IMM-124E has strong binding and neutralising activity against a wide range of LPS antigens. It is 
hypothesised that IMM-124E anti-LPS activity decreases the challenge of LPS to the liver and down-
regulates the key T regulatory cell population associated with chronic inflammation and other 
metabolic defects associated with NASH.  
 
In addition to its potential effect on bacterial translocation, IMM-124E contains adjuvants which 
promote regulatory T cells that suppress inflammation in target organs. The dual function of this 
product may be synergistic in alleviating NASH (Adar et al. 2012). 
 

 
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A clear unmet medical need remains in the treatment of NASH and an oral, well tolerated treatment 
for this condition is needed. Bovine colostrum, either as standard or hyperimmune colostrum, has an 
excellent safety profile [Sarker et al., 1998; Tacket et al., 1992; Mitra et al., 1995; Opekun et al., 
1999].   
 
 
Dose Rationale 
3.5.1.1 Pharmacodynamic Dose Modeling 
Preclinical models of NASH do not provide reliably predictable data for allometric scaling. Further the 
open-label single-center investigator initiated trial conducted in a small number of subjects (n=10) 
with type 2 diabetes and NASH (1800mg daily for 30 days) was not of sufficient size or duration to 
answer whether the response was optimal. Empirically, the 1800mg/day dose will be included in this 
clinical trial and a higher dose evaluated to establish a dose response curve.  
 
3.5.1.2 Safety Dose Modeling  
IMM-124E is well tolerated in clinical studies and in the market place. While the typical dose for 
traveler’s diarrhea is 600mg/day, doses as high as 10g four times daily have been studied. Adverse 
reactions have been few in number and mild in severity. In most clinical studies of bovine colostrum, 
there have been no treatment related adverse events reported and no clear pattern in events [Tacket et 
al., 1992; Shield et al., 1993; Mitra et al., 1995; Sarker et al., 1998; Huppertz et al., 1999; Opekun et 
al.,1999].  
 
Adverse events observed include: 
 
nausea, flatulence [Rump et al., 1992; Plettenberg et al., 1993] 
 
nausea and vomiting in 1/24 patients [Greenberg and Cello 1996] 
 
mild diarrhea in 1/8 adult volunteers [Lissner et al., 1998] 
 
Tacket et al. (1988) reported no adverse clinical signs, but transient moderate elevations in serum 
levels of hepatic transaminases in volunteers who received bovine immunoglobulin concentrates 
prepared against E. coli (5/10) and rotavirus (2/10). This effect was attributed to diets high in protein 
provided at the hospital. Colostrum administration should be avoided in person allergic to cow’s milk 
or with lactose intolerance.  
 
The known safety profile of bovine colostrum gives a substantial therapeutic index. Therefore, the 
highest dose to be evaluated will be 3600mg/day.  
 
 
Discussion of Study Design and Choice of Control Group(s) 
A placebo controlled, randomized, double blind design represents the highest standard of clinical trial 
design available. The study will be multicenter to allow recruitment to occur in a reasonable 
timeframe.  Given the known safety profile of IMM-124E, a parallel design with two dose levels is 
proposed. 
 

 
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4. OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
The primary objectives of this study are to: 
 
Evaluate the safety and preliminary efficacy of two dose levels of IMM-124E in reducing liver 
fat evaluated on MRI compared with placebo in subjects with biopsy proven NASH.  
 
The secondary objectives are to: 
 
Determine the pharmacokinetic profile of IMM-124E; 
 
Assess the impact of treatment with IMM-124E on markers of glucose metabolism and on 
serum lipid profile; 
 
Assess the impact of treatment on liver function over 24 weeks; 
 
Establish the recommended dose. 
 
Exploratory objectives are to investigate the impact of treatment on potentially relevant immune and 
metabolic biomarkers associated with NASH. 
 
 
4.2 
Endpoints 
Safety and efficacy measures for NASH subjects receiving IMM-124E compared with subjects 
receiving placebo: 
 
Primary endpoints: 
Safety:  
 
Incidence and severity of adverse events and changes in vital signs and clinical laboratory 
parameters 
 
Efficacy:       
 
Mean change from Baseline in the percentage fat content of the liver measured by MRI at 
Week 24  
 
Secondary endpoints:  
Pharmacokinetics:  
 
Serum concentration of IMM-124E bovine antibodies over time (if measurable) including, but 
not limited to, maximum observed concentration (Cmax), minimum observed concentration 
(Cmin) and area under the concentration-time curve (AUC), and, if feasible, elimination half-
life (T½) 
Metabolic markers: 
 
BMI, waist circumference, waist:hip ratio, HBA1C and HOMA-IR 
 
Serum lipid profile – total cholesterol, triglycerides, LDL and HDL fractions 
Liver function: 
 
Mean change from Baseline in serum ALT, AST, bilirubin, albumin and GGT at Weeks 4, 8, 
12, 16, 20 and 24  
 
Proportion of subjects whose ALT at Week 24 is within reference range defined a <19IU/L for 
women and <30IU/L for men 
 
The proportion of subjects demonstrating a decrease in serum ALT at 24 weeks compared to 
baseline equal or greater than 30% compared to placebo 
MRI: 
 
The proportion of subjects demonstrating a decrease in Liver percent fat by MRI at 24 weeks 
compared to baseline equal greater than 5% compared to placebo 
 
The proportion of subjects demonstrating a decrease in Liver percent fat by MRI at 24 weeks 
compared to baseline equal greater than 10% compared to placebo 
 

 
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Exploratory endpoints: 
 
Mean serum concentrations of: LPS, CK-18 fragments and adiponectin and subsets of cytokines 
IL6, IL-1α, IL1β, IL-2, IL-3, IL-4 IL-10, IL-13, IL-12, IL-17α, IL-23, IFNγ TGFβ and TNFα 
 
Serum metabolomics  
 
Relative levels of regulatory T cells in PBMC samples, including CD4, CD8, CD25, FoxP3, 
NKT and CD62 
 
Characterization of the gut microbiome. 
 
Explore a dose effect 

 
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5. STUDY DESIGN 
5.1 
Study Design 
This is a randomized, double blind, placebo controlled, 3-arm parallel group, multi-dose, multi-center 
study 
 
5.2 
Dosing Regimens 
There are 3 regimens in this study as described in Table 2 below. 
 
Table 2:   IMM-124E daily dose levels 
Treatment 
arm 
IMM-124E Dose  
A 
600mg three times daily  
B 
1200mg three times daily 
C 
matching placebo only, three times daily 
 
At least 40 subjects will be enrolled into each cohort. For each subject, the 24 week primary treatment 
period will consist of three times daily oral administration of the allocated IMM-124E dose or 
matching placebo.  
 
5.3 
Study Sites 
This will be a multicenter study involving approximately 30 clinical study sites. 
 
5.4 
Estimated Duration of the Study 
The recruitment period will be approximately 24 months. The Screening period will be up to 45 days 
and subjects will receive treatment for 24 weeks. Subjects who withdraw from treatment will be 
followed for 28 days after treatment cessation, where possible.  

 
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6. SUBJECT POPULATION 
6.1 
Subject Selection and NumbersThe nature of the study and the potential risks will be 
explained to all candidates. Written informed consent will be obtained from each subject prior to 
performing any screening procedures. There will be no exemptions and subjects must satisfy all 
eligibility criteria in order to participate. At least 120 subjects will be enrolled. 
Inclusion and exclusion criteria are to be determined at Screening unless otherwise indicated. 
 
6.2 
Inclusion Criteria 
The criteria for entry into the study are: 
 
1. Age ≥18 years  
2. Provision of written informed consent 
3. Diagnosis of NASH, histologically proven within 12 months of Screening with all of the 
following criteria met: 
• NASH activity score (NAS) of 4 or more 
• Cytologic ballooning score of at least 1  
• 10% or more macrovesicular steatosis 
• Hematoxylin & Eosin (H&E) stained slides and/or paraffin block available for 
independent assessment 
4. HBA1C of ≤ 9.0  
5. Agree to the use of effective contraceptive measures if either male or female of child 
bearing potential 
 
6.3 
Exclusion Criteria 
The criteria for exclusion from the study are: 
 
1. Presence of vascular liver disease or cirrhosis  
2. Presence of liver disease from other cause (autoimmune, metabolic, medication induced) 
3. BMI <25kg/m2 
4. Alcohol use >30g/day 
5. Type 1 diabetes 
6. History of major bariatric surgery (not including balloon / sleeve gastrectomy) 
7. Weight loss or gain of 5kg or more in the past 6 months or >10% change in bodyweight in 
the past 12 months  
8. Contraindication for MRI 
9. Inadequate venous access 
10. Lactating/breastfeeding/pregnant at Screening or Baseline 
11. HIV antibody positive, hepatitis B surface antigen positive (HBsAg) or hepatitis C virus- 
RNA positive 
12. Receiving an elemental diet or parenteral nutrition 
13. Concurrent conditions: 
 
Inflammatory bowel disease 
 
Unstable angina, myocardial infarction, transient ischemic events, or stroke within 24 
weeks of Screening 
 
Ongoing infectious disease 
 
Ongoing multi-systemic immune-mediated disease 
 
Concurrent or past malignant disease  
 
Any other concurrent condition which, in the opinion of the investigator, could impact 
adversely on the subject participating or on the interpretation of the study data 

 
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14. Concurrent medications including: 
 
Anti-NASH therapy(s) taken for more than 10 continuous days in the last 3 months. 
These include S-adenosyl methionine (SAM-e), betaine, milk thistle, bacterial 
probiotic supplements (other than yoghurt or other natural food sources), vitamin E 
and gemfibrozil.  
 
 
NOTE: If determinant biopsy is performed while on stable treatment – subject 
is eligible; 
 
Wash out for any of the anti-NASH therapies is as follow: under 10 days no 
washout required, more than 10 days and up to 3 months treatment requires 6 
weeks washout. Any treatment of over 3 months would require to re-biopsy to 
ensure histological eligibility 
 
Thiazolidinediones (glitazones), dipeptidyl peptidase 4 inhibitors (gliptins) or 
glucagon-like peptide-1 analogs in the last 6 months.  
NOTE: if determinant biopsy is performed while on stable treatment of at 
least 6 months – subject is eligible. 
 
NOTE: Allowable anti-diabetic treatment includes metformin and/or 
sulfonylureas administered at constant dose for at least 2 months prior to 
study entry  
 
NOTE: Subjects treated with Insulin are eligible if clinically stable on insulin 
treatment (i.e. no recurrent acute hypo-/hyperglycemic episodes diagnosed 
clinically and by Glucose serum levels of <50 mg/dL and >200 mg/dL 
respectively) for at least 2 months prior to study entry 
 
immune modulatory agents including: 
 
Within 3 months of study entry:  
 
systemic steroids for more than 7 days 
 
daily treatment with multiple non-steroidal anti-inflammatory drugs 
(such as aspirin >100mg/day, ibuprofen, naproxen, meloxicam, 
celecoxib) for more than 1 month 
 
In the last 12 months: 
 
azathioprine, 6-mercaptopurine, methotrexate, cyclosporin, anti-
TNFα therapies (infliximab, adalimumab, etanercept) or anti-integrin 
therapies (namixilab) 
 
more than 10 consecutive days oral or parenteral antibiotics within 4 weeks prior to 
study entry NOTE: subjects administered with antibiotics for more the 5 days prior to 
study entry would not be included in the stool and PBMC analysis) 
 
Variable dose of anti-lipidemic agents (HMG Co-A reductase inhibitors – “statins”) in 
the 3 months prior to Screening  
15. The following laboratory abnormalities:  
 
Neutrophil count ≤ 1.0 x 109/L 
 
Platelets <100 x 109/L 
 
Hemoglobin <10g/dL  
 
Albumin < 3.5g/dL 
 
International Normalized Ratio (INR) >1.5 
 
Total bilirubin >1.5 x upper limit of reference range (unless Gilbert’s syndrome or 
extrahepatic source as denoted by increased indirect bilirubin fraction) 
 
Either creatinine clearance ≤ 60 mL/minute calculated by Cockroft-Gault or creatinine 
>1.5x upper limit of reference range (see Section 6.4.2).  
16. Known substance abuse, including inhaled or injected drugs in the year prior to Screening 
17. Cow milk allergy, lactose intolerance or any known or suspected hypersensitivity to study 
products  
 

 
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6.4 
Other Study Eligibility Criteria Considerations 
In order to assess any potential impact on subject eligibility with regard to safety, the investigator must 
refer to the relevant document(s) for detailed information regarding warnings, precautions, 
contraindications, adverse events, and other significant data pertaining to the investigational product(s) 
being used in this study. Such documents may include, but are not limited to, the Investigator’s 
Brochure.  
 
 
Contraception 
All women of child bearing potential (defined as sexually mature women who have had menses within 
the preceding 24 months and have not undergone hysterectomy, bilateral oophorectomy or tubal 
ligation) must have a negative pregnancy test (with a sensitivity of at least 50IU/mL) performed at 
Screening and at Baseline. 
 
Women of child bearing potential must agree not to attempt to become pregnant or undergo in vitro 
fertilization and, if participating in sexual activity that could lead to pregnancy, must use two reliable 
methods of contraception simultaneously while receiving protocol-specified medication and for 28 
days after stopping the medication. Male subjects must agree to use two reliable methods of 
contraception simultaneously while receiving protocol-specified medication and for 28 days after 
stopping the medication if their partner is of child bearing potential. 
 
A combination of two of the following methods must be used: 
 
Condoms (male or female) with or without a spermicidal agent 
 
Diaphragm or cervical cap with spermicide 
 
Intra Uterine Device 
 
Hormonal-based contraception 
 
Women who are not of reproductive potential (who have been postmenopausal for at least 24 
consecutive months or have undergone hysterectomy, bilateral oophorectomy or tubal ligation) are not 
required to use contraception. 
 
 
Renal Function 
Renal function eligibility may be determined by either estimated creatinine clearance calculated by 
Cockroft-Gault formula or serum creatinine.  
 
The Cockcroft-Gault Formula is: 
 
Creatinine clearance (mL/min) = (140-age) x (Bodyweight in kg) x (0.85 if female) 
 
 
 
 
 
(72 x Serum creatinine (mg/dL) 
 
 
6.5 
Subject Enrollment 
Before subjects may be entered into the study, Immuron requires a copy of the site’s written 
institutional review board (IRB) or human research/independent ethics committee (HREC/IEC) 
approval of the protocol, informed consent form, and all other subject information, as applicable. All 
subjects or legally acceptable representatives must personally sign and date the consent form before 
enrolment.  
 
All subjects who provide written informed consent will be sequentially assigned a Subject Number. 
This number will be used to identify the subject throughout the clinical study and must be used on all 
study documentation related to that subject. Subjects who meet the inclusion/exclusion criteria will be 
randomly assigned to treatment using a permuted block randomization.  
 

 
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All screening tests and procedures should be performed within the 45 days prior to enrolment in the 
study at Baseline, unless otherwise indicated. Randomization and enrolment will be conducted as 
described in Section 8. 
 

 
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7. SCHEDULE OF ASSESSMENTS AND PROCEDURES 
7.1 
Study Schedule of Evaluations 
The schedule of assessments is presented in Table 1. 
 
7.2 
Study Procedures and Assessment Periods 
The study procedures to be conducted for each subject enrolled in the study are listed below. 
Additional information on the study procedures is provided in Section 7.4. Any deviation from 
protocol procedures must be noted in the source notes and the Sponsor notified. 
 
Additional visits and/or assessments may be conducted as clinically indicated. For these additional 
assessments, data may be collected on unscheduled Case Report Form (CRF) pages provided, together 
with all adverse events (AEs) and concurrent medication that must be recorded throughout the study 
period. 
 
 
Screening Assessments 
Subjects will be screened up to 45 days prior to treatment initiation to determine eligibility for 
participation in the study. Screening assessments may be conducted on different days during this 45 
day period, if required.  
 
The following will be performed and documented during Screening: 
 
 
Obtain written informed consent prior to any study related procedures 
 
Demographic data (see Section 7.3.1) 
 
Medical history (see Section 7.3.1) 
 
A complete physical examination including: (see Section 7.3.2) 
 vital signs (blood pressure, temperature, heart rate and respiratory rate: see Section 7.3.3) 
 bodyweight 
 height 
 assessment of all appropriate body systems to determine study eligibility 
 
12-lead electrocardiogram (EKG) (see Section 7.3.4) 
 
Medication history and concurrent medication assessment (see Section 9.2) 
 
Collection of urine for dipstick urinary testing (see Section 7.3.6) 
 
Collection of blood samples for:  
 Hematology (see Section 7.3.6) 
 Coagulation (see Section 7.3.6) 
 Clinical chemistry (see Section 7.3.6) 
 Alfa-feto protein (see Section 7.3.6) 
 HBA1C (see Section 7.3.6) 
 HIV, HCV and HBV serology (see Section 7.3.7) 
 Pregnancy test for women of childbearing potential (see Section 7.3.7) 
 
Results of all screening tests must be available and reviewed against the eligibility criteria (see 
Section 6) prior to the subject’s Baseline visit.  
Subjects meeting all the inclusion criteria and none of the exclusion criteria will return to the clinic 
within 45 days after commencement of Screening for MRI scan as part of the Baseline evaluations. 
 
 
Randomization Process 
Upon completion of screening assessments and confirmation that the subject meets all eligibility 
criteria, baseline MRI scan is to be performed and valid result from central imaging lab to be obtained. 
Upon receipt of scan results the subject will be randomized to study treatment at the Baseline visit 
(See Section 8.1 and the Study Reference Manual). The randomization number will be recorded in the 
subject’s study documentation.  

 
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Day 0: Baseline Evaluations and Study Medication Administration  
Upon completion of screening assessments and confirmation that the subject meets all eligibility 
criteria (up to 45 days), baseline MRI scan of the liver (Section 7.3.13) is to be performed. Valid result 
for baseline MRI scan by the central imaging lab (VirtualScopics) must be obtained before 
randomization. 
 
