Clinical trial NCT04618744
Conditions: Diabetes Mellitus, Type 2 NASH - Nonalcoholic Steatohepatitis
Sponsor: Oramed, Ltd.
Start date: 2020-11-24; Completion date: 2022-06-27
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, randomized, placebo-controlled, multi-center study using the oral ORMD-0801 insulin formulation in patients with NASH and confirmed type 2 DM.

Detailed description:
This is a double-blind, randomized, placebo-controlled, multi-center study using the oral ORMD-0801 insulin formulation in patients with NASH and confirmed type 2 DM. The study will consist of a Screening Phase, Placebo Run-in Phase, Treatment Phase and an End-of-Study Phase. Approximately 36 subjects will be randomized in a 2:1 ratio to receive either 8 mg ORMD-0801, 1 capsule twice a day (once in the morning approximately 30 to 45 minutes prior to breakfast and no later than 10 AM, and once at night between 8 PM to Midnight and no sooner than 1 hour after dinner) or matching placebo.

Arms: arm 1: Fish oil arm 2: ORMD-0801 (insulin) capsule Dose: 8 mg BD Dosage Regimen: 1 capsule twice a day (once in the morning approximately 30 to 45 minutes prior to breakfast and no later than 10 AM, and once at night between 8 PM to Midnight and no sooner than 1 hour after dinner) Mode of Administration: Oral
Interventions: intervention 1: ORMD-0801 (Insulin) capsule 8 mg BD intervention 2: Placebo
Intervention descriptions: intervention 1: 8 mg ORMD-0801, 1 capsule, twice a day, once in the morning and once in the evening. intervention 2: Matching Placebo

Protocol documents:
Prot_SAP_000.pdf: 
Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 1 of 62  
 
 
 
 
Clinical Study Protocol: ORA-D-N02 
Study Title: 
A Double-Blind, Randomized, Placebo-controlled, Multi-
center Study to Assess the Safety and Efficacy of Oral Insulin 
to Reduce Liver Fat Content in Type 2 Diabetes Patients with 
Nonalcoholic Steatohepatitis (NASH) 
Protocol Number: 
ORA-D-N02 
Study Phase:  
Phase 2 
Principal 
Investigator: 
Joel M. Neutel, M.D. 
Orange County Research Center (OCRC) 
14351 Myford Rd., Suite B 
 Tustin, CA 92780 
Sponsor: 
Oramed Ltd. 
Hi-Tech Park 2/4 Givat Ram 
PO Box 39098 
Jerusalem, 91390, Israel 
Name of Sponsor 
Signatory: 
Miriam Kidron, PhD 
Chief Scientific Officer and Director 
Oramed Ltd. 
Protocol Version: 
2 
Date of Version: 
Version 2: August 25, 2020  
CONFIDENTIALITY STATEMENT: THIS DOCUMENT IS THE PROPERTY OF ORAMED LTD. 
AND MAY NOT—IN FULL OR IN PART—BE PASSED ON, REPRODUCED, PUBLISHED, OR 
DISTRIBUTED TO ANY PERSON, OR SUBMITTED TO ANY REGULATORY AUTHORITY, 
WITHOUT THE EXPRESS WRITTEN PERMISSION OF ORAMED LTD. OR THEIR OFFICIAL 
REPRESENTATIVES. 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 2 of 62  
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE 
The undersigned has reviewed and approved Protocol No. ORA-D-N02 for issuance: 
 
  Miriam Kidron, PhD 
Chief Scientific Officer and Director 
Oramed Ltd. 
 
 
 
Signature 
 
Date 
 
 
 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 3 of 62  
INVESTIGATOR SIGNATURE PAGE 
I have read this protocol and agree: 
● To conduct the study as outlined herein, in accordance with Good Clinical Practices 
(GCPs), the Declaration of Helsinki and complying with the obligations and 
requirements of Clinical Investigators and all other requirements listed in 21 CFR 
part 312 and according to the study procedures provided by Oramed Ltd. and local 
regulations. 
● Not to implement any changes to the protocol without prior agreement from the 
Sponsor and prior review and written approval from the IRB or IEC, except as would 
be necessary to eliminate an immediate hazard to study subject (s), or for 
administrative aspects of the study. 
● To ensure that all persons assisting me with the study are adequately informed about 
the Investigational Product(s) and of their study-related duties as described in the 
protocol. 
● To completely inform all subjects in this study concerning the pertinent details and 
purpose of the study prior to their agreement to participate in the study in accordance 
with GCP and regulatory authority requirements. 
● To be responsible for maintaining each subject’s consent form in a secure study file 
and providing each subject with a signed copy of the consent form. 
● That I am thoroughly familiar with the appropriate use of the Investigational 
Product(s), as described in the protocol, and any additional information provided to 
me by, or on behalf of Oramed Ltd. 
 