Subjects meeting all of the inclusion and none of the exclusion criteria and have a valid baseline MRI 
result will attend the Baseline Visit (Day 0) within 14 days of the baseline MRI. At the Baseline Visit 
subjects will be randomized and receive study medication.  
The following procedures performed and documented: 
 
Urine pregnancy test for women of childbearing potential (see Section 7.3.10) 
 
A targeted physical examination (see Section 7.3.2) 
 
Adverse event (AE) assessment (see Section 10.2) 
 
Measurement of vital signs (blood pressure, temperature, heart rate and respiratory rate) (see 
Section 7.3.3) 
 
Measurement of bodyweight and waist and hip circumferences (see Section 7.3.3) 
 
Concurrent medication recording (see Section 9) 
 
Diet and exercise counseling and 7-day diary issue  (see Section 7.3.5) 
 
Administration of the Alcohol Use Disorders Identification Test (AUDIT) questionnaire 
 
Collection of blood and serum samples for:  
 Hematology (see Section 7.3.6)  
 Coagulation (see Section 7.3.6) 
 Fasting clinical chemistry (see Section 7.3.6) 
 Fasting lipid analysis, including HOMA-IR (see Section 7.3.6) 
 Pharmacokinetics - prior to study drug administration (see Section 7.3.8) 
 PBMCs (see Section 7.3.9) – selected sites only 
 Biomarker analysis, including for CK-18 fragments,  LPS, adiponectin, GLP-1 and 
cytokines (see Section 7.3.9) 
 Serum metabolomics  
 
Collection of a stool sample for microbiome assessment (see Section 7.3.11) – selected sites 
onlySubject randomization and dispensing of study medication (see Section 8). The first dose 
should be taken in the clinic where possible. Study treatment will be administered as described 
in Section 8.5.4  
 
If a subject is screened and eligible for the study, but unable to participate immediately, they may be 
rescreened once, under a new Subject identification number. Rescreening of these subjects must be 
discussed and agreed with the Medical Monitor. Subjects with laboratory abnormalities that are 
exclusionary, but inconsistent with previous history, may be re-tested once.  
 
 
 
Day 3  
The following procedures will be performed by either phone call or clinic visit: 
 
AE assessment (see Section 10.2) 
 
Concurrent medication recording (see Section 9) 
 
 
Day 7 
Subjects will return to the clinic and the following procedures will be performed: 
 
A targeted physical examination (see Section 7.3.2) 
 
AE assessment (see Section 10.2) 
 
Vital signs (blood pressure, temperature, heart rate and respiratory rate) (see Section 7.3.3) 

 
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 
Concurrent medication recording (see Section 9) 
 
Collection of blood and serum samples for:  
 Hematology (see Section 7.3.6)  
 Coagulation (see Section 7.3.6) 
 Fasting clinical chemistry (see Section 7.3.6) 
 Fasting lipid analysis, including HOMA-IR (see Section 7.3.6) 
 
 
Day 14 
Subjects will return to the clinic and the following procedures will be performed: 
 
A targeted physical examination (see Section 7.3.2) 
 
AE assessment (see Section 10.2) 
 
Vital signs (blood pressure, temperature, heart rate and respiratory rate) (see Section 7.3.3) 
 
Concurrent medication recording (see Section 9) 
 
7-day diary review and counseling (see Section 7.3.5) 
 
Collection of blood and serum samples for:  
 Hematology (see Section 7.3.6)  
 Coagulation (see Section 7.3.6) 
 Fasting clinical chemistry (see Section 7.3.6) 
 Fasting lipid analysis, including HOMA-IR (see Section 7.3.6) 
 
 
Weeks 4, 8, 12, 16 and 20  
Subjects will return to the clinic at Weeks 4, 8, 12, 16 and 20 and the following tests will be 
performed: 
 
A targeted physical examination (see Section 7.3.2) 
 
AE assessment (see Section 10.2) 
 
Vital signs (blood pressure, temperature, heart rate and respiratory rate) (see Section 7.3.3) 
 
Measurement of bodyweight and waist and hip circumferences (see Section 7.3.3) 
 
Diet and exercise counseling (see Section 7.3.5) 
 
Concurrent medication recording (see Section 9) 
 
Study medication accountability and dispensing (see Section 8) 
 
Urine pregnancy test 
 
Collection of blood and serum samples for: 
 Hematology (see Section 7.3.6)  
 Coagulation (see Section 7.3.6) 
 Fasting clinical chemistry (see Section 7.3.6) 
 Fasting lipid analysis, including HOMA-IR (see Section 7.3.6) 
 
Additional assessments at Week 4 and 12 are: 
 
Collection of blood and serum samples for: 
 Pharmacokinetics (see Section 7.3.8) 
 Biomarker analysis including CK-18 fragments, LPS, adiponectin, GLP-1 and 
cytokines (see Section 7.3.9) 
 Collection of a stool sample for microbiome assessment (see Section 7.3.11) – selected 
sites only. 
 
Additional assessments at Week 12 only are: 
 
Collection of blood sample for measurement of HBA1C and PBMCs (at selected sites only) 
 
Administration of the AUDIT questionnaire 
 
Diet and exercise 7-day diary issue (see Section 7.3.5) 
 
Additional assessments at Week 16 only are: 
 
Diet and exercise 7-day diary review (see Section 7.3.5) 

 
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Unscheduled Visit 
Subjects who require an unscheduled visit will have the following tests performed where possible: 
 
 
A targeted physical examination (see Section 7.3.2) 
 
AE assessment (see Section 10.2) 
 
Vital signs (blood pressure, temperature, heart rate and respiratory rate) (see Section 7.3.3) 
 
Concurrent medication recording (see Section 9) 
 
Collection of blood and serum samples for: 
 Hematology (see Section 7.3.6)  
 Coagulation (see Section 7.3.6) 
 Clinical chemistry (see Section 7.3.6) 
 
 
Week 24 (or early withdrawal from treatment) 
All subjects will return to the clinic and the following procedures performed and documented 
 
 
A targeted physical examination (see Section 7.3.2) 
 
AE assessment (see Section 10.2) 
 
Vital signs (blood pressure, temperature, heart rate and respiratory rate) (see Section 7.3.3) 
 
Measurement of bodyweight and waist and hip circumferences (see Section 7.3.3) 
 
Concurrent medication recording (see Section 9) 
 
Study medication accountability (return of all unused medication) (see Section 8) 
 
Diet and exercise counseling  and 7-day diary issue (see Section 7.3.5) 
 
Administration of the AUDIT questionnaire 
 
MRI scan (see Section 7.3.13) 
 
Urine pregnancy test for women of childbearing potential (see Section 7.3.10) 
 
Collection of blood and serum samples for: 
 Hematology (see Section 7.3.6)  
 Coagulation (see Section 7.3.6) 
 Fasting clinical chemistry (see Section 7.3.6) 
 Fasting lipid analysis, including HOMA-IR (see Section 7.3.6) 
 HBA1C 
 Pharmacokinetics (see Section 7.3.8) 
 PBMCs (see Section 7.3.9) – at selected sites only 
 Biomarker analysis including CK-18 fragments, LPS, adiponectin, GLP-1 and cytokines 
(see Section 7.3.9) 
 Serum metabolomics 
 
Collection of a stool sample for microbiome assessment (see Section 7.3.11) – selected sites 
only. 
 
 
 
Week 28 (Post-treatment Follow-up) 
Subjects will return to the clinic 4 weeks after completion of treatment at Week 24 or early withdrawal 
and the following assessments will be performed: 
 
 
A targeted physical examination (see Section 7.3.2) 
 
AE assessment (see Section 10.2) 
 
Vital signs (blood pressure, temperature, heart rate and respiratory rate) (see Section 7.3.3) 
 
Concurrent medication recording (see Section 9) 
 
Urine pregnancy test for women of childbearing potential (see Section 7.3.10) 
 
Collection of blood and serum samples for: 
 Hematology (see Section 7.3.6)  

 
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 Coagulation (see Section 7.3.6) 
 Fasting clinical chemistry (see Section 7.3.6) 
 Diet and exercise 7-day diary review (see Section 7.3.5) 
 
7.3 
Details of Study Assessments and Data Collection  
 
Demographic Data, Medical History, Medication History and Concurrent 
Medication 
Demographic data will include sex, ethnicity and date of birth. The medical history will include any 
diagnosed medical (including intermittent) conditions or surgical history. All NASH medication 
history, and concurrent medication, including non-prescription medication, will be collected and 
recorded in the CRF. 
 
 
Physical Examination and Targeted Examination 
A complete physical examination will include head, ears, eyes, nose, throat, heart, lungs, abdomen, 
lymph nodes, musculoskeletal and neurological assessment and skin. Genitourinary system will be 
examined only when clinically indicated.  
 
A targeted physical examination will be performed throughout the study to determine physical 
findings of systems appropriate to assessing the clinical status of the subject relative to study treatment 
and their disease. In particular, subjects will be monitored throughout the study for gastrointestinal 
events. Other body systems should be examined as clinically indicated.  
 
 
Vital Signs 
Vital signs to be measured are: 
 
Body temperature (degrees Celsius [°C]) 
 
Respiratory rate (breaths/min) 
 
Pulse rate (beats/min), 
 
Blood Pressure (millimeters mercury [mmHg]) 
 
BP and pulse are to be recorded after the subject has been resting semi-supine for at least 10 minutes. 
If there are abnormalities, at least two further repeat BP measurements will be performed to confirm 
results. Refer to the Study Reference Manual for more details of the methods to be used. 
 
Body weight (kg, without shoes), waist circumference (centimeters, light clothing) and waist/hip ratio 
will be measured and recorded throughout the study.  
 
Height (centimeters [cm], without shoes) will be measured and documented at the Screening visit. 
 
 
Electrocardiograms 
EKG recordings in this clinical trial will be performed at Screening in a standardized manner as 
outlined in the Study Reference Manual. Repeat measurements will be performed if there are any 
clinical abnormalities observed or artifacts are present. All EKG recordings will be reviewed by the 
Investigator or medically qualified nominee. 
 
The EKG recordings will be performed once the subject has been resting semi-supine for at least 10 
minutes and will be measured over approximately 3 minutes, in triplicate. The following parameters 
will be reported: QRS, QT, QTcB, RR and PR intervals and Heart Rate. Any clinically significant out 
of range or arrhythmia alarms will be printed out and retained in the subject’s notes and reported as 
AEs. 
 

 
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Diet and Exercise Counseling and Assessment 
Counseling of study participants regarding diet and exercise will be required during the study.  
Appendix E provides a standard set of questions to assist in holding an open discussion with goal 
setting and review at each monthly study visit. 
 
 
Food and beverage consumption and physical activities will be collected through subject completion 
of a prospective 7-day diet and exercise diary card issued at Baseline, W12 and W24 visits (Appendix 
F).  An AUDIT questionnaire (Appendix D) will be completed at these visits in order to confirm that 
alcohol consumption is low and does not change during the course of the study. 
 
Written guidance on diary completion will be provided. Staff should ensure subjects understand how 
to complete the cards and understand the importance of recording the information.  Food and drink 
consumed, including alcohol, and all exercise (including manual work) will be recorded in the diary 
each day for a week following the visit.  
 
The completed diary cards will be returned and reviewed with the subject at the next scheduled study 
visit.  Major changes in diet and exercise habits will be discussed and recorded in the CRF. 
 
 
Safety Laboratory Assessments 
Blood will be collected at Screening, Baseline, and scheduled clinic visits (except D3) and at the 
Withdrawal visit if applicable. These should be collected within the visit window period required for 
the visit date (see Section 7.4). Urine will be collected at Screening only.  
 
Clinical chemistry will be performed at the Baseline visit and scheduled clinic visits (except D3) with 
the subject having fasted for at least 8 hours before sample collection.  HOMA-IR score will be 
calculated when fasting glucose and insulin measurements have been reported, according to the 
HOMA-IR algorithm (Appendix C).   
 
 Table 3: Safety Laboratory Parameters 
Test 
Parameters 
Hematology 
(Screening, Baseline, D7, 
D14, W4 and 4 weekly 
thereafter) 
Hemoglobin, hematocrit, red blood cell (RBC) and RBC morphology, white blood 
cell (WBC) and differential WBC count, platelet count, mean corpuscular volume 
(MCV), mean corpuscular hemoglobin concentration (MCHC) and neutrophil 
count.  
Coagulation 
(Screening, Baseline, D7, 
D14, W4 and 4 weekly 
thereafter) 
Prothrombin time (PT), partial thromboplastin time (PTT), and International 
Normalized Ratio (INR). 
Clinical Chemistry 
(Screening, then fasting 
at Baseline, D7, D14, W4 
and 4 weekly thereafter) 
Sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatine 
phosphokinase, creatinine, total protein, albumin, serum amylase (fractionated if 
> upper limit of normal (ULN)), lipase, phosphate, GGT, AST, ALT, alkaline 
phosphatase, total bilirubin, calcium, uric acid, glucose and insulin.  
CRP and C-peptide will be included at Baseline, W4, W12 and W24 only. 
Serum lipid panel 
(Baseline, D7, D14, W4 
and 4 weekly thereafter) 
Total cholesterol, triglycerides, high and low density lipoproteins 
Blood glucose (average) 
(Screening, W12 and 
W24) 
HBA1c  
Urine 
(Screening only) 
Specific gravity, protein, glucose, blood, leukocytes, pH, ketones, bilirubin, 
urobilinogen, nitrites 
 
 

 
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Screening & Serology Laboratory Parameters 
The following laboratory assessments will be conducted at Screening to confirm the absence of 
excluded diagnoses: 
 
Table 4:  Screening tests - serum 
Test Parameters 
Alfa-feto protein 
HIV antibodies, hepatitis B surface antigen (HBsAg) and HCV-
RNA  
* Results will be acceptable for eligibility within range of 6 months 
prior to screening. 
Pregnancy test (women of childbearing potential only) 
 
 
Blood Samples for Pharmacokinetics  
Serum concentrations of IMM-124E will be quantified, where possible, at Baseline (prior to taking 
study medication), W4, W12 and W24. The data and actual times of blood sample collection will be 
recorded in the 24 hour format. At least 2 aliquots of 1mL of serum will be collected and stored at 
≤ -70°C at each time-point, prior to analysis.  
 
 
Biomarkers 
Blood samples will be taken to prepare serum aliquots for measurement of biomarkers relevant to 
steatohepatitis. At least 3 aliquots of 1 mL of serum will be collected at Baseline, W4, W12 and W24 
(see Table 5) and stored at ≤ -70°C for biomarker evaluation including serum cytokine concentrations 
and other markers of immunological response. C-peptide and C-reactive protein analysis will be 
included in addition to a standard clinical chemistry panel at Baseline, W4, W12 and W24. 
 
In addition, PBMCs will be collected at Baseline, W12 and W24 from patients recruited at selected 
sites and for whom stool samples will also be collected for microbiome analysis. Details regarding the 
required method of collection, preparation and storage of PBMCs will be included in the Study 
Reference Manual.  
 
  Table 5:  Biomarkers for analysis 
Test Parameters 
CK-18 fragments, LPS fragments, adiponectin, GLP-1 and cytokines - (IL)-6, IL-1α, IL1β, IL-2, 
IL-3, IL-4 IL-10, IL-13, IL-12, IL-17α, IL-23, IFN-γ, TGF-β and TNFα 
(CRP and C-peptide will be analyzed with clinical chemistry safety panel – see Table 3) 
 
PBMCs –Treg population cell counts including CD4+, CD8+, CD25+,FoxP3+, NKT (CD3+ and 
CD56+), CD62+ and CD69+ 
 
Serum metabolomics  
 
Any unused biomarker samples will continue to be stored for up to 5 years for the future assessment of 
pharmacodynamic and/or markers of response in NASH, unless the study subject requests to have the 
sample(s) destroyed earlier.  
 
 
Urine Pregnancy Test 
Prior to administration of the first dose of study medication at Baseline and 4 weekly thereafter, 
women of childbearing potential will require confirmation of non-pregnancy by collection of a mid-
stream urine specimen and testing with a standard commercially available urine pregnancy test kit. In 
case such test is not available or deemed unsatisfactory at specific site, a blood pregnancy test will be 
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Fecal Samples for Microbiome Assessment (selected sites only) 
Stool specimens should be collected in a clean, dry container at Baseline and on or before W4, W12 
and W24. It should be stored prior to the visit according to directions until delivered to the clinic 
where the sample will be stored at -70°C or below. Please refer to the Study Reference Manual for 
details of the collection and storage of fecal samples.  
 
 
Handling and Processing of Biological Specimens 
Biological specimens collected during the trial may contain pathogens. All personnel involved in 
collecting and handling biological specimens should follow appropriate precautionary procedures for 
handling biohazardous materials as currently recommended by the national regulatory authority. The 
processing of all biological specimens will be in accordance with the site’s standard practices. 
 
Further details of the handling of biological samples can be found in the Study Reference Manual. 
 
 
Disease Assessment 
NAS score will be determined on the most recent biopsy not greater than 12 months before Screening. 
Liver biopsy slides will be made available for central confirmatory review by a pathologist expert in 
liver pathology.  
 
Subjects will be staged using HOMA-IR which estimates steady state beta cell function (%B) and 
insulin sensitivity (%S), as percentages of a reference population (see Appendix C) 
 
Liver MRI will be performed according to a standard protocol at each center at Baseline and W24 and 
transmitted to a central radiological co-ordinating centre to be read by a radiologist blinded to clinical 
information and treatment allocation. Please refer to the Study Reference Manual for further details. 
 
Measure of end-stage liver disease (MELD) score will be determined at intervals throughout the study 
according to the following formula: 
 
3.78x ln[serum bilirubin (mg/dL)] + 11.2x ln[INR] + 9.57x ln[serum creatinine (mg/dL)] + 6.43 
 
Refer to Study Reference Manual for further information. 
 
7.4 
Visit/Assessment Windows 
Assessments should occur on the days and at the times specified in Section 7.3 and Table 1. The date 
of visits will be calculated from the date of the Baseline visit (D0). These should occur, wherever 
possible, on the exact day or number of weeks after the Baseline visit. The visit/assessment windows 
are specified in Table 6.  
 
  
Table 6:  Visit/assessment windows 
Assessments 
Acceptable Window 
Screening 
-45 to Day 0 
Baseline 
Day 0 
Up to and including Week 4 
± 1 day 
Week 8 to Week 24 
± 3 days 
Post-treatment Follow-up 
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8. STUDY DRUGS 
8.1 
Randomization 
Subjects will be randomized to one of three treatment groups using a permuted block randomization 
algorithm supplied by a statistician blinded to patient data.   
 
NASH without insulin resistance or diabetes may be clinically different to NASH with pre-diabetes or 
diabetes. Equal numbers of patients in each treatment arm is targeted. Randomization will be 
proportional (1:1:1) and stratified by Baseline HBA1C < 6.0 or >6.0 – 9.0.  (See Section 7.2.2 and the 
Study Reference Manual) 
 
Additionally, to ensure baseline Hepatic Fat Fraction (HFF) would not be a confounding factor, subjects 
will be stratified for baseline HFF according to the following groups ≤10%, 10%<X≤20%, 20%<X<30% 
and ≥30%.  
 
If a subject discontinues from the study, the randomization code will not be reused, and the subject will 
not be allowed to re-enter the study.  
 
8.2 
Blinding 
This is a double blind study. Therefore, subjects, investigational site staff and Sponsor clinical staff will 
remain blinded to treatment allocation.  
 
8.3 
Unblinding Procedures 
In case of emergency and the need to know details of a subject’s study treatment, an unblinding 
procedure to provide access to code-break information will be provided. Secure access to codebreak 
information will be provided to the Investigator at each study site.  The Investigator will discuss with 
the Sponsor any unblinding prior to it taking place, unless immediate knowledge of the treatment 
allocated is required for the Subject’s care.  
 
Reason(s) for unblinding will be clearly documented and the details included in the study report.  
 
8.4 
Formulation 
 
Investigational Products 
Table 7 is a summary of the characteristics of the investigational products to be supplied in this study. 
 
 Table 7:  Investigational Products 
Name: 
IMM-124E  
Characteristics & Physical State: 
Off white tablets containing 600mg of IMM-124E  
Formulated & Supplied by: 
Immuron Ltd. 
Storage Conditions:  
Store at 2-8 degrees C 
Package: 
HDPE bottle 
 
 
Name: 
Placebo to match active 
Characteristics & Physical State: 
Off white tablets containing 600mg of milk powder (Pro-Milk 
85®) 
Supplied by: 
Immuron Ltd. 
Storage Conditions:  
Store at 2-8 degrees C  
Package: 
HDPE bottle 

 
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Table 8 a summary of the treatment regimens and tablet allocation for each of the three treatment 
cohorts.  
Table 8:  Treatment regimen and tablet allocation 
Treatment 
Arm 
IMM-124E Dose  
(600mg tab) 
Regimen 
Tablet allocation per dose  
 
A 
600mg three times 
daily   
2 tablets (1 
from each 
bottle) taken 
three times 
daily on an 
empty 
stomach 
 
IMM-124E 
Placebo 
B 
1200mg three times 
daily  
 
IMM-124E 
IMM-124E 
C 
matching placebo 
three times daily 
 
Placebo 
Placebo 
 
Supply, Packaging and Labeling, Storage and Handling 
IMM-124E must be stored in a secure area with access limited to the pharmacist and authorized staff. 
The bottles and outer packaging will be stored refrigerated between 2 and 8 degrees Celsius, prior to 
dispensing to patients, in a controlled and monitored facility.  
 
At a minimum, the immediate packaging will include the following information: 
 
 
Sponsor name 
 
Protocol number 
 
Pack/treatment number 
 
Product name/drug code 
 
Number of tablets 
 
Directions for use, including route of administration  
 
Batch/lot number 
 
Storage conditions 
 
Period of use (use by, expiry or retest date, as applicable, in month/year format)  
 
Additional information and specific cautionary statements will be included according to local law. 
 
The packaging lot numbers will be recorded on the investigational product accountability record.  
 
A Pharmacy reference manual containing detailed information regarding the storage, dispensing and 
accountability of IMM-124E will be provided as a separate document. 
 
 
Dispensing and Accountability 
The investigator will be responsible for ensuring accurate records are maintained for all study 
medications dispensed and returned. The inventory must be available for inspection by the study 
monitor. Study drug supplies, and the dispensing logs, must be accounted for by the study monitor and 
returned to the drug repository for destruction at the end of the study. 
 
When requested in writing by the Sponsor, used and/or unused study medication supplies may be 
destroyed by the investigator provided such disposition can be performed safely. Records shall be 
maintained by the investigator of any such alternate disposition of the study medication. These records 
must show the identification and quantity of each unit disposed of, the method of destruction (taking 
into account the requirements of local law), and the person who disposed of the test substance. Such 
records shall be submitted to the sponsor. 
 
For additional information, please refer to the Study Reference Manual for this study. 
 

 
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Dosage and Administration of Study Drugs 
IMM-124E and matching placebo tablets may be either chewed before swallowing or swallowed whole 
three times daily per oral on an empty stomach. No intra-subject dose adjustment of IMM-124E will be 
allowed during this study. 
Range of +/- 15% (85-115%) is the acceptable compliance range. 
Any poor compliance out of this range will be considered as protocol deviation. 
Any poor compliance should be escalated to Immuron and will potentially result in subject's termination 
from the study. 

 
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9. CONCURRENT MEDICATIONS AND TREATMENTS 
At each study visit or contact, the Investigator should question the subject or their legal representative 
about any medication taken, including vitamin supplements and herbal remedies. Any concurrent 
medications will be recorded in the subject’s records and the CRF. Any changes in doses or introduction 
of new medications during the course of the study will also be recorded. 
 
9.1 
Special Dietary Requirements 
There are no special dietary requirements. 
 
9.2 
Concurrent Medications/Treatments Not Permitted 
 
Prior to Study Entry 
Refer to Exclusion Criteria in Section 6.3. 
 
 
During the Study Dosing Period 
Throughout the study medication dosing period, subjects may not receive any of the following 
concomitant medications: 
 
 
other anti-NASH therapy(s) including, SAM-e, betaine, milk thistle and probiotic supplements 
(not including yoghurt); 
 
thiazolidinediones (glitazones), dipeptidyl peptidase 4 inhibitors (gliptins) or GLP-1 analogs, 
unless the subject was recruited on a stable dose.  
 
Allowable anti-diabetic treatment includes insulin, metformin and/or sulfonylureas 
administered at constant dose for at least 2 months prior to study entry;  
 
immune modulatory agents including  
o systemic steroids for more than 7 days 
o multiple non-steroidal anti-inflammatory drugs such as aspirin (>100mg/day), 
ibuprofen, naproxen, meloxicam, celecoxib; 
o azathioprine, 6-mercaptopurine, methotrexate, cyclosporin, anti-TNFα therapies 
(infliximab, adalimumab, etanercept) or anti-integrin therapies (namixilab). 
 
Treatment with antilipidemic agents (HMG Co-A reductase inhibitors – “statins”), vitamin E, 
gemfibrozil and allowable antidiabetic treatment (metformin and/or sulfonylurea) must be stable 
throughout the study. 
 
Antibiotics should be taken if clinically indicated but avoided where possible.   
 

 
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10. ADVERSE EVENT REPORTING AND MANAGEMENT 
10.1 
Safety Parameters 
Safety parameters will include adverse events, vital signs and clinical laboratory tests. 
 
10.2 
Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical investigation subject administered 
an investigational product (whether it is the experimental product or the control) and which does not 
necessarily have a causal relationship with the investigational product. An AE can therefore be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. Pre-existing events, 
which increase in frequency or severity or change in nature during or as a consequence of use of a 
drug in human clinical trials, will also be considered as AEs. AEs may also include pre- or post-
treatment complications that occur as a result of protocol-mandated procedures (e.g. invasive 
procedures such as biopsies). 
 
Any AE (i.e. a new event or an exacerbation of a pre-existing condition) with an onset date after study 
drug administration up to the last day on study (including the follow-up, off study medication period 
of the study), should be recorded on the appropriate CRF page(s). 
 
An AE does not include: 
 
medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an adverse event 
 
pre-existing diseases or conditions present or detected prior to start of study drug 
administration, that do not worsen 
 
situations where an untoward medical occurrence has not occurred (e.g. hospitalization for 
elective surgery, social and/or convenience admissions) 
 
overdose of either study drug or concomitant medication without any signs or symptoms 
unless the subject is hospitalized for observation. 
 
 
 
Assessment of AEs 
All AEs will be assessed by an investigator and recorded in the subject medical record, including the 
date of onset and resolution, severity, relationship to study drug, outcome and action taken with study 
medication. See Appendix A for details of toxicity grade scales (TGS) relevant to vital signs, 
gastrointestinal and general system and clinical laboratory adverse events. 
 
For all other reported adverse events, severity should be recorded and graded as: 
 
Table 9: Severity Grades 
Grade 
Severity 
Comments 
1 
Mild 
Aware of sign or symptom, but easily tolerated 
2 
Moderate 
Discomfort enough to cause interference with usual 
activities 
3 
Severe 
Incapacitating with inability to work or perform usual 
activities 
4 
Life-threatening 
Participant is at immediate risk of death 
5 
Fatal 
Any event causing death 
 

 
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The relationship to study drug therapy should be assessed using the following definitions: 
 
Table 10: Adverse Event Causality Definitions 
Causality 
Comment 
Unrelated 
AE is clearly due to extraneous causes (e.g. underlying disease, environment, known 
effect of another drug) 
Unlikely 
The temporal association between the AE and study drug is such that study drug is not 
likely to have any reasonable association with the AE 
Possible 
The AE could have been produced by the subject’s clinical state or study drug 
Probable 
The AE follows a reasonable temporal sequence from the time of study drug 
administration, abates upon discontinuation of the study drug and cannot be reasonably 
explained by the known characteristics of the subject’s clinical state 
Definite 
The AE follows a reasonable temporal sequence from the time of study drug 
administration, abates upon discontinuation of the study drug and/or reappears when 
study drug is re-introduced 
 
These criteria, in addition to good clinical judgment, should be used as a guide for determining the 
causal assessment. If it is felt that the event is not related to study drug therapy, then an alternative 
explanation should be provided. 
 
 
Adverse Event Reporting Period 
All adverse events, regardless of severity, causality or seriousness must be reported from the date of 
informed consent until 28 days after the last dose of study medication. However, any adverse event 
that the investigator believes is at least possibly related to study medication should be reported 
regardless of time elapsed from the final dose. 
 
10.3 
Serious Adverse Events 
 
Serious Adverse Event Definition 
A serious adverse event (SAE) is defined as follows: 
 
Any adverse drug experience occurring at any dose that results in any of the following outcomes: 
 
death 
 
life-threatening situation (subject is at immediate risk of death) 
 
inpatient hospitalization or prolongation of existing hospitalization (excluding those for study 
therapy or placement of an indwelling catheter, unless associated with other serious events) 
 
persistent or significant disability/incapacity 
 
congenital anomaly/birth defect in the offspring of a subject who received study drug 
 
other: Important medical events that may not result in death, be immediately life-threatening, 
or require hospitalization, may be considered a SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such events are: 
o intensive treatment in an emergency room or at home for allergic bronchospasm 
o blood dyscrasias or convulsions that do not result in hospitalization 
o development of drug dependency or drug abuse 
 
 
Clarification of Serious Adverse Events 
Death is an outcome of an AE, and not an AE in itself. In reports of death due to “Disease 
Progression”, where no other information is provided, the death will be assumed to have resulted from 
progression of the disease being treated with the study drug. 

 
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All deaths, regardless of cause, must be reported to Immuron for subjects on study and within 28 days 
of last administration of study drug. 
“Occurring at any dose” does not imply that the subject is receiving study drug at the time of the 
event. Dosing may have been given as treatment cycles or interrupted temporarily prior to the onset of 
the SAE, but may have contributed to the event. 
“Life-threatening” means that the subject was at immediate risk of death from the event as it occurred. 
This does not include an event that might have led to death, if it had occurred with greater severity. 
Complications that occur during hospitalizations are AEs. If a complication prolongs hospitalization, it 
is a SAE. 
“In-patient hospitalization” means the subject has been formally admitted to a hospital for medical 
reasons, for any length of time. This may or may not be overnight. It does not include presentation and 
care within an emergency department. 
The investigator should attempt to establish a diagnosis of the event based on signs, symptoms and/or 
other clinical information. When available, a diagnosis should be documented as the AE and/or SAE 
and not the individual signs/symptoms. 
 
Serious Adverse Event Reporting Requirements 
Immuron has requirements for expedited reporting of SAE’s that meet specific criteria to worldwide 
regulatory authorities; therefore, all appropriate parties must be notified immediately of any SAE that 
occurs after the first dose of study drug has been administered. The procedures for reporting all SAEs, 
regardless of causal relationship, are as follows: 
 
 
Complete the “Serious Adverse Event Report” CRF page 
 
Send the SAE report to the Sponsor SAE hotline within 24 hours of the investigator’s 
knowledge of the event: 
 
Telephone:  +972 545 641464  
Fax:   
+972 15354 9277334  
Email:  
SAE@immuron.com 
 
 
For fatal or life-threatening events, also send copies of hospital case reports, autopsy reports, 
and other documents when requested and applicable 
 
Immuron may request additional information from the investigator to ensure the timely completion of 
accurate safety reports. 
 
The investigator must take all therapeutic measures necessary for resolution of the SAE. Any 
medications necessary for treatment of the SAE must be recorded in the concomitant medication 
section of the subject’s CRF. 
 
 
Investigator Reporting Requirements for SAEs 
A SAE may qualify for reporting to regulatory authorities if the SAE is considered to have a possible 
causal relationship to the study drug and is unexpected/unlisted based upon the current Investigator’s 
Brochure. In this case, all investigators will receive a formal notification describing the SAE. 
Where this is required by local regulatory authorities, and in accordance with the local institutional 
policy, the investigator should notify (in writing) the Institutional Review Board (IRB)/Ethics 
Committee (IEC) of SAEs according to local timelines. 

 
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10.4 
Follow up of Serious and Non-serious Adverse Events 
Follow-up of SAEs and non-serious AEs will continue through the last day on study (including 
follow-up) until the investigator and/or Immuron determine that the subject’s condition is stable, 
whichever is longer. Immuron may request that all clinically significant AEs be followed until 
resolution or for a period of 30 days after. 
 
10.5 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs or 
SAEs 
All laboratory values must be reviewed by the investigator. Given that all laboratory data are collected 
and statistically analyzed with respect to relevant reference ranges, laboratory abnormalities that occur 
without related clinical symptoms and signs should generally not be recorded as adverse events unless 
they represent a clinically significant event. Where possible, the overall diagnosis rather than the 
laboratory abnormality should be recorded as the AE. This will avoid duplication of laboratory 
abnormalities in both the AE and laboratory reports.  
Any laboratory test result that meets the criteria for a SAE (refer to Section 10.3.1) should be recorded 
as an AE, the AE page of the CRF completed and a SAE form also completed in order for the sponsor 
to collect additional information about that abnormality, including information regarding relationship 
to study product or other causes, any action taken and resolution. 
 
 
10.6 
Guidance for Discontinuation of Treatment 
To date, no specific toxicities have been identified that result from IMM-124E treatment.  
Any toxicities and/or abnormal laboratory findings should be investigated for etiology and graded 
according to Table 8 (Section 10.2.1) and Appendix A.  
 
The following toxicity management will be followed: 
 
Grade 1 or 2: Patients may continue study drug.   
Grade 3: Patients with any Grade 3 toxicity considered to be at least possibly related to 
treatment (i.e. treatment related events) should be evaluated carefully by the investigator prior 
to continuing study drug. Investigators may discuss individual cases with the Medical 
Monitor.  
Grade 4: Patients developing any Grade 4 toxicity should have treatment interrupted, unless 
the Grade 4 toxicity is clearly unrelated to study drug and continued treatment does not pose a 
serious risk to the patient.  After the event has returned to normal or baseline levels, study 
drug may be re-started.  If the toxicity re-appears, the investigator should contact the Medical 
Monitor to discuss the subject’s withdrawal.  
 
For any subject experiencing any event (irrespective of severity) which, in the opinion of the 
Investigator, contraindicates further dosing in that subject and the event is considered to be at least 
possibly related to treatment (or where causality to study treatment cannot be ruled out – see Section 
10.2.1), continued dosing of the subject should be interrupted. In all cases, the final treatment 
decisions, made in response to toxicity, are the responsibility of the Principal Investigator. A careful 
evaluation of the potential risk/benefit will dictate the optimal therapeutic course. Should treatment be 
interrupted, re-initiation will follow review of the available safety data and in agreement with the 
Sponsor. There will be no dose reduction or modification. 
 
If the investigator deems that management of the patient’s medical condition requires knowledge of 
the study treatment regimen, then the Medical Monitor must be contacted for consultation and the 
procedures described in Section 8.2 followed. If a patient dies from an event that is considered to be at 
least possibly related to treatment, continued dosing of all study participants should be interrupted: 

 
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Clinically significant suspected adverse drug reactions, and serious adverse events considered to be 
related to study procedures will be followed until resolved or considered stable. All subjects who 
experience a study drug related AE should be followed until resolution of the AE, even if the subject 
has discontinued study drug.  
 
If an unscheduled interruption of study drug occurs, the study site should notify the sponsor at the 
earliest possible time. A missed dose will not be made up. In the event that a subject requires an 
unscheduled interruption of study drug under conditions other than those associated with toxicity, the 
case will be reviewed by the Sponsor to determine whether such a subject will be allowed to resume 
study drug. 
 
Subjects withdrawn from study drug will be treated as deemed appropriate by the investigator. Follow-
up procedures should be performed and the appropriate CRFs should be completed.  
  
10.7 
Warnings and Precautions 
The adverse event profile in humans is IMM-124E has not been fully characterized. In clinical trials 
and commercial use at doses equal or lower than those used in this study, IMM-124E was well 
tolerated with a safety profile expected of bovine colostrum. The most common adverse reactions 
expected include modified bowel movements and nausea.  
 
For further information regarding warnings and precautions with the study drug, please refer to the 
Investigator’s Brochure for Imm-124E. 
 
10.8 
Risks for Women of Childbearing Potential or During Pregnancy 
The risks of treatment with IMM-124E during pregnancy have not been evaluated. Human IgG is 
known to cross the placental barrier. Therefore, IMM-124E has the potential to cause fetal harm when 
administered to pregnant women and pre-menopausal women of childbearing potential must follow a 
medically prescribed birth control regimen or agree to abstinence while participating in the study and 
for 30 days following the last dose of study drug. 
 
10.9 
 Procedures to be Followed in the Event of Pregnancy 
The subject must be instructed to inform the investigator IMMEDIATELY if she becomes pregnant 
during the study and seek advice regarding discontinuation of study medication. Whenever possible, 
treatment should be discontinued. The investigator should report all pregnancies to the Sponsor within 
24 hours of becoming aware of the pregnancy. The outcome of pregnancies in a subject enrolled in the 
study must be reported. 
 