   
Principal Investigator  
(Name and Title) 
Address 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 4 of 62  
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required 
by the following: 
● United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
● E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (2018) 
 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Good Clinical Practice Training. 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 5 of 62  
CONFIDENTIAL 
SYNOPSIS 
Title 
A Double-Blind, Randomized, Placebo-controlled, Multi-center 
Study to Assess the Safety and Efficacy of Oral Insulin to Reduce 
Liver Fat Content in Type 2 Diabetes Patients with Nonalcoholic 
Steatohepatitis (NASH) 
Indication 
Nonalcoholic Steatohepatitis (NASH) and Type 2 Diabetes Mellitus 
(T2DM) 
Clinical Phase 
Phase 2 
Test Product 
Details 
 
ORMD-0801 (insulin) capsule 
Dose: 8 mg BID 
Dosage Regimen: 8 mg BID (one capsule in the morning, prior to 
breakfast and one capsule at night) 
Dosage Form: Soft gel capsule (1 capsule contains 8 mg of insulin) 
Mode of Administration: Oral 
Primary 
Objective 
To evaluate the safety of oral insulin in patients with nonalcoholic 
steatohepatitis (NASH) and type 2 DM. 
Secondary 
Objective 
To assess whether oral insulin may be effective in reducing liver fat 
content and inflammation in patients with NASH and type 2 DM.  
Total Sample Size Approximately 36 patients with NASH and Type 2 DM will be 
randomized in order to complete approximately 30 subjects in this 
multi-center study.  
Study Design 
This is a double-blind, randomized, placebo-controlled, multi-center 
study using the oral ORMD-0801 insulin formulation in patients 
with NASH and confirmed type 2 DM. The study will consist of a 
Screening Phase, Placebo Run-in Phase, Treatment Phase and an 
End-of-Study Phase. Approximately 36 subjects will be randomized 
in a 2:1 ratio to receive either 8 mg ORMD-0801, 1 capsule twice a 
day (once in the morning approximately 30 to 45 minutes prior to 
breakfast and no later than 10 AM, and once at night between 8 PM 
to Midnight and no sooner than 1 hour after dinner) or matching 
placebo.   
Study Endpoints 
The primary endpoint of this trial will evaluate safety of ORMD-0801 
in patients with nonalcoholic steatohepatitis (NASH) and type 2 DM.  
Secondary endpoints will evaluate the effectiveness of ORMD-0801 in 
reducing liver fat content in patients with NASH and type 2 DM by 
measuring the final and baseline differences in the MRI-PDFF. 


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 6 of 62  
CONFIDENTIAL 
Summary of 
Assessments 
Safety Assessments:  
Safety will be assessed by monitoring adverse events including 
hypoglycemia, physical exam, vital signs (blood pressure 
(SBP/DBP), heart rate and oral temperature), ECG and clinical 
laboratory assessments.   
Efficacy Assessments:  
Efficacy will be assessed by measuring the final and baseline 
differences in fat content obtained from MRI-PDFF results.  
Duration of 
Participation 
Screening Phase: up to 42 days prior to the Treatment Phase 
Placebo Run-in Phase: 2 weeks  
Treatment Phase: 12 weeks 
End-of-Study (EOS) Phase: 4 weeks after completion of the 
Treatment Phase 
Subject Selection 
Criteria 
Inclusion Criteria 
1. Male or female aged 18-70 years. 
2. BMI ≥25.  
3. Known type 2 DM according to American Diabetic 
Association (one of the three needed): Fasting Plasma Glucose 
≥126 mg/dl or 2h postprandial (PG) following 75g OGTT ≥200 
mg/dl or HbA1c > 6.5%28 or on treatment with metformin only 
or metformin in addition to no more than two of the following 
medications sulfonylurea, DPP-4 inhibitors, GLP-1 receptor 
agonists, Thiazolidinediones (TZDs). 
4. Diagnosis of NAFLD by non-invasive determination of hepatic 
steatosis grade S1, defined as hepatic steatosis>8%. by MRI- 
PDFF and CAP FibroScan ≥ 238 dB/m. 
5. Liver enzyme abnormalities: ULN≤5 times.  
6. Fibrosis score 1≤F≤3 as defined by FibroScan measurement 
(Liver stiffness measurement, LSM) of 6 ≤ LSM ≤ 12 kPa. 
7. Signature of the written informed consent. 
8. Negative serum pregnancy test at study entry for women of 
childbearing potential (WCBP). 
9. Women of childbearing potential (WCBP) must have a 
negative urine pregnancy test result prior to the start of run-in 
period and at initiation of active dosing. Males and females of 
childbearing potential must use two methods of contraception 
(double barrier method), one of which must be an acceptable 
barrier method from the time of screening to the last study visit 
(22 weeks). Barrier methods of contraception include male 
condoms plus spermicide, diaphragm with spermicide plus 
male condom, and cervical cap with spermicide plus male 
condom. Acceptable methods of birth control include 
abstinence, oral contraceptives, surgical sterilization, 