In the event that the study drug is being used to treat an existing medical condition, prior to 
discontinuing therapy, the investigator should counsel the subject and discuss the risks of continuing 
study drug dosing and the possible effects on the fetus. Subjects should also be counseled regarding 
the potential for recurrence of their underlying disease if treatment is stopped and the availability of 
alternative treatment options. 
 
Monitoring of the subject should continue until conclusion of the pregnancy. The outcome of the 
pregnancy should be reported to the Sponsor.  

 
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11. SUBJECT COMPLETION/WITHDRAWAL 
11.1 
Subject Completion 
A subject will be deemed to have completed the study once all trial procedures have been conducted. 
Any AEs or SAEs still ongoing at the time of the Exit Evaluation will be followed in accordance with 
Section 10.4. 
 
11.2 
Criteria for Premature Withdrawal from Treatment or the Study 
Subjects have the right to withdraw from treatment or the study at any time for any reason. The 
investigator must make every reasonable effort to keep each subject in the study except where 
termination or withdrawal is for reasons of safety. The investigator also has the right to withdraw 
subjects from treatment or the study in the event of intercurrent illness, AEs, pregnancy, treatment failure 
after a prescribed procedure, protocol violations, administrative reasons or other reasons. 
 
The reasons for withdrawal of the subject must be recorded on the CRF. 
 
The following are also considered justifiable reasons for subject withdrawal: 
 
 
The need to take medication which may interfere with study measurements 
 
Intolerable/unacceptable adverse experiences (see Section 10.7) 
 
Major violation or deviation of study protocol 
 
Non-compliance of subject with protocol 
 
Subject unwilling to proceed and/or consent is withdrawn 
 
Withdrawal from the study is, in the investigator’s judgment, in the subject’s best interest 
 
Pregnancy of female study subject at any time during the study period (if applicable) 
 
It is understood by all concerned that an excessive rate of withdrawals from the study can render the 
study difficult to interpret. Therefore, unnecessary withdrawal of subjects from the study should be 
avoided. 
 
Immuron may also decide to stop the study and withdraw all subjects for safety or other reasons. 
 
11.3 
Withdrawal of Subjects from Study drug 
Section 10.6 provides guidance for dose discontinuation of Study drug in the event of AEs or abnormal 
laboratory values. If a subject permanently discontinues study drug, for example as a result of an AE, 
subjects should be encouraged to continue participation in the study in order to obtain ongoing 
measurement of study outcomes to minimize missing data. At a minimum, every attempt should be 
made to continue to follow the subject until resolution of the adverse event. All subjects who discontinue 
study medication dosing should be followed for at least 28 days after the last dose of Study drug in order 
to monitor subjects for possible post-treatment events which may occur after Study drug has been 
discontinued. 
 
11.4 
Withdrawal of Subjects from the Study 
Should a subject decide to withdraw from the study, all efforts will be made to complete and report the 
observations as thoroughly as possible. 
 
The investigator should contact the subject either by telephone or through a responsible relative to 
determine, if possible, the reason for withdrawal. A complete final evaluation at the time of the subject 
withdrawal should be made with an explanation of why the subject is withdrawing from the study. 
 
If the reason for removal of a subject from the study is an AE or an abnormal laboratory test result, the 
principal reason will also be recorded on the CRF. Where possible, subjects should be followed until 
the AE is resolved or the abnormal laboratory test has returned to normal.  

 
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11.5 
Replacement of Withdrawn Subjects 
Any subjects who discontinue of their own volition or by a decision of the Investigator are defined as 
“withdrawals”. Early withdrawals will be replaced to reach the predefined sample size of subjects 
completing the study.   
 
 
  

 
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12. STATISTICAL ANALYSIS 
The study is a randomized, double-blind, placebo controlled, multicenter Phase 2 trial designed to 
describe the safety and preliminary efficacy of two IMM124-E dose groups as compared to placebo in 
a population of subjects diagnosed with NASH.   The safety profile will be described by the incidence 
of treatment emergent adverse events (TEAE) as well as changes in vital signs, and laboratory 
measurements.  Trends in efficacy will be examined primarily via reductions from baseline in liver fat 
content and serum ALT.   Given the exploratory nature of the trial, adjustments for multiple endpoints 
and/or multiple comparisons will not be made.  
 
The following section describes the general analytic approach to the analysis of the study.  Details of 
the analysis will be provided in a separate Statistical Analysis Plan (SAP) which will be completed 
prior to any blind break. 
 
12.1 
Sample Size Determination 
The power to detect a difference between placebo and active treatment with respect to changes from 
baseline in liver fat content and serum ALT has been determined for a sample size of 40 patients per 
arm. The sample size for the current study is based on a review of the literature to obtain estimates to 
inform sample size/power calculations. Estimates are based on published results of randomized 
placebo controlled treatment studies in populations of patients similar to those proposed for this study 
and in which one or both endpoints have been reported. Fat quantification by MRI, rather than other 
methods, have been included. (Belfort 2006; Promrat 2010; Ratziu 2008; Sanyal 2010 and Le 2012).  
 
Further, since the endpoint is the change from Baseline, plausible estimates of the degree of 
correlation between pre and post-baseline measurements were also incorporated into the variance 
estimates.  Given the wide range of results observed in the literature, several “what if” scenarios were 
examined.  As such, the current sample size was considered sufficient for the exploratory objectives of 
the study for the given range of plausible treatment effects and variance estimates.  There will be no 
adjustment for multiple comparisons between the 3 treatment groups. 
 
Fat Liver Content Change from Baseline: 
The current sample size of 40 subjects per group should yield approximately 85% power to detect a 
treatment effect of at least -5% with respect to the difference in the mean change from Baseline 
between one of the IMM-124E treatment groups and placebo assuming a standard deviation (SD) of 
7.3% (α=0.05; two-tailed; unpaired t-test).  The SD of 7.3% for the change from Baseline endpoint 
was derived assuming 1) SDs of 6% for each timepoint, 2) equal variances in each treatment group 
and 3) a low to moderate correlation of 0.25 between pre- and post-Baseline measurements.  
 
 
12.2 
Analysis Populations 
The populations for analysis will be as follows: 
 
 
Full Analysis Set (FAS) for Primary Assessment of Efficacy 
The FAS includes all subjects who received at least one dose of study medication. Only subjects with 
clear documentation that no study medication was received will be excluded. In the event of treatment 
allocation errors, subjects will be analyzed for efficacy according to the treatment to which they were 
randomized.  
 
 
Safety Analysis Set 
The Safety Analysis Set includes all randomized subjects who received at least one dose of study 
medication.  Only subjects with clear documentation that no study medication was received may be 
excluded.  In the event of treatment errors, subjects will be analyzed for safety according to the 
treatment received. 

 
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Per Protocol Analysis Set  
The Per Protocol Analysis Set includes all subjects who complete 24 weeks of study treatment and 
have MRI and ALT measured at Baseline and at Week 24 and no major protocol violations, 
determined prior to break of the treatment blind.  
 
 
Intention-To-Treat (ITT) Analysis Set  
The ITT analysis set includes all patients randomized to treatment. An ITT analysis will only be 
implemented in the event that one or more patients are randomized but do not receive any treatment. 
 
12.3 
Subject Disposition, Baseline Demographics and Disease Status 
Subject disposition will be tabulated by treatment arm and overall and will include the number of 
subjects randomized, received study drug, withdrawals etc. Subjects for whom treatment unblinding 
was required, including reason(s) will be included. In addition, demographic and baseline information, 
including Baseline NAS, diabetes status and concurrent medical conditions, will be summarized and 
tabulated by treatment group. The purpose of these summaries is to characterize the study population 
and to describe any baseline imbalances. 
12.4 
Statistical Analysis Plan 
A detailed SAP in which all aspects of data analysis will be defined in detail and prepared prior to the 
blind break. 
 
The SAP will include details of the following: 
 
 
Definitions of analysis populations 
 
Description of any data transformations and data derivations to be used together with rationale 
and references 
 
Details of the statistical methods to be conducted, together with methods used to estimate 
corresponding confidence intervals  
 
Details of methods for checking the appropriateness of the chosen statistical model 
 
Discussion of the use of covariates and subgroups 
 
Discussion of any multiplicity and adjustment procedures to be implemented.  
 
Methods of dealing with missing values and outliers together with details of any sensitivity 
analyses to be performed 
 
Specification of any subgroup or interaction analyses 
 
Example table and listing shells to indicate the proposed presentation of the data. 
 
12.5 
Efficacy Analyses 
Primary determination of efficacy will be assessed by the measurement and comparison of the change 
in percentage liver fat by MRI at Week 24 for each treatment group. For each variable, summary 
tables will be produced by time point and by dose level. All data will be listed and outcomes by 
treatment, including pooled data for both active treatment groups, will be formally compared. The 
analysis will include determination of confidence intervals about the treatment group means.  
 
 
Other Efficacy Analyses  
Other efficacy analyses to investigate outcomes for secondary efficacy endpoints and including 
sensitivity analyses will be documented as part of the SAP.  
 
Analysis of primary and secondary efficacy endpoints by diabetes status will be descriptive only. 
 
 

 
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Exploratory Analyses 
Exploratory and/or data driven analyses will be identified as such and documented in the final Clinical 
Study Report. 
 
 
Final Analysis 
After the last study participant has completed Week 24 (and the subsequent 28 day follow up) the data 
will be analyzed and the primary clinical/statistical study report will be prepared.  
 
 
12.6 
Analysis of Safety 
 
Incidence of Adverse events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be 
summarized according to the number of subjects experiencing specific events, reported by system 
organ class, high level group term, high level term and preferred term. AEs will also be presented by 
severity and relationship to treatment. All data will be listed. 
 
 
Clinical Laboratory Parameters 
Routine samples are being collected for assessment of clinical chemistry and hematology. Summary 
tables at each time point and by toxicity grade will be presented by dose level. All data will be listed. 
 
 
Vital Signs 
Vital signs are being assessed frequently across the duration of the study. Summary tables will be 
produced for each sign (temperature, heart rate, respiratory rate, systolic and diastolic blood pressure) 
and by toxicity grade. All data will be listed. 
 
12.7 
Analysis of Pharmacokinetics 
 
 
As serum concentrations of IMM-124E are not expected, concentrations of IMM-124E antibodies will 
be collected and simple concentrations of IMM-124E will be summarized by treatment visit. Actual 
dosing and sampling times will be captured. Serum concentrations of at least the lower limit of 
quantitation will be used in the analysis. 
 
12.8 
Interim Analysis  
An un-blinded efficacy and safety interim analysis is scheduled 
The interim analysis will be conducted on all primary and secondary outcome unblended data by a 
third party, 
The interim analysis will be carried out when at least 22 eligible subjects complete the full 24 weeks 
of treatment and have verified baseline and 24 weeks MRI data.  
The goals of the interim analysis are as follow: 
1. Full efficacy analysis  
2. Full safety analysis  
3. Determining the best performing dose  
4. To correct for sample size. 
 
To account for multiple comparisons between the interim and final analyses, the critical alpha level for 
the interim analysis will be set at 0.0000147 while the critical alpha level for the final analysis will be 
set at 0.0499.  These values are based on 25% of the study endpoints being available for the interim 
analysis and symmetric two-tailed tests being used within the O’Brien-Fleming spending function. 
The study will not be terminated for either success or failure. The purpose of this interim analysis will 

 
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be to verify, and if necessary re-calculate, the required study sample size and to potentially discontinue 
the worse performing dose arm. 
 
The Interim-Analysis will be carried out by a third party so both sponsor and investigators would 
remain blinded to the allocation of subjects within the study groups. 
 

 
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13. GENERAL STUDY ADMINISTRATION 
13.1 
Ethical Aspects 
 
Local Regulations/Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformance with the protocol, the 
“Declaration of Helsinki and its amendments, and with the requirements of national drug and data 
protection laws of the countries in which the research is conducted. 
 
The investigator will also ensure that the basic principles of “Good Clinical Practice” as outlined in 21 
Code of Federal Regulations (CFR) 312, subpart D, and 21 CFR Parts 50 and 56 are adhered to, 
together with USA CFRs regarding Investigational New Drugs (INDs) and any local guidelines or 
regulations. 
 
 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from each subject 
participating in this study or legally acceptable representative after adequate explanation of the aims, 
methods, objectives and potential hazards of the study, prior to undertaking any study related 
procedures. A legally acceptable representative is an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s participation in the 
clinical study. The investigator must also explain to the subject that they are completely free to refuse 
to enter the study or to withdraw from it at any time for any reason. 
 
A generic informed consent form template is provided in Appendix B for the investigator to prepare 
the informed consent document to be used at his or her site. The written informed consent document 
should be prepared in the language(s) of the potential subject population. 
 
The investigator must utilize an IRB/IEC approved consent form for documenting written informed 
consent. The original signed informed consent form should be retained in accordance with institutional 
policy, and a copy of the signed consent form should be provided to the subject or legally acceptable 
representative. 
 
 
Institutional Review Boards/Ethics Committees 
A copy of the protocol, proposed informed consent form, other written subject information, and any 
proposed advertising material must be submitted to the IRB/IEC for written approval. A copy of the 
written approval of the protocol and informed consent form must be received by Immuron before 
recruitment of subjects into the study and shipment of investigational product. Approval from the 
committee must be obtained before starting the study and should be documented in a letter to the 
investigator specifying the protocol number and version and the date on which the committee met and 
granted the approval. 
 
Any modifications made to the protocol and/or informed consent form after receipt of IRB or IEC 
approval must also be submitted by the investigator to the committee in accordance with institutional 
procedures and regulatory requirements. 
 
When no local review board exists, the investigator is expected to submit the protocol to a regional 
committee. If no regional committee exists, the Sponsor will assist the investigator in submitting the 
protocol to a central Ethics Review Committee. 
 
 
Conditions for Modifying the Protocol 
Protocol modifications which could potentially adversely affect the safety of participating subjects or 
which alter the scope of the investigation, the scientific quality of the study, the experimental design, 
dosages, duration of therapy, assessment variables, the number of subjects treated or subject selection 

 
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criteria, may be made only after consultation between an appropriate representative of the Sponsor and 
the investigator. 
 
Protocol modifications (amendments) must be prepared by a representative of the Sponsor and initially 
reviewed and approved by the responsible medical monitor, scientist and (when applicable) the 
statistician. 
 
All protocol modifications must be submitted to the IEC/IRB and responsible regulatory authority in 
accordance with local requirements. Approval must be awaited before significant changes can be 
implemented i.e. if the risk benefit ratio is affected and/or the modification represents a change in 
basic trial definitions such as objectives, design, sample size or outcome measures. 
 
In the event of an emergency, the investigator may institute any medical procedures deemed 
appropriate. However, all such procedures must be promptly reported to Immuron, the Immuron 
Medical Monitor and the IEC/IRB. 
 
Administrative changes of the protocol are defined as minor corrections and/or clarifications that have 
no effect on the way the study is to be conducted or on the safety of the subjects. These administrative 
changes will be agreed upon by Immuron and the investigator, and will be documented in a 
memorandum. The investigator will then notify the IEC/IRB of such administrative changes. 
 
 
Conditions for Terminating the Study 
The study may be prematurely terminated by the IEC/IRB or relevant regulatory authorities if the 
perception of the benefit/risk becomes unfavorable for continuation of the study. 
 
Additionally, Immuron reserves the right to terminate the study at any time on the basis of new 
information regarding safety or efficacy, or if study progress is unsatisfactory, or for other valid 
administrative or commercial reasons. 
 
Should this be necessary, the procedures will be arranged on an individual study basis after review and 
consultation by all parties. In terminating the study, Immuron and the investigator will ensure that 
adequate consideration is given to the protection of the subjects’ interests. The Investigator should 
promptly inform the subjects and ensure appropriate therapy and follow-up, and inform the relevant 
regulatory authorities and the IRB/IEC. All delivered study materials must be collected and all CRFs 
completed to the extent possible. 
 
13.2 
Study Documentation, CRFs and Record Keeping 
 
Investigator Files/Retention of Documents 
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 documents should be classified into two separate categories: 
 
(1) Investigator Site File (ISF), and  
(2) Subject clinical source documents. 
 
The ISF will contain the protocol/amendments, CRFs, query forms, IRB/IEC and governmental 
approval with correspondence, informed consent, drug records, staff curriculum vitae and 
authorization forms and other appropriate documents and correspondence. 
 
Subject clinical source documents include subject hospital/clinic records, physician’s and nurse’s 
notes, appointment books, original laboratory reports, EKG, EEG, X-ray, pathology and special 
assessment reports, and consultant letters. All clinical study documents must be retained by the 

 
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Investigator until at least 2 years after the last approval of a marketing application in an International 
Conference on Harmonization (ICH) region (i.e. USA, Europe, or Japan) and until there are no 
pending or contemplated marketing applications in an ICH region; or if no application is filed or if the 
application is not approved for such indication, until 2 years after the investigation is discontinued and 
regulatory authorities have been notified. The investigator must notify Immuron prior to destroying 
any clinical study records. 
 
Should the investigator wish to assign the study records to another party or move them to another 
location, Immuron must be notified in advance. 
 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of the 
documents, special arrangements must be made between the investigator and Immuron to store these 
in a sealed container(s) offsite so that they can be returned sealed to the investigator in case of a 
regulatory audit. Where source documents are required for the continued care of the subject, 
appropriate copies should be made for storage offsite. 
 
 
Background Data 
The investigator shall supply the Sponsor, on request, with any required background data from the 
study documentation or clinic records. This is particularly important when CRFs are illegible or when 
errors in data transcription are suspected. In case of special problems and/or governmental queries or 
requests for audit inspections, it is also necessary to have access to the complete study records, 
provided that subject confidentiality is protected. 
 
 
Audits and Inspections 
An audit is a systematic and independent examination of trial related activities and documents to 
determine whether the evaluated trial related activities were conducted, and the data were recorded, 
analyzed and accurately reported according to the protocol, Immuron’ SOPs and those of their 
designees, GCP and the applicable regulatory requirement(s). 
 
Authorized representatives of Immuron, its designee, a regulatory authority, or the IRB/IEC may visit 
the center to perform audits or inspections. The investigator should contact Immuron immediately if 
they are contacted by a regulatory agency about an inspection at their center. If an audit or inspection 
occurs, the PI and institution agree to allow the auditor/inspector direct access to all relevant 
documents and allocate their time and the time of their staff to the auditor/inspector to discuss findings 
and any relevant issues. 
 
 
Case Report Forms 
For each subject who provides consent, CRFs must be completed and be signed by the principal 
investigator or co-investigator. This also applies to records for those subjects who fail to complete the 
study (even during the screening period if a CRF was initiated). If a subject withdraws from the study, 
the reason must be recorded on the CRF. If a subject is withdrawn from the study because of a 
treatment-limiting AE, thorough efforts should be made to clearly document the outcome. 
 
All forms should be typed or filled out using a black ball-point pen, and must be legible. Errors should 
be crossed out but not obliterated, the correction inserted, and the change initialed and dated by the 
investigator or his/her authorized delegate. The CRFs, as well as the protocol, are confidential. The 
CRFs remain the property of the sponsor at all times. 
 
13.3 
Monitoring the Study 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the CRFs for consistency. 
 

 
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It is understood that the responsible Sponsor monitor, as a Immuron representative, will contact and 
visit the investigator regularly and that he/she will be allowed, on request, to inspect the various 
records of the trial (CRFs and other pertinent data) provided that subject confidentiality is maintained 
in accord with local requirements. 
 
It will be the monitor’s responsibility to inspect the CRFs at regular intervals throughout the study, to 
verify the adherence to the protocol and the completeness, consistency and accuracy of the data being 
entered on them. The PI agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any relevant 
issues. 
 
13.4 
Confidentiality of Trial Documents and Subject Records 
The investigator must assure the subjects’ anonymity will be maintained and that their identities are 
protected from unauthorized parties. On CRFs or other documents submitted to the Sponsor, subjects 
should not be identified by their names, but by the subject’s initials and an identification code. The 
investigator should keep a subject identification log showing codes, names and addresses. Documents 
not for submission to Immuron (e.g. subject’s written consent forms, identification log), should be 
maintained by the investigator in strict confidence. 
 
All information concerning the study treatment and the Sponsor company and its operation, such as 
patent applications, formulae, manufacturing processes, basic scientific data and material not 
previously published are considered confidential and shall remain the sole property of the Sponsor. 
The investigator agrees to use this information only in accomplishing the study and will not use it for 
any other purposes without written consent from the Sponsor. 
 
13.5 
Publication of Data and Protection of Trade Secrets 
In accord with standard editorial and ethical practice, Immuron will support publication of multicenter 
trials only in their entirety and not as individual site data.  
 
The results of this study may be published or presented at scientific meetings. If this is envisaged, the 
investigator agrees to submit all manuscripts or abstracts to Immuron prior to submission. This allows 
the Sponsor to protect proprietary information and to provide comments based on information from 
other studies that may not yet be available to the investigator. 
 
Any formal publication of the study in which input of Immuron personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and the 
appropriate Immuron personnel. Authorship will be determined by an mutual agreement prior to the 
start of the study. The number of subjects enrolled will be taken into consideration in the selection of 
authors. Additional authors will be agreed prior to the completion of the study. Investigators who do 
not enroll any subjects into the study will not be included in this list. 
 
13.6 
Anticipated Subject Accrual and Duration of the Study 
It is anticipated that recruitment of subjects will take approximately 12 months form initiation of the 
first study site.  The investigator should continually compare the actual and expected accrual rates, and 
make every effort to ensure that they are as closely matched as possible. If the investigator anticipates 
major problems with recruitment, or delay in the expected completion date, he/she should discuss this 
with Immuron as early as possible. 

 
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Ther.; Vol 45: No.4 (193-202) 2007. 
Tacket CO, et al., Efficacy of bovine milk immunoglobulin concentrate in preventing illness after 
Shigella flexneri challenge. Am J Trop Med Hyg 1992;47:276-83. 
Tacket, CO, et al., Protection by milk immunoglobulin concentrate against oral challenge with 
enterotoxigenic Escherichia coli. N Engl J Med, 1988;318:1240-3. 
Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a 
follow-up study. Hepatology 1995;22:1714-1719. 
Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a 
followup study. Hepatology 1995; 22: 1714-1719. 
Vernon G., Baranova A., Younossi Z.M., Systematic review: the epidemiology and natural history of 
non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Ther. 
2011; 34: 274-285 
Williams C.D., Stengal, J., Asike, M.I., Torres, D.M., Shaw, J., Contreras, M., Landt, C.L., Harrison, 
S.A.: Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a 
Largely Middle-Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective Study. 
Gastroenterology, Volume 140, Issue 1, January 2011, Page e12 

 
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Yokoo T., Collins J., Hanna R., Bydder M., Middleton M., Sirlin C.: Effects of Intravenous 
Gadolinium Administration and Flip Angle on the Assessment of Liver Fat and Signal Fraction with 
opposed-phase and in-phase imaging. J. Mag. Res. Imag. 28:246-251 (2008). 
Yoneda M et al. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic 
steatohepatitis (NASH) and also of the severity of fibrosis in NASH.  J Gatroenterol, 2007; 42:573-
582. 
World Gastroenterology Organisation Global Guidelines, Nonalcoholic Fatty Liver Disease, and 
Nonalcoholic Steatohepatitis, June 2012 
 
 
 

 
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15. APPENDICES 
 
 

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APPENDIX A ADVERSE EVENT TOXICITY GRADING SCALES 
 
 The following toxicity grading scales (TGS) have been adapted from the FDA Guidelines for Toxicity 
Grading Scales for healthy adult and adolescent volunteers involved in clinical studies of preventive 
vaccines. The parameters described in the tables below provide further information on which to base 
assessment of the severity for AEs which may be reported in this study.  These include vital signs, 
gastrointestinal and other systemic events and clinical laboratory tests. These guidelines should be 
reviewed in the context of the values measured at Screening and Baseline. 
 
These TGS do not address all potential adverse events. All other adverse events reported during the 
study must be recorded, including an assessment of severity as described in Section 10.2.2 (Table 8) of 
this protocol.  
 
 
Clinical abnormalities 
 
 
Vital Signs *  
Mild (Grade 1)  Moderate(Grade 
2)  
Severe 
(Grade 3)  
Potentially Life  
Threatening  
(Grade 4)  
Fever (°C) **  
(°F) **  
38.0 – 38.4  
100.4 – 101.1  
38.5 – 38.9  
101.2 – 102.0  
39.0 – 40  
102.1 – 104  
> 40  
> 104  
Tachycardia - beats 
per  
minute  
101 – 115  
116 – 130  
> 130  
Emergency Room 
(ER) visit or  
hospitalization for  
arrhythmia  
Bradycardia - beats 
per  
minute***  
50 – 54  
45 – 49  
< 45  
ER visit or  
hospitalization for  
arrhythmia  
Hypertension 
(systolic) -  
mm Hg  
141 – 150  
151 – 155  
> 155  
ER visit or  
hospitalization for  
malignant  
hypertension  
Hypertension 
(diastolic) -  
mm Hg  
91 – 95  
96 – 100  
> 100  
ER visit or  
hospitalization for  
malignant  
hypertension  
Hypotension 
(systolic) –  
mm Hg  
85 – 89  
80 – 84  
< 80  
ER visit or  
hospitalization for  
hypotensive shock  
Respiratory Rate – 
breaths  
per minute  
 
17 – 20  
21 – 25  
> 25  
Intubation  
 
 * Subject should be at rest for all vital sign measurements.  
 **Oral temperature; no recent hot or cold beverages or smoking.  
 *** When resting heart rate is between 60 – 100 beats per minute. Use clinical judgement when 
characterizing bradycardia among some healthy subject populations, for example, conditioned 
athletes 
 
 

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APPENDIX A - Clinical abnormalities, continued 
 
Systemic General 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening (Grade 
4) 
Nausea/vomiting 
No 
interference 
with activity or 
1 - 2 
episodes/24 
hours 
Some 
interference 
with activity or 
> 2 
episodes/24 
hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2 - 3 loose 
stools or < 
400 gms/24 
hours 
4 - 5 stools or 
400 - 800 
grams/24 hours 
6 or more watery 
stools or > 
800gms/24 
hours or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No 
interference 
with activity 
Repeated use 
of non-narcotic 
pain reliever > 
24 hours or 
some 
interference 
with activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue 
No 
interference 
with activity 
Some 
interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
 
 
No 
interference 
with activity 
Some 
interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
 
 
 
 
 
Systemic Illness 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening (Grade 
4) 
Illness or clinical 
adverse event (as 
defined according 
to applicable 
regulations) 
No 
interference 
with activity 
Some 
interference 
with activity not 
requiring 
medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 
 

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APPENDIX A - Laboratory Abnormalities  
 
Serum  
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Sodium – 
Hypernatremia 
mEq/L 
132 – 134 
130 – 131 
125 – 129 
< 125 
Sodium – 
Hypernatremia 
mEq/L 
144 – 145 
146 – 147 
148 – 150 
> 150 
Potassium – 
Hyperkalemia 
mEq/L 
5.1 – 5.2 
5.3 – 5.4 
5.5 – 5.6 
> 5.6 
Potassium – 
Hypokalemia 
mEq/L 
3.5 – 3.6 
3.3 – 3.4 
3.1 – 3.2 
< 3.1 
Glucose – 
Hypoglycemia 
mg/dL 
65 – 69 
55 – 64 
45 – 54 
< 45 
Glucose – 
Hyperglycemia 
Fasting – mg/dL 
Random – mg/dL 
100 – 110 
110 – 125 
111 – 125 
126 – 200 
>125 
>200 
Insulin 
requirements or 
hyperosmolar 
coma 
Blood Urea 
Nitrogen 
BUN mg/dL 
23-26 
27 – 31 
> 31 
Requires dialysis 
Creatinine – mg/dL 
 
1.5 – 1.7 
1.8 – 2.0 
2.1 – 2.5 
> 2.5 or requires 
dialysis 
Calcium – 
hypocalcemia 
mg/dL 
 
8.0 – 8.4 
7.5 – 7.9 
7.0 – 7.4 
< 7.0 
Calcium – 
hypercalcemia 
mg/dL 
10.5 – 11.0 
11.1 – 11.5 
11.6 – 12.0 
> 12.0 
Magnesium – 
hypomagnesemia 
mg/dL 
 
1.3 – 1.5 
1.1 – 1.2 
0.9 – 1.0 
< 0.9 
Phosphorous – 
hypophosphatemia 
mg/dL 
2.3 – 2.5 
2.0 – 2.2 
1.6 – 1.9 
< 1.6 
CPK – mg/dL 
 
1.25 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 –10 x ULN 
> 10 x ULN 
Albumin – 
Hypoalbuminemia 
g/dL 
2.8 – 3.1 
2.5 – 2.7 
< 2.5 
-- 

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APPENDIX A – Laboratory Abnormalities, continued 
Serum  
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4)** 
Total Protein – 
Hypoproteinemia 
g/dL 
5.5 – 6.0 
5.0 – 5.4 
< 5.0 
-- 
Alkaline phosphate 
– increase by 
factor 
1.1 – 2.0 x ULN 
2.1 – 3.0 x ULN 
3.1 – 10 x ULN 
> 10 x ULN 
Liver Function 
Tests –ALT, AST 
increase by factor 
 
1.1 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
> 10 x ULN 
Bilirubin – when 
accompanied by 
any increase in 
Liver Function 
Test increase by 
factor 
1.1 – 1.25 x ULN 
1.26 – 1.5 x ULN 
1.51 – 1.75 x ULN 
> 1.75 x ULN 
Bilirubin – when 
Liver Function 
Test is normal; 
increase by factor 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.0 – 3.0 x ULN 
> 3.0 x ULN 
Cholesterol 
 
201 – 210 
211 – 225 
> 226 
--- 
Pancreatic 
enzymes – 
amylase, lipase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
 
 

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APPENDIX B MODEL PATIENT INFORMATION SHEET  
 
 
 
Title 
A phase II, randomized, double-blind, placebo-
controlled study of IMM-124E for patients with non-
alcoholic steatohepatitis. 
Protocol Number 
IMM-124E-2001 
Project Sponsor 
 
Immuron Limited 
Principal Investigator 
[Insert name] 
 
Associate Investigator(s) 
[Insert name, if required or delete] 
 
Location 
[Insert site location] 
 
 
 
Part 1 
What does my participation involve? 
 
1 
Introduction 
 
You are invited to take part in this research project. This is because you have a condition called 
non-alcoholic steatohepatitis (NASH).  The research project is a clinical trial, also known as a 
‘study’, to test a new treatment for NASH called IMM-124E. 
 
This Participant Information Sheet and Consent Form tells you about the research project. It 
explains the tests and treatments involved. Knowing what is involved will help you decide if you 
want to take part in the research. 
 
Please read this information carefully. Ask questions about anything that you don’t understand 
or want to know more about. Before deciding whether or not to take part, you might want to talk 
about it with a relative, friend or your local doctor. 
 
Participation in this research is voluntary. If you don’t wish to take part, you don’t have to. You 
will receive the best possible care whether or not you take part. 
 
If you decide you want to take part in the research project, you will be asked to sign the consent 
form.  
 
By signing it you are telling us that you: 
• understand what you have read; 
• consent to take part in the research project; 
• consent to have the tests and treatments that are described; 
 
• consent to the use of your personal and health information as described. 
 
You will be given a copy of this Participant Information and Consent Form to keep. 
 
 
 
 
 
 

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2  
What is the purpose of this research? 
 
The aim of this clinical trial is to test the safety and effectiveness of IMM-124E for treatment of 
NASH.  
 
IMM-124E is made from the first milk of dairy cows that have been vaccinated against bacteria 
that can cause diarrhea and vomiting in humans. These types of bacteria are also thought to 
contribute to the symptoms of NASH. IMM-124E does not contain the bacteria. IMM-124E 
contains proteins from the cows milk that may protect against the effects of the bacteria.  
 
Tablets with a lower dose of the active ingredient in IMM-124E is available without prescription 
in Australia and other countries for the prevention of traveler’s diarrhea (for people 6 years and 
over).  It is not approved for the treatment of NASH in any country.  This means it must be 
tested to see if it is an effective treatment for NASH. 
 
IMM-124E has only been investigated in one other 4 week study of people with NASH.  Further 
research is needed to learn more about how IMM-124E works, what dose to give and its safety 
and effectiveness for treatment of this condition.  This study will provide important information 
which may be reviewed in the future by regulatory authorities and used to plan further research. 
 
This research has been funded by Immuron Limited. 
 
3 
What does participation in this research involve? 
 
If you agree to take part, you will be asked to sign the consent form before any study 
assessments are performed. You will visit the clinic to see if you are eligible to take part.  If you 
are eligible, there will be a phone call visit and 10 more visits to the clinic over approximately 32 
weeks. Additional visits may be necessary if you experience any health problems or difficulties 
during the study. Your study doctor can advise you if these are needed. 
Physical assessments and blood tests will be required at the screening visit to find out whether 
you are eligible to take part. These assessments will confirm that you don’t have any other 
conditions which would exclude you and that you are well enough to participate. Assessments 
throughout the study will continue to monitor your health and provide valuable information about 
changes that occur while you are on treatment. 
You will be participating in a randomized controlled research project. Sometimes we do not 
know which treatment is best for treating a condition. To find out, we need to compare different 
treatments. Groups of participants receive the treatment and information is collected. The 
results for each group are compared to see if one is better. To make sure the groups are the 
same, each participant is put into a group by chance (random). This research project has been 
designed to make sure the researchers interpret the results in a fair and appropriate way and 
avoids study doctors or participants jumping to conclusions.   
If you are eligible for this study, you will be randomly put into a group to receive one of the 3 
different treatments being studied: either IMM-124E at a dose of 600 milligrams (mg) or 1200mg 
or matching placebo tablets, three times a day. A placebo is a medication with no active 
ingredients. It looks like the active treatment, but it is not. In this study you have a 2 in 3 chance 
of receiving one of the active treatments. Neither you nor the study staff will know which 
treatment you are on, although they are able to find out if necessary.  
You will be given the first dose of treatment in the clinic and enough tablets to take at home for 
4 weeks treatment.  You will be asked to take 2 tablets each morning, 2 in the middle of the day 
and 2 each night, preferably with a minimum of 1 hour fasting before and 1/2 hour after. At each 
4 weekly clinic visit you will be given more tablets to continue taking at home, for a total of 24 
weeks treatment. 
 

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The following is a detailed summary of how often the clinic visits occur, the procedures and 
tests which will be done and the time commitment involved in taking part in the study: 
Visit Day or 
Week (from 
Baseline 
visit) 
 
Procedure 
Approximate 
Visit 
Duration 
Screening, up 
to 45 days 
before study 
drug dosing  
 Answer your questions about the study and sign the 
consent form, if you have not already done so. 
 The study doctor will examine you and measure your 
blood pressure, temperature, heart rate, breathing rate, 
weight, height and waist and take an electronic trace of 
your heart rhythm (EKG). 
 You will be asked questions about your medical history, 
your current health and any medicines you are taking, 
including herbal preparations.  
 Blood samples will be collected using a needle and 
syringe (55mL or about 11 teaspoons of blood) and 
prepared for testing for:  
o HIV, hepatitis B and hepatitis C virus 
exposure; 
o alpha-feto protein (a marker of liver cancer).  
o hematology and clinical chemistry (tests of 
general health and wellbeing also known as 
‘safety blood tests); 
o HBA1C (test for average blood glucose 
levels);  
o blood clotting time; 
o pregnancy, if you are a woman able to have 
children (pregnancy can be also tested by 
urine). 
 A urine sample for safety screening.     
 
2 hours 
Day 0 visit 
(Baseline) 
 
Before the baseline visit you will be sent for a magnetic 
resonance (MR) scan of your abdomen to measure the 
fat levels in your liver.  
 
(Selected sites only)  You will be asked to collect a 
sample of your feces in the 24 hours before you come to 
the clinic. You will be given instructions on how to collect 
and store it. This will be used to test the types of bacteria 
in your digestive system.   
 
You will be asked to fast for at least 8 hours before you 
come to the clinic. You will not be allowed to drink 
alcohol, coffee, tea and other drinks while fasting. 
However, you can drink as much water as you would like.  
 
The study doctor will examine you and measure your 
blood pressure, temperature, heart rate, breathing rate, 
weight, waist and hips. 
 