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 7 of 62  
CONFIDENTIAL 
vasectomy, the contraceptive patch, and the contraceptive ring. 
If a subject is not usually sexually active but becomes active, 
he or his partner should use medically accepted forms of 
contraception. Sperm donations will not be allowed for the 
duration of the study and for 90 days after the last dose of 
study drug. 
Females of non-childbearing potential are defined as 
postmenopausal who a) had more than 24 months since last 
menstrual cycle with menopausal levels of FSH (FSH Level > 
40), b) who are surgically menopausal (surgical sterility 
defined by tubal occlusion, bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy). 
10. For hypertensive patients, hypertension must be controlled by 
stable dose of anti-hypertensive medication for at least 2 
months prior to screening (and the stable dose can be 
maintained throughout the study) with BP < 150/<95 mmHg 
11. Patients previously treated with vitamin E (>400IU/day), 
Polyunsaturated fatty acid (>2g/day) or Ursodeoxycholic acid 
fish oil can be included if drugs are stopped at least 3 months 
prior to enrolment and up to the end of the study. 
12. Glycaemia must be controlled (Glycosylated Hemoglobin A1C 
≤8.5%) while any HbA1c increment should not exceed 1% 
during 6 months prior to enrolment). 
Exclusion Criteria 
1. Patients with active (acute or chronic) liver disease other than 
NASH (e.g. viral hepatitis, genetic hemochromatosis, Wilson 
disease, alpha-1 antitrypsin deficiency, alcohol liver disease, 
drug induced liver disease) at the time of enrolment. 
2. ALT or AST > 5 times ULN. 
3. Abnormal synthetic liver function (serum albumin ≤3.5gm%, 
INR >1.3). 
4. Known alcohol and/or any other drug abuse or dependence in 
the last five years. 
5. Weight >120 Kg (264.6 lbs.). 
6. Known history or presence of clinically significant, 
cardiovascular, gastrointestinal, metabolic (other than diabetes 
mellitus), neurologic, pulmonary, endocrine, psychiatric, 
neoplastic disorder or nephrotic syndrome. 
7. History or presence of any disease or condition known to 
interfere with the absorption, distribution, metabolism or 
excretion of drugs including bile salt metabolites (e.g. 
inflammatory bowel disease (IBD), previous intestinal (ileal or 
colonic) operation, chronic pancreatitis, celiac disease or 
previous vagotomy. 
8. Weight loss of more than 5% within 6 months prior to 
enrolment. 


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 8 of 62  
CONFIDENTIAL 
9. History of bariatric surgery. 
10. Uncontrolled blood pressure BP ≥150/≥95. 
11. Non type 2 DM (type 1, endocrinopathy, genetic syndromes 
etc.). 
12. Patients with HIV. 
13. Daily alcohol intake >20 g/day (2 units/day) for women and 
>30 g/day (3 units/day) for men. 
14. Treatment with anti-diabetic medications other than metformin 
and more than two of the following medications sulfonylurea, 
DPP-4 inhibitors, GLP-1 receptor agonists, TZDs. 
15. Metformin, fibrates, statins, not provided on a stable dose in 
the last 6 months. 
16. Patients who are treated with valproic acid, Tamoxifen, 
methotrexate, amiodarone. 
17. Chronic treatment with antibiotics (e.g. Rifaximin). 
18. Homeopathic and/or Alternative treatments. Any treatment 
must be stopped before the screening period.  
19. Uncontrolled hypothyroidism defined as Thyroid Stimulating 
Hormone >2X the upper limit of normal (ULN). Thyroid 
dysfunction controlled for at least 6 months prior to screening 
is permitted. 
20. Patients with renal dysfunction: eGFR< 40 ml/min. 
21. Unexplained serum creatinine phosphokinase (CPK) >3X the 
upper limit of normal (ULN). Patients with a reason for CPK 
elevation may have the measurement repeated prior