You will be asked questions about your current health 
and any new medicines you have taken since the 
screening visit. 
 
Your completed 7-day diary will be collected and 
reviewed and you will be asked detailed questions about 
your diet and physical exercise. 
 3 hours 

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Visit Day or 
Week (from 
Baseline 
visit) 
 
Procedure 
Approximate 
Visit 
Duration 
 
If you are a woman able to have children, a urine sample 
will be collected and tested to confirm you have not 
become pregnant. 
 
 
Blood samples will be collected (up to 75mL or about 15 
teaspoons of blood) and prepared for testing:  
o hematology and clinical chemistry 
o blood lipid (fat) levels,  
o blood clotting time 
o serum biomarkers of NASH ‘activity’ -  CK-18 
(fibrosis) and LPS (fragments from gut bacteria) 
o levels of immune markers including cytokines 
(cell signaling molecules) and (selected sites 
only) white blood cells 
o levels of IMM-124E 
o metabolomics – blood testing for small molecules 
that can potentially identify disease state 
 
You will be allocated and dispensed study medication 
and will take the first dose in the clinic. 
 
Day 3 
 
A telephone call will be made to you to find out how you 
are feeling and what medications you are taking. 
 
Telephone 
call 
Day 7   
and  
Day 14 visits  
 
 
 
You will be asked to fast for at least 8 hours before you 
come to the clinic (drink water only). 
 
The study doctor will examine you and measure your 
blood pressure, temperature, heart rate, and breathing 
rate.    
 
You will be asked questions about your current health 
and medicines you have been taking. 
 
Blood samples will be collected (30mL or about 6 
teaspoons of blood) and prepared for testing:  
o 
hematology and clinical chemistry 
o 
blood lipid (fat) levels,  
o 
blood clotting time 
 
 1 hour 
Week 4, 8,12, 
16 and 20 
visits 
 
 
 
You will be asked to fast for at least 8 hours before you 
come to the clinic (drink water only).    
 
The study doctor will examine you and measure your 
blood pressure, temperature, heart rate, breathing rate, 
weight, waist and hips. 
 
You will be asked questions about your current health 
and any new medicines you have taken since your last 
visit. 
 
You will be asked detailed questions about your diet and 
physical exercise. 
 
Blood samples will be collected (30mL or about 6 
teaspoons of blood) and prepared for testing:  
o hematology and clinical chemistry 
o lipid (fat) levels,  
 1 hour 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Visit Day or 
Week (from 
Baseline 
visit) 
 
Procedure 
Approximate 
Visit 
Duration 
o clotting time 
You will be allocated and dispensed enough study 
medication for 4 weeks treatment. 
 
If you are a woman able to have children, a urine sample 
will be collected and tested to confirm you have not 
become pregnant. 
At Week 4 only: 
Additional blood samples (20mL or about 4 teaspoons of 
blood) will also be collected and prepared for testing:  
o biomarkers of NASH ‘activity’   
o levels of immune markers (cytokines)   
o levels of IMM-124E 
 
(Selected sites only)  You will be asked to collect a 
sample of your feces in the 24 hours before you come to 
the clinic.   
At Week 12 only: 
Additional blood samples (up to 55mL or about 11 teaspoons 
of blood) will also be collected  and prepared for testing:  
o biomarkers of NASH ‘activity’   
o levels of immune markers including cytokines and 
(selected sites only) white blood cells 
o levels of IMM-124E 
 
You will be issued with a 7-day diet and exercise diary 
card to complete during the next week. 
 
(Selected sites only)  You will be asked to collect a 
sample of your feces in the 24 hours before you come to 
the clinic.  
 
 
 
 
 
 
 
 
 
 
 
+1 hour 
 
Week 24 
 
You will be asked to fast for at least 8 hours before you 
come to the clinic (drink water only).    
 
The study doctor will examine you and measure your 
blood pressure, temperature, heart rate, breathing rate, 
weight, waist and hips. 
 
You will be asked questions about your current health 
and medicines you have been taking 
 
You will be asked detailed questions about your diet and 
physical exercise. 
 
You will be sent for a magnetic resonance (MR) scan of 
your abdomen to measure the fat levels in your liver. 
 
Blood samples will be collected (up to 75mL or about 15 
teaspoons of blood) and prepared for testing:  
o hematology and clinical chemistry 
o lipid (fat) levels,  
o clotting time 
o biomarkers of NASH ‘activity’   
o levels of immune markers including cytokines and 
(selected sites only) white blood cells 
o levels of IMM-124E  
o Metabolomics – blood testing for small molecules 
that can potentially identify disease state  
2 hours 

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Visit Day or 
Week (from 
Baseline 
visit) 
 
Procedure 
Approximate 
Visit 
Duration 
 
If you are a woman able to have children, a urine sample 
will be collected and tested to confirm you have not 
become pregnant. 
 
You will be asked to return any unused medication to the 
clinic. 
 
(Selected sites only)  You will be asked to collect a 
sample of your feces in the 24 hours before you come to 
the clinic.  
 
 
Week 28 or 
early 
withdrawal 
 This final visit after completing the study treatment is to 
review how you are feeling and what medications you are 
taking. 
 As previously, you will be asked to fast for at least 8 
hours before you come to the clinic.      
 The study doctor will examine you and measure your 
blood pressure, temperature, heart rate, breathing rate, 
weight and waist. 
 
Blood samples will be collected (15mL or about 3 
teaspoons of blood) and prepared for testing:  
o hematology and clinical chemistry 
o clotting time 
 
You will be asked questions about your current health 
and medicines you have been taking 
 
You will be asked detailed questions about your diet and 
physical exercise. 
 
1 hour 
 
 
There are no additional costs associated with participating in this research project, nor will you 
be paid. All medication, tests and medical care required as part of the research project will be 
provided to you free of charge.  
 
You may be reimbursed for any reasonable travel, parking, meals and other expenses 
associated with the research project visits. 
 
 
If you decide to participate in this research project, the study doctor will inform your primary care 
doctor. 
 
4 
What do I have to do? 
 
You will need to attend each of the clinic visits on the study visit days specified.  
 
You may need to follow a diet and exercise program that has been recommended to help 
manage your NASH. It is important that you continue to follow your program throughout the 
study.  You will be asked regularly to report what you have had to eat and drink and what type 
and how much exercise you have had. 
 

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It is important that you agree to take the study medication you are allocated three times each 
day according to the instructions you will be given. If you miss a dose, you should take the next 
dose as planned and let the study staff know at your next visit.  
 
The study doctor will ask about medications you are taking at the time you are screened.  You 
are also asked to tell the study doctor if you take any prescribed, over-the-counter, herbal or 
other medicines during the course of the study. This is to be sure that you are not taking 
anything that could interact with the study medication or affect the study results.  
 
You are not allowed to take some types of medication for a period of time before the Screening 
visit and while you are on the study.  
 
The medications you are not allowed are:  
 
 
SAM-e (also known as S-adenosyl methionine), betaine (trimethylglycine or TMG), milk 
thistle and probiotic supplements (but you are allowed to eat yoghurt or other natural food 
sources of probiotics) for more than 10 days in the 3 months before and during the study; 
you could be eligible if you haven't used such drugs for less than 3 months and if you have 
stopped taking them 6 weeks before the screening visit. 
 
corticosteroid tablets or injections (for example dexamethasone and cortisone) for more than 
7 consecutive days in the 6 months before the Screening visit and during the study; 
 
daily treatment with more than one non-steroidal anti-inflammatory drugs, NSAIDs - for 
example aspirin (except if a very low dose for heart health), ibuprofen, Nurofen®);  naproxen 
Naprosyn®, meloxicam, Mobic® and celecoxib , Celebrex®) for more than 1 month within 3 
months before the Screening visit and during the study; 
 
azathioprine (Imuran®);  6-mercaptopurine (Purinethol®); methotrexate (Rheumatrex® and 
Trexall®), cyclosporine (Neoral, Cicloral, Sandimmun), anti-TNF alpha therapies (infliximab, 
adalimumab, etanercept) and anti-integrin therapies (namixilab) in the 12 months before the 
Screening visit and during the study. 
 
You may not be eligible for this study if you have not had a liver biopsy in the last 12 months to 
confirm that you have NASH.  You may also not be eligible if you have been diagnosed with 
certain other medical conditions. You will not be allowed to start treatment if your screening test 
results show you are not well enough to do so. If you are allergic to cow’s milk or have lactose 
intolerance you will also not be able to take part, because the study drug is prepared from cow’s 
milk and contains lactose. 
 
5 
Other relevant information about the research project 
 
It is anticipated that at least 120 people with NASH will be included in this study at an estimated 
30 clinical trial sites. These include sites located in the United States, Australia and other 
potential locations.   
  
6 
Do I have to take part in this research project? 
 
Participation in any research project is voluntary. If you do not wish to take part, you do not have 
to. If you decide to take part and later change your mind, you are free to withdraw from the 
project at any stage. 
 
If you do decide to take part, you will be given this Participant Information and Consent Form to 
sign and you will be given a copy to keep. 
 
Your decision whether to take part or not to take part, or to take part and then withdraw, will not 
affect your routine treatment, your relationship with those treating you or your relationship with 
this institution. 
 
 

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7 
What are the alternatives to participation?  
 
 
You do not have to take part in this research project to receive treatment at this hospital.  Other 
options may be available to you. There are currently no approved medicines specifically for 
treatment of NASH. Your study doctor will discuss options for your treatment with you before 
you decide whether or not to take part in this research project.  You can also discuss options 
with your local doctor. 
 
 
8 
What are the possible benefits of taking part? 
 
We cannot guarantee or promise that you will receive any benefits from this research. However, 
possible benefits may include reducing the amount of fat in your liver and improving 
measurements of your liver function.   
 
Even if you do not benefit from the treatment you receive in this study, the information collected 
may help researchers to learn more about NASH and how to treat it. Other people may benefit 
from this knowledge in the future.  
 
9 
What are the possible risks and disadvantages of taking part? 
 
Side effects 
 
Medical treatments often cause side effects. You may have none, some or all of the effects 
listed below, and they may be mild, moderate or severe. If you have any of these side effects, or 
are worried about them, talk with your study doctor. Your study doctor will also be looking out for 
side effects. 
 
There may be side effects that the researchers do not expect or do not know about and that 
may be serious. Tell your study doctor immediately about any new or unusual symptoms that 
you get. 
 
Many side effects go away shortly after treatment ends. However, sometimes side effects can 
be serious, long lasting or permanent. If a severe side effect or reaction occurs, your study 
doctor may need to stop your treatment. Your study doctor will discuss the best way of 
managing any side effects with you. 
 
To date, possible side effects reported in clinical trials of IMM-124E have been few, mild to 
moderate and not permanent. There have been no severe or life threatening events. There has 
been no clear pattern to events observed.  These events include: 
 
nausea 
 
vomiting  
 
flatulence (bloating or wind) 
 
mild diarrhea 
 
raised levels of some liver enzymes 
 
There is a possibility that you will experience an allergic reaction. Allergic reactions may be mild, 
such as skin rashes or hives, or severe or life-threatening such as difficulty breathing or 
swallowing. If this occurs immediately it is called anaphylaxis.   
 
For your safety, the first dose of study drug will be given when you are still at the clinic. 
 
Pregnancy 
 

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The effects of IMM-124E on an unborn child and newborn baby are not known. Because of this, 
it is important that research project participants are not pregnant or breast-feeding and do not 
become pregnant during the course of the research project. You must not participate in the 
research if you are pregnant or trying to become pregnant, or breast-feeding. If you are female 
and child-bearing is a possibility, you will be required to undergo a pregnancy test prior to 
commencing the research project.  If you are male, you should not father a child or donate 
sperm for at least 3 months after the last dose of study medication. 
 
Both male and female participants are strongly advised to use effective contraception during the 
course of the research and for a period of 3 months after completion of the research project. 
You should discuss methods of effective contraception with your study doctor. 
 
If you are a female participant and you do become pregnant whilst participating in the research 
project, you should advise your study doctor immediately. Your study doctor will withdraw you 
from the research project and advise on further medical attention should this be necessary. You 
must not continue in the research if you become pregnant. 
 
If you are a male participant you should advise your study doctor if you father a child while 
participating in the research project. Your study doctor will advise on medical attention for your 
partner should this be necessary. 
 
Blood Tests 
 
Having blood samples taken may cause some discomfort or bruising. Sometimes the blood 
vessel may swell or blood may clot in the blood vessel or the place where the blood was taken 
from becomes inflamed. Rarely, some people have fainted. Infection or bleeding might occur.   
 
When taking larger quantities of blood, people may become anemic (low red blood cell count); 
this will be monitored in the study. 
 
Scans using Magnetic Resonance Imaging 
 
MRI stands for magnetic resonance imaging. A MRI scanner is a machine that uses 
electromagnetic radiation (radio waves) in a strong magnetic field to take clear pictures of the 
inside of the body.  Electromagnetic radiation is not the same as ionising radiation used, for 
example, in X-rays. The pictures taken by the machine are called MRI scans. 
We will ask you to lie on a table inside the MRI scanner. The scanner will record information 
about your liver. It is very important that you keep very still during the scanning. When you lie on 
the table, we will make sure you are in a comfortable position so that you can keep still. The 
scanner is very noisy and we can give you some earphones to reduce the noise. Some people 
may experience symptoms of claustrophobia from lying in a confined space. If you do 
experience discomfort at any time during the scan, you will be able to alert staff by pressing on 
a call button provided to you. 
 
There are no proven long-term risks related to MRI scans as used in this research project. MRI 
is considered to be safe when performed at a center with appropriate procedures. However, the 
magnetic attraction for some metal objects can pose a safety risk, so it is important that metal 
objects are not taken into the scanner room. 
 
We will thoroughly examine you to make sure there is no reason you should not have the scan.  
You must tell us if you have metal implanted in your body, such as a pacemaker or metal pins. 
 
The scans we are taking are for research purposes. They are not intended to be used like scans 
taken for a full clinical examination. The scans will not be used to help diagnose, treat or 
manage a particular condition. A specialist will look at your MRI scans for features relevant to 
the research project. On rare occasions, the specialist may find an unusual feature that could 

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have a significant risk to your health. If this happens, we will contact you to talk about the 
findings. We cannot guarantee that we will find any/all unusual features. 
 
10 
What will happen to my test samples? 
 
By consenting to take part in this study, you also consent to the collection, storage and use of 
your blood samples and urine samples. During the course of the study blood samples will be 
taken on 11 occasions.  The total volume of blood taken for the entire study will be about 600mL 
(about 1.4 cups).  In comparison, one standard blood donation is 470mL.   
 
Collected blood samples will be used to check your general health at screening and throughout 
the study. The proposed blood tests also include a screening test for HIV (also called the ‘AIDS’ 
virus) and hepatitis. This is because the study doctors need to know whether you have any 
other condition that affects your liver.  You will receive information and counselling before the 
test. If a test shows you have HIV or Hepatitis, you will have follow-up counselling and medical 
advice.  If your test results are positive, the study doctors are required by law to notify 
government health authorities.  Signing the consent form means that you agree to have this 
testing; it will not be done without your consent. 
 
Your blood will also be tested to ensure that clotting time is normal and, if you are a woman able 
to have children, to check you are not pregnant. Urine will be collected to confirm the health of 
your kidneys and, if you are a woman able to become pregnant, to do a final check that you are 
not pregnant before starting treatment with the study medication and at the end of the study.    
 
Serum will be prepared from some of the blood you give (serum is the clear liquid that carries 
red and white blood cells). It will be tested for the presence of the study medication, for a bi-
product of gut bacteria (lipopolysaccharide) and for fats, glucose and insulin. Some of the serum 
will also be stored to test for the levels of biomarkers which are associated with NASH.  White 
blood cells which relate to infection and immunity will be also be collected for analysis. Some of 
these samples may be stored for testing at a later stage.  All other urine and blood samples will 
be destroyed after they have been tested. 
 
Your blood samples will be labelled with your unique study number (but not your name). 
   
Samples of your blood or tissue obtained for the purpose of this research project may be 
transferred to Immuron Limited (the Sponsor) or an organisation working on its behalf. Your 
tissue will not be sold by [Name of institution], however [Name of institution] may charge study 
doctors a fee to recover some of the costs of storing and administering the samples. 
 
Once your blood or tissue samples are transferred to Immuron, [Name of institution] will not be 
able to control whether Immuron transfers or sells your samples at some future date, however 
[Name of institution]  will not knowingly transfer your samples to anyone who has expressed 
intent to sell the samples. 
 
11 
What if new information arises during this research project? 
 
Sometimes during the course of a research project, important new information becomes 
available about the treatment that is being studied. If this happens, your study doctor will tell you 
about it and discuss with you whether you want to continue in the research project. If you decide 
to withdraw, your study doctor will make arrangements for your regular health care to continue. 
If you decide to continue in the research project you will be asked to sign an updated consent 
form. 
Also, on receiving new information, your study doctor might consider it to be in your best 
interests to withdraw you from the research project. If this happens, he/ she will explain the 
reasons and arrange for your regular health care to continue. 
 

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12 
Can I have other treatments during this research project? 
 
Whilst you are participating in this research project, you may not be able to take some or all of 
the medications or treatments you have been taking for your condition or for other reasons. It is 
important to tell your study doctor and the study staff about any treatments or medications you 
may be taking, including over-the-counter medications, vitamins or herbal remedies, 
acupuncture or other alternative treatments. You should also tell your study doctor about any 
changes to these during your participation in the research project. Your study doctor should also 
explain which treatments or medications need to be stopped for the time you are involved in the 
research project. 
 
13 
What if I withdraw from this research project? 
 
If you decide to withdraw from the project, please notify a member of the research team before 
you withdraw. This notice will allow that person or the research supervisor to discuss any health 
risks or special requirements linked to withdrawing. 
 
If you do withdraw your consent during the research project, the study doctor and relevant study 
staff will not collect additional personal information from you, although personal information 
already collected will be retained to ensure that the results of the research project can be 
measured properly and to comply with law. You should be aware that data collected by the 
Sponsor up to the time you withdraw will form part of the research project results.  If you do not 
want them to do this, you must tell them before you join the research project. 
 
14 
Could this research project be stopped unexpectedly? 
 
This research project may be stopped unexpectedly for a variety of reasons. These may include 
reasons such as: 
• Unacceptable side effects being reported 
• The drug being shown not to be effective 
• The drug being shown to work and not needing further testing 
• The decision is made in the commercial interests of the sponsor or by local regulatory/health 
authorities.  
 
15 
What happens when the research project ends? 
 
 
Once you have completed 24 weeks of treatment you will return to the clinic 4 weeks later for a 
final check-up. Your doctor will discuss with you options available for the continued treatment of 
your NASH.  
 
Once all the participants have completed treatment in the study, the treatment blind will be 
broken. This means that the treatment each participant was taking and the results of the testing 
done can be analysed together.  The results of the analysis will be published. Your doctor 
may/will provide you with a lay summary of the overall results of the study. 
 
Part 2 
How is the research project being conducted? 
 
16 
What will happen to information about me? 
 
By signing the consent form you consent to the study doctor and relevant research staff 
collecting and using personal information about you for the research project. Any information 
obtained in connection with this research project that can identify you will remain confidential.   
Your information will only be used for the purpose of this research project and it will only be 
disclosed with your permission, except as required by law. 
 

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Information about you may be obtained from your health records held at this and other health 
services for the purpose of this research. By signing the consent form you agree to the study 
team accessing health records if they are relevant to your participation in this research project. 
 
Your health records and any information obtained during the research project may be inspected 
by relevant regulatory authorities, including the US Food and Drug Administration (FDA) and the 
Australian Therapeutics Goods Administration (TGA), authorised representatives of the 
Sponsor, Immuron, the institution relevant to this Participant Information Sheet, [Name of 
institution], or as required by law. By signing the Consent Form, you authorise release of, or 
access to, this confidential information to the relevant study personnel and regulatory authorities 
as noted above.  
 
Information about your participation in this research project may be recorded in your health 
records. 
 
Any information obtained for the purpose of this research project that can identify you will be 
treated as confidential and securely stored.  It will be disclosed only with your permission, or as 
required by law. 
 
It is anticipated that the results of this research project will be published and/or presented in a 
variety of forums. In any publication and/or presentation, information will be provided in such a 
way that you cannot be identified, except with your permission. Your individual data will only 
ever be linked with your unique study identification number, not your name. In most cases, your 
data will be combined with others who received the same study medication and compared with 
the results for the other treatment groups. 
 
In accordance with relevant Australian and/or [Name of state/territory] privacy and other relevant 
laws, you have the right to request access to your information collected and stored by the 
research team. You also have the right to request that any information with which you disagree 
be corrected. Please contact the study team member named at the end of this document if you 
would like to access your information. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials. gov, as required by 
U.S. Law and on the Australian clinical trials registry website http://www.anzctr.gov.au. These 
websites will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search these websites at any time. 
 
 
17 
Complaints and compensation 
 
If you suffer any injuries or complications as a result of this research project, you should contact 
the study team as soon as possible and you will be assisted with arranging appropriate medical 
treatment. If you are eligible for Medicare, you can receive any medical treatment required to 
treat the injury or complication, free of charge, as a public patient in any Australian public 
hospital. 
 
There are two avenues that may be available to you for seeking compensation if you suffer an 
injury as a result of your participation in this research project: 
 
• The Sponsor of this research project, Immuron Limited, has agreed to comply with guidelines 
for compensation in for injury resulting from participation in a Company-sponsored clinical trial 
as applicable in [Country].  Details of the process and conditions are set out in the [Reference 
document].  In accordance with these Guidelines, the sponsor will determine whether to pay 
compensation to you, and, if so, how much.  The research staff will give you a copy of the 
Guidelines together with this Participant Information and Consent Form.  If you have any 

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questions about the Guidelines, please ask to speak to [Name of designated person, 
associated with the research trial or in the organization, capable of explaining the Guidelines]. 
• You may be able to seek compensation through the courts. 
 
18 
Who is organizing and funding the research? 
 
This research project is being conducted, sponsored and funded by Immuron Limited. 
 
You will not benefit financially from your involvement in this research project even if, for 
example, your samples (or knowledge acquired from analysis of your samples) prove to be of 
commercial value to Immuron Limited. 
 
In addition, if knowledge acquired through this research leads to discoveries that are of 
commercial value to Immuron Limited the study doctors or their institutions, there will be no 
financial benefit to you or your family from these discoveries. 
 
[Name of institution] will receive a payment from Immuron for undertaking this research project.  
 
No member of the research team will receive a personal financial benefit from your involvement 
in this research project (other than their ordinary wages). Add any declarations of interest of 
study doctors, sponsors and institutions 
 
19 
Who has reviewed the research project? 
 
 
 
All research involving humans is reviewed by an independent group of people called an 
Independent Ethics Committee (IEC), also known as a [Institutional Review Board (IRB) or   
Human Research Ethics Committee (HREC)].  The ethical aspects of this research project have 
been approved by [Name of IEC].  
 
This project will be carried out according to the ICH Harmonised Tripartite Guideline 
For Good Clinical Practice (E6) and [ list other relevant documents e.g.Australian National 
Statement on Ethical Conduct in Human Research (2007)]. This documents have been 
developed to protect the interests of people who agree to participate in human research studies. 
 
Approval has also been granted by [Name of institution]. 
 
20 
Further information and who to contact 
 
The person you may need to contact will depend on the nature of your query. If you want any 
further information concerning this project or if you have any medical problems which may be 
related to your involvement in the project (for example, any side effects), you can contact the 
principal study doctor on [phone number] or any of the following people: 
 
 Clinical contact person 
 
For matters relating to research at the site at which you are participating, the details of the local 
site complaints person are: 
 
Complaints contact person 
Name 
[Name] 
Position 
[Position] 
Telephone 
[Phone number] 
Email 
[Email address] 
Name 
[Name] 
Position 
[Position] 

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If you have any complaints about any aspect of the project, the way it is being conducted or any 
questions about being a research participant in general, then you may contact: 
 
 
Reviewing HREC/IRB approving this research and HREC/IRB Executive Officer details 
 
Local HREC/IRB Office contact (Single Site -Research Governance Officer) 
Telephone 
[Phone number] 
Email 
[Email address] 
Reviewing HREC name 
[Name] 
Executive Officer 
[Name] 
Telephone 
[Executive Officer Phone number] 
Email 
[Executive Officer Email address] 
Name 
[Name] 
Position 
[Position] 
Telephone 
[Phone number] 
Email 
[Email address] 

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APPENDIX C HOMEOSTATIC MODEL ASSESSMENT OF INSULIN RESISTANCE  
   
SCORE 
 
The following formula is to be used to calculate the HOMA-IR score based on laboratory reported 
measurements of serum fasting glucose and insulin as required: 
 
 
HOMA-IR = glucose (mmol/L*) x insulin (mU/mL) 
 
 
 
 
 
 
22.5 
 
* To convert mg/dL to mmol/L, divide by 18 
 
 

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APPENDIX D ALCOHOL USE DISORDERS IDENTIFICATION TEST (AUDIT) 
QUESTIONNAIRE 
 
Please circle the answer that is correct for you: 
 
1. How often do you have a drink containing alcohol? 
· Never 
· Monthly or less 
· 2-4 times a month 
· 2-3 times a week 
· 4 or more times a week 
 
2. How many standard drinks containing alcohol do you have on a typical day when 
drinking? 
· 1 or 2 
· 3 or 4 
· 5 or 6 
· 7 to 9 
· 10 or more 
 
3. How often do you have six or more drinks on one occasion? 
· Never 
· Less than monthly 
· Monthly 
· Weekly 
· Daily or almost daily 
 
4. During the past year, how often have you found that you were not able to stop 
drinking once you had started? 
· Never 
· Less than monthly 
· Monthly 
· Weekly 
· Daily or almost daily 
 
5. During the past year, how often have you failed to do what was normally expected 
of you because of drinking? 
· Never 
· Less than monthly 
· Monthly 
· Weekly 
· Daily or almost daily 
 
6. During the past year, how often have you needed a drink in the morning to get 
yourself going after a heavy drinking session? 
· Never 
· Less than monthly 
· Monthly 
· Weekly 
· Daily or almost daily 
 
 
 
 

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7. During the past year, how often have you had a feeling of guilt or remorse after 
drinking? 
· Never 
· Less than monthly 
· Monthly 
· Weekly 
· Daily or almost daily 
 
8. During the past year, have you been unable to remember what happened the night 
before because you had been drinking? 
· Never 
· Less than monthly 
· Monthly 
· Weekly 
· Daily or almost daily 
 
9. Have you or someone else been injured as a result of your drinking? 
· No 
· Yes, but not in the past year 
· Yes, during the past year 
 
10. Has a relative or friend, doctor or other health worker been concerned about your 
drinking or suggested you cut down? 
· No 
· Yes, but not in the past year 
· Yes, during the past year 
 
 
Scoring the audit 
Scores for each question range from 0 to 4, with the first response for each question 
(eg never) scoring 0, the second (eg less than monthly) scoring 1, the third (eg 
monthly) scoring 2, the fourth (eg weekly) scoring 3, and the last response (eg. daily 
or almost daily) scoring 4. For questions 9 and 10, which only have three responses, 
the scoring is 0, 2 and 4 (from left to right). 
 
A score of 8 or more is associated with harmful or hazardous drinking, a score of 13 
or more in women, and 15 or more in men, is likely to indicate alcohol dependence. 
 
1Saunders JB, Aasland OG, Babor TF et al. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative 
project on early detection of persons with harmful alcohol consumption II. Addiction 1993, 88: 791–803. 
 
 
As the alcohol content of a “standard drink or unit” varies by country, responses will be converted to 
grams of alcohol. The calculated quantity of alcohol will be recorded in the subject’s CRF.  
 
Examples of standard alcohol units are as follows: 
 
US – 1 standard drink is equivalent to 14g of alcohol 
Australia: - 1 standard drink is equivalent to 10g of alcohol 
UK – 1 standard drink is equivalent to 7.9g (10ml) of alcohol 
 
Country specific “standard drink/ unit” charts will be provided to participating clinical trial sites to 
assist patients and site staff in estimating alcohol consumption. 
 
 

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APPENDIX E STANDARDIZED DIET AND EXERCISE COUNSELING 
 
At each visit, it is recommended that patients be engaged in a discussion about diet and exercise in the 
management of their NASH and relevant factors associated with the metabolic syndrome.  It is 
suggested that the discussion follow a ‘counseling style’ which includes clear and easy-to-manage 
recommendations which align with a patient’s preferences (Bellantini et al 2008).  
 
The following is a simple five step procedure which may assist in conducting the discussion*: 
 
1. 
Open the discussion “What you eat and how much you exercise is very important for your 
health and for the management of your NASH (diabetes, high cholesterol, etc).” 
a) 
Visit 1 invitation – “I recommend that we review your current habits and try to make 
some improvements.” 
b) 
Subsequent visit invitation  – “Let’s review progress with your plan.” 
 
2. Using open questions, assess the patient’s motivation, past diet experience and current diet. 
 
3. Focus on problem areas:  “Based on your current diet, I recommend that we focus on making some 
changes to your to e.g. high fat intake, excess calories, inadequate intake of fruits and vegetables.” 
 
4. Discuss and negotiate a plan, including two or three simple and specific dietary and physical 
activity goals, addressing possible barriers and ways to handle them.   
 
Determine whether the patient needs additional information or help; refer to a dietician as needed. 
 
5. Follow-up at each return visit to assess progress (see step 1b). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Adapted from recommendations presented at the “Innovative Teaching Strategies for Training Physicians in Clinical Nutrition: The 
Nutrition Academic Award (NAA) Medical Schools” symposium given at the 2002 Experimental Biology meeting on April 20,2002, New 
Orleans, LA. The symposium was sponsored by The American Society for Nutritional Sciences. The proceedings are published as a 
supplement to The Journal of Nutrition. 
 
 
 
 
 
 

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APPENDIX F DIET AND EXERCISE DIARY CARD 
 
 
 
 
 

 
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APPENDIX G PROTOCOL AMENDMENT #3 – SUMMARY OF CHANGES 
 
 
RATIONALE FOR PROTOCOL AMENDMENT No. # 3 
 
This protocol amendment has been generated to achieve the following goals: 
1. to improve recruitment by eliminating the ALT eligibility requirement and using ALT as a secondary endpoint instead of a primary endpoint  
2. to allow for a planned interim analysis  
3. to allow for MRI-based stratification  
4. extend screening period from 28 days to 45 days to allow for better operational streamlining  
5. to better clarify existing wording and phrasing issues within the protocol  
6. correct typo and add administrative changes 
 
 
The following sections of the protocol have been amended to reflect changes in study procedure.   
 
 
1. Administrative Protocol Amendments 
 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Cover page and footer 
Version 1.2 (Incorporating Amendment 
1 and 2) 24 June 2015 
Version 1.3 (Incorporating Amendment 3) 
08 May 2016 
Version number updated to indicate 
protocol amendment throughout 
document 
 
Cover page 
Level 1, 18 Kavanagh street 
Unit 10,  25 – 37  Chapman Street,  
Blackburn North VIC 3130 
Change to the Immuron office address 
Table of contents 
Changes in page numbering  
Changes in page numbering  
Changes to reflect the actual contents and 
applicable page numbering 

 
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2. Formal Protocol Amendments 
 
Section 
Original Text 
Revised to Read 
Rationale for Change 
Study synopsis and main body 
of the protocol 
To evaluate the safety and preliminary efficacy 
of two dose levels of IMM-124E in reducing 
liver fat and/or serum ALT compared with 
placebo in subjects with biopsy proven NASH.  
To evaluate the safety and preliminary efficacy 
of two dose levels of IMM-124E in reducing 
liver fat evaluated by MRI compared with 
placebo.  
To achieve a better study design 
with a single primary endpoint 
and to improve recruitment due 
to the ALT requirement, ALT 
was removed from the primary 
endpoints  
Study synopsis and main body 
of the protocol 
Efficacy:    
Mean change from Baseline in the percentage 
fat content of the liver measured by MRI at 
Week 24;  
Mean change from baseline in serum ALT at 
week 24. 
Efficacy:  
Mean change from Baseline in the percentage 
fat content of the liver measured by Magnetic 
Resonance Imaging (MRI) at Week 24. 
To achieve a better study design 
with a single primary endpoint 
and to improve recruitment due 
to the ALT requirement, ALT 
was removed from the primary 
endpoints 
Study synopsis and main body 
of the protocol 
 
Mean serum concentrations of: LPS, CRP, 
CK-18 fragments, C-peptide and 
adiponectin and subsets of cytokines IL6, 
IL12, IFNγ and TNFα; 
PBMC samples, including CD4, CD8, CD25, 
FoxP3, NKT and CD62; 
iome. 
 
Mean serum concentrations of: 
lipopolysaccharide (LPS), C-reactive 
protein (CRP), cytokeratin (CK)-18 
fragments, C-peptide , glucogon-like 
peptide (GLP)-1 and adiponectin and 
subsets of inflammatory cytokines: 
interleukin (IL)-6, IL-1α, IL1β, IL-2, IL-4 
IL-10, IL-13, IL-12, IL-17, IL-23 interferon 
gamma (IFNγ), Transforming Growth 
Factor Beta )TGF-β and  tumor necrosis 
factor alpha (TNFα); 
 
Metabolomics; 
 
Relative levels of regulatory T cells in 
peripheral blood mononuclear cells 
(PBMC) samples, including CD4, CD8, 
CD25, FoxP3, NKT, CD62 and CD69 T 
cells; 
 
Characterization of the gut 
microbiome. 
To get a better perspective on the 
immunological effect additional 
interleukins and other 
immunological markers had been 
added to the panel as per the 
existing literature.  

 
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 
Explore a dose effect. 
 
Study synopsis and main body 
of the protocol 
Up to 28 days for Screening and 24 weeks of 
treatment.   
Up to 45 days for Screening and 24 weeks of 
treatment.   
Change to study duration 
participant 
Study synopsis and main body 
of the protocol 
Approximately 120, randomized 1:1:1 
 
Treatment allocation will be stratified by status 
defined as being normal (HBA1C <6.0) or 
diabetic (having a diagnosis of Type II diabetes 
and/or HBA1C >6.0 and < 9.0 whether or not 
receiving allowable medication). 
at least 120, randomized 1:1:1 
 
Treatment allocation will be stratified by the 
following: 
 
Baseline MRI Liver Fat, according to 
the following scale: ≤10%, 
10%<X≤20%, 20%<X<30% and ≥30% 
 
Diabetic status defined as being normal 
(HBA1C <6.0) or diabetic (having a 
diagnosis of Type II diabetes and/or 
HBA1C >6.0 and < 9.0 whether or not 
receiving allowable medication). 
To avoid bias created by baseline 
MRI, stratification was added at 
baseline.  
Study synopsis and main body 
of the protocol 
IMM-124E tablet 
 
IMM-124E 600mg tablet 
 
Study Drug – dose specification 
Exclusion criteria 6 (in study 
synopsis and main body of the 
protocol) 
History of bariatric surgery  
History of major bariatric surgery (not including 
balloon / sleeve gastrectomy); 
 
To better define the excluded 
population. 
Exclusion criteria 13 (in study 
synopsis and main body of the 
protocol) 
Concurrent conditions 
 
Inflammatory bowel disease; 
 
Unstable angina, myocardial infarction, 
transient ischemic events, or stroke 
within 24 weeks of Screening; 
 
Ongoing infectious, ongoing multi-
systemic immune-mediated and/or 
concurrent or past malignant disease; 
 
Any other concurrent condition which, 
in the opinion of the investigator, could 
impact adversely on the subject 
Concurrent conditions 
• Inflammatory bowel disease; 
• Unstable angina, myocardial infarction, 
transient ischemic events, or stroke 
within 24 weeks of Screening; 
• Ongoing infectious disease 
• ongoing multi-systemic immune-
mediated disease  
• concurrent or past malignant disease;  
• Any other concurrent condition which, in 
the opinion of the investigator, could 
The changes made here are to 
better clarify the eligibility 
criteria as per questions coming 
from clinical sites  

 
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participating or on the interpretation of 
the study data; 
impact adversely on the subject 
participating or on the interpretation of 
the study data; 

 
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Exclusion criteria 14 (in study 
synopsis and main body of the 
protocol) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent medications including: 
o anti-NASH therapy(s) taken for more than 10 
continuous days in the last 3 months. 
These include S-adenosyl methionine (SAM-e), 
betaine, milk thistle, bacterial 
probiotic supplements (other than yoghurt or 
other natural food sources), vitamin E 
and gemfibrozil. 
 
NB: If vitamin E or gemfibrozil are 
used, the dose must be stable and liver 
biopsy confirming diagnosis of NASH 
subsequent to commencing treatment; 
 
Wash out for any of the anti-NASH 
therapies is as follow: under 10 days no 
washout required, more than 10 days and up to 
3 months treatment requires 6 
weeks washout. Any treatment of over 3 months 
would require to re-biopsy to 
ensure histological eligibility 
o thiazolidinediones (glitazones), dipeptidyl 
peptidase 4 inhibitors (gliptins) or 
glucagon-like peptide-1 analogs in the last 6 
months. If treatment commenced and is 
stable for more than 6 month prior to the 
determinant biopsy and the dose is still 
stable at time of study entry, subjects will be 
eligible for recruitment. 
o Allowable anti-diabetic treatment includes 
metformin and/or sulfonylureas 
administered at constant dose for at least 2 
months prior to study entry; 
Concurrent medications including: 
o 
anti-NASH therapy(s) taken for more than 
10 continuous days in the last 3 months. 
These include S-adenosyl methionine 
(SAM-e), betaine, milk thistle, probiotic 
supplements (other than yoghurt), vitamin 
E and gemfibrozil. 
 
NOTE: if determinant biopsy is 
performed while on stable 
treatment – subject is eligible; 
 
Wash out for any of the anti-
NASH therapies is as follows: 
under 10 days no washout 
required, more than 10 days and 
up to 3 months treatment requires 
6 weeks washout. Any treatment 
of over 3 months would require to 
re-biopsy to ensure histological 
eligibility 
o 
thiazolidinediones (glitazones), dipeptidyl 
peptidase 4 inhibitors (gliptins) or 
glucagon-like peptide-1 analogs  in the last 
6 months. NOTE: if determinant biopsy is 
performed while on stable treatment of at 
least 6 months – subject is eligible.  
o 
NOTE: Allowable anti-diabetic treatment 
includes metformin and/or sulfonylureas 
administered at constant dose for at least 2 
months prior to study entry.    
o 
NOTE: Subjects treated with Insulin are 
eligible if clinically stable on insulin 
treatment (i.e. no recurrent acute hypo-
/hyperglycemic episodes diagnosed 
clinically and by Glucose serum levels of 
<50 mg/dL and >200 mg/dL respectively) 
for at least 2 months prior to study entry. 
Clarifying Exclusion criteria 14 

 
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o Subjects treated with Insulin are eligible if 
clinically stable on insulin treatment (i.e. 
no recurrent acute hypo-/hyperglycemic 
episodes diagnosed clinically and by Glucose 
serum levels of <50 mg/dL and >200 mg/dL 
respectively) for at least 2 months prior 
to study entry. 
o immune modulatory agents including: 
In the last 3 months 
 
systemic steroids for more than 7 days 
 
daily treatment with multiple non-
steroidal anti-inflammatory drugs 
(such as aspirin >100mg/day, ibuprofen, 
naproxen, meloxicam, 
celecoxib) for more than 1 month within 3 
months prior to study 
entry; 
In the last 12 months 
 
azathioprine, 6-mercaptopurine, 
methotrexate, cyclosporin, anti- 
TNFα therapies (infliximab, adalimumab, 
etanercept) or anti-integrin 
therapies (namixilab) ; 
o more than 10 consecutive days oral or 
parenteral antibiotics within 4 weeks prior to 
study entry (Note: such subjects would not be 
included in the stool and PBMC 
analysis); 
o variable dose of anti-lipidemic agents (HMG 
Co-A reductase inhibitors –a“statins”) in 
the 3 months prior to Screening. 
o 
immune modulatory agents including 
 
within 3 months of study entry; 
 
systemic steroids for 
more than 7 days 
 
daily treatment with 
multiple non-steroidal 
anti-inflammatory drugs 
(such as aspirin 
(>100mg/day), ibuprofen, 
naproxen, meloxicam, 
celecoxib) for more than 
1 month; 
 
In the last 12 months: 
 
azathioprine, 6-
mercaptopurine, 
methotrexate, 
cyclosporin, anti-TNFα 
therapies (infliximab, 
adalimumab, etanercept) 
or anti-integrin therapies 
(namixilab) ; 
o 
More than 10 consecutive days oral or 
parenteral antibiotics within 4 weeks prior 
to study entry NOTE: subjects administered 
with antibiotics for more the 5 days prior to 
study entry would not be included in the 
stool and PBMC analysis). 
o 
Variable dose of antilipidemic agents (3-
hydroxy-3-methyl-glutaryl (HMG)-Co-A 
reductase inhibitors – “statins”) in the 3 
months prior to study entry.  
 

 
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Study Synopsis and main body 
of the protocol 
Sample size determination 
Further, since the endpoint is the change from 
Baseline, plausible estimates of the degree of 
correlation between pre and post-baseline 
measurements were also incorporated into the 
variance estimates. Given the wide range of 
results observed in the literature, several “what 
if” scenarios were examined. As such, the 
current sample size was considered sufficient 
for the exploratory objectives of 
the study for the given range of plausible 
treatment effects and variance estimates. Due to 
the exploratory objectives of the protocol, no 
adjustment for the two co-primary endpoints 
was made. Additionally, there will be no 
adjustment for multiple comparisons between 
the 3 treatment groups. 
Further, since the endpoint is the change from 
Baseline, plausible estimates of the degree of 
correlation between pre and post-baseline 
measurements were also incorporated into the 
variance estimates.  Given the wide range of 
results observed in the literature, several “what 
if” scenarios were examined.  As such, the 
current sample size was considered sufficient 
for the exploratory objectives of the study for 
the given range of plausible treatment effects 
and variance estimates.  There will be no 
adjustment for multiple comparisons between 
the 3 treatment groups. 
Sample size determination 
Study Synopsis and main body 
of the protocol 
Interim analysis section 12.8 
Not applicable  
Interim analysis  
An un-blinded efficacy and safety interim 
analysis is scheduled 
The interim analysis will be conducted on all 
primary and secondary outcome unblended data 
by a third party, 
The interim analysis will be carried out when at 
least 22 eligible subjects complete the full 24 
weeks of treatment and have verified baseline 
and 24 weeks MRI data.  
The goals of the interim analysis are as follow: 
5. Full efficacy analysis  
6. Full safety analysis  
7. Determining the best performing dose  
8. To correct for sample size. 
 
Allowing for an interim analysis 
during the course of the clinical 
study 

 
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To account for multiple comparisons between 
the interim and final analyses, the critical alpha 
level for the interim analysis will be set at 
0.0000147 while the critical alpha level for the 
final analysis will be set at 0.0499.  These 
values are based on 25% of the study endpoints 
being available for the interim analysis and 
symmetric two-tailed tests being used within the 
O’Brien-Fleming spending function. The study 
will not be terminated for either success or 
failure. The purpose of this interim analysis will 
be to verify, and if necessary re-calculate, the 
required study sample size and to potentially 
discontinue the worse performing dose arm. 
The Interim-Analysis will be carried out by a 
third party so both sponsor and investigators 
would remain blinded to the allocation of 
subjects within the study groups. 
Table 1. Table of assessments 
And Baseline evaluation and 
study medication 
administration section 7.2.3 
And Week 24 section 7.2.9 
And Table 5 
Not applicable 
Serum Metabolomics 
Addition of serum metabolomics 
to the procedures of baseline and 
week  24 visits to evaluate the 
effect by other means 
Table 1. Table of assessments  
Comment 1 
1 Must be collected after subject has fasted 
for at least 8 hours (except for Screening 
and W28 assessment). Including: sodium, 
potassium, chloride, bicarbonate, blood 
urea nitrogen, creatine phosphokinase, 
creatinine, total protein, albumin, serum 
amylase (fractionated if > greater than 
upper limited of reference range), serum 
lipase, phosphate, GGT, AST, ALT, 
1 Must be collected after subject has fasted 
for at least 8 hours (except for Screening 
and W28 assessment). Including: sodium, 
potassium, chloride, bicarbonate, blood 
urea nitrogen, creatine phosphokinase, 
creatinine, total protein, albumin, serum 
amylase (fractionated if > greater than 
upper limited of reference range), serum 
lipase, phosphate, GGT, AST, ALT, 
alkaline phosphatase, total bilirubin, 
Clarification for the chemistry 
parameters to be assessed. 

 
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alkaline phosphatase, total bilirubin, 
calcium, uric acid, glucose and insulin. 
calcium, uric acid, glucose and insulin. In 
addition CRP and C-peptide will be 
included at the following visits: Baseline, 
W4, W12 and W24. 
Table 1. Table of assessments  
Comment 4 
4Serum biomarkers – CK-18, CRP, C-
peptide, LPS, adiponectin, GLP-1 and 
cytokines 
4Serum biomarkers – CK-18, LPS, 
adiponectin, GLP-1 and cytokines (IL-1α, 
IL1β, IL-2, IL-3, IL-4, IL-6, IL-10, IL-13, 
IL-12, IL-17α, IL-23, IFNγ, TGF-β and 
TNFα) 
Removing CRP and C-peptide 
as these parameters are being 
assessed in clinical chemistry.  
Specifying all cytokines to be 
assessed – see rationale above  
Table 1. Table of assessments  
Comment 6 
Table 4 screening tests – 
serum  
No comment 6 
 
6 (including HIV, HCV and HBV test) 
results will be acceptable for eligibility 
within range of 6 months prior to screening. 
Additional comment to clarify the 
timeline of serology requirement 
for screening 
Table 1. Table of assessments  
Comment 7 
No comment 7 
7 MRI: Baseline MRI to be performed as 
soon as subject eligibility is determined. 
Week 24 MRI to be done within +/- 2 
weeks week 24. 
 
Additional comment to clarify the 
timeline of MRI in 
screening/baseline visit and week 
24. 
Table 1. Table of assessments  
Comment 8 
No comment 8 
8 Randomization is to be done within 2 
weeks post baseline MRI, when the MRI 
result is available for stratification (hepatic 
fat fraction form – to be received by central 
imaging lab).  
Additional comment to clarify the 
timeline for randomization. The 2 
weeks are required to obtain the 
MRI result from central imaging 
lab. 
Endpoint section 4.2 
Secondary endpoint 
Liver function: 
 
Mean change from Baseline in serum 
ALT, AST, bilirubin, albumin and GGT 
at Weeks 4, 8, 12, 16, 20 and 24.  
 
Proportion of subjects whose ALT at 
Week 24 is within reference range 
defined a <19IU/L for women and 
<30IU/L for men. 
Liver function: 
 
Mean change from Baseline in serum 
ALT, AST, bilirubin, albumin and 
GGT at Weeks 4, 8, 12, 16, 20 and 24.  
 
Proportion of subjects whose ALT at 
Week 24 is within reference range 
defined a <19IU/L for women and 
<30IU/L for men. 
Definition of endpoints  

 
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 
The proportion of subjects 
demonstrating a decrease in serum 
ALT at 24 weeks compared to baseline 
equal or greater than 30% compared to 
placebo. 
Endpoint  
section 4.2  
Secondary endpoint 
 
MRI: 
 
The proportion of subjects 
demonstrating a decrease in Liver 
percent fat by MRI at 24 weeks 
compared to baseline equal greater 
than 5% compared to placebo. 
 
The proportion of subjects 
demonstrating a decrease in Liver 
percent fat by MRI at 24 weeks 
compared to baseline equal greater 
than 10% compared to placebo. 
Definition of endpoints 
Endpoint  
section 4.2 Exploratory 
endpoints 
 
Mean serum concentrations of: LPS, 
CRP, CK-18 fragments, C-peptide and 
adiponectin and subsets of cytokines 
IL6, IFNγ and TNFα; 
 
Relative levels of regulatory T cells in 
PBMC samples, including CD4, CD8, 
CD25, FoxP3, NKT and CD62; 
 
Characterization of the gut microbiome. 
 
Mean serum concentrations of: LPS, 
CK-18 fragments and adiponectin and 
subsets of cytokines IL6, IL-1α, IL1β, 
IL-2, IL-3, IL-4 IL-10, IL-13, IL-12, IL-
17α, IL-23, IFNγ TGFβ and TNFα; 
 
Serum metabolomics  
 
Relative levels of regulatory T cells in 
PBMC samples, including CD4, CD8, 
CD25, FoxP3, NKT and CD62; 
 
Characterization of the gut microbiome. 
Definition of endpoints with the 
addition of serum immunological 
and metabolomics markers  
Randomization Process  
section 7.2.2 
Upon completion of screening assessments and 
confirmation that the subject meets all eligibility 
criteria, the subject will be randomized to study 
treatment at the Baseline visit (See Section 8.1 
and the Study Reference Manual). The 
randomization number will be recorded in the 
subject’s study documentation.  
 
Upon completion of screening assessments and 
confirmation that the subject meets all eligibility 
criteria (up to 45 days):  
 
Baseline MRI scan of the liver (Section 
7.3.13) is to be done. 
Valid result for baseline MRI scan by the 
central imaging lab (VirtualScopics) must be 
obtained before randomization. 
After determining eligibility, the 
subject should undergo liver MRI 
scan. The MRI result (hepatic fat 
fraction %) to be available before 
randomization. The hepatic fat 
fraction will be utilized as 
stratification factor.  

 
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Randomization (Day 0) should take place within 
14 days after baseline MRI scan was done.  
Once a subject is eligible to be randomized and 
to receive study medication, the following 
procedures are to be performed and 
documented: 
 
Baseline evaluation and study 
medication administration 
section 7.2.3 
Prior to randomization, final confirmation of 
eligibility will be performed through the review 
of the inclusion/exclusion criteria. Subjects 
meeting all of the inclusion and none of the 
exclusion criteria 
will be eligible to be randomized and to receive 
study medication and the following procedures 
performed and documented: 
 
Prior to randomization, final confirmation of 
eligibility will be performed through the review 
of the inclusion/exclusion criteria. Then subjects 
will undergo MRI scan. Subjects meeting all of 
the inclusion and none of the exclusion criteria 
and have a valid result for their baseline MRI 
scan by the central imaging lab (VirtualScopics) 
will be eligible to be randomized and to receive 
study medication and the following procedures 
performed and documented: 
 
Urine pregnancy test 
Section 7.3.10 
Prior to administration of the first dose of study 
medication at Baseline and 4 weekly thereafter, 
women of childbearing potential will require 
confirmation of non-pregnancy by collection of 
a mid-stream urine specimen and testing with a 
standard commercially available urine 
pregnancy test kit. 
Prior to administration of the first dose of study 
medication at Baseline and 4 weekly thereafter, 
women of childbearing potential will require 
confirmation of non-pregnancy by collection of 
a mid-stream urine specimen and testing with a 
standard commercially available urine 
pregnancy test kit. In case such test is not 
available or deemed unsatisfactory at specific 
site, a blood pregnancy test will be performed. 
Adding the possibility to perform 
urine pregnancy test by blood 
test, instead of urine kit - in case 
this is not available.  
Randomization section 8.1 
Not applicable  
Additionally, to ensure baseline Hepatic Fat 
Fraction (HFF) would not be a confounding 
factor, subjects will be stratified for baseline HFF 
according to the following groups ≤10%, 
10%<X≤20%, 20%<X<30% and ≥30%. 
Defining the way subjects are to 
be randomized by baseline MRI 
fat fraction  
Dosage and Administration of 
study drugs section 8.4.4 
IMM-124E and matching placebo tablets may 
be either chewed before swallowing or 
swallowed whole three times daily per oral on 
IMM-124E and matching placebo tablets may be 
either chewed before swallowing or swallowed 
whole three times daily per oral on an empty 
Clarification of allowed IMP 
compliance range. 

 
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an empty stomach. No intra-subject dose 
adjustment of IMM-124E will be allowed 
during this study. 
stomach. No intra-subject dose adjustment of 
IMM-124E will be allowed during this study. 
Range of +/- 15% (85-115%) is the acceptable 
compliance range. 
Any poor compliance out of this range will be 
considered as protocol deviation. 
Any poor compliance should be escalated to 
Immuron and will potentially result in subject's 
termination from the study. 
Appendix B Model patient 
information sheet 
Section 3 - What does 
participation in this research 
involve?  
You will be given the first dose of treatment in 
the clinic and enough tablets to take at home for 
4 weeks treatment.  You will be asked to take 2 
tablets each morning, 2 in the middle of the day 
and 2 each night on an empty stomach, 
preferably 1 hour before or 3 hours after eating. 
At each 4 weekly clinic visit you will be given 
more tablets to continue taking at home, for a 
total of 24 weeks treatment. 
You will be given the first dose of treatment in 
the clinic and enough tablets to take at home for 
4 weeks treatment.  You will be asked to take 2 
tablets each morning, 2 in the middle of the day 
and 2 each night on an empty stomach, preferably 
with a minimum of 1 hour fasting before and 1/2 
hour after. At each 4 weekly clinic visit you will 
be given more tablets to continue taking at home, 
for a total of 24 weeks treatment. 
Clarifying the timing of drug 
administration and the 
recommendation to administer on 
an empty stomach. 
Appendix B Model patient 
information sheet 
Screening visit 
Blood samples will be collected using a needle 
and syringe (30mL or about 6 teaspoons of 
blood) 
Blood samples will be collected using a needle 
and syringe (55mL or about 11 teaspoons of 
blood) 
Correction of the total amount of 
blood to be withdrawn during the 
visit.  
Appendix B Model patient 
information sheet 
Day 0 visit (Baseline) and 
Week 24 
Not applicable 
metabolomics – blood testing for small 
molecules that can potentially identify disease 
state 
Adding metabolomics to baseline 
and week 24 visits and explaining 
what metabolomics is.  
Appendix B Model patient 
information sheet 
Day 7 and Day 14 visits 
Blood samples will be collected (20mL or about 
4 teaspoons of blood) 
Blood samples will be collected (30mL or about 
6 teaspoons of blood) 
Correction of the total amount of 
blood to be withdrawn during the 
visit.  
Appendix B Model patient 
information sheet  
Week 4, 8,12, 16 and 20 visits 
Blood samples will be collected (20mL or about 
4 teaspoons of blood) 
Blood samples will be collected (30mL or about 
6 teaspoons of blood) 
Correction of the total amount of 
blood to be withdrawn during the 
visit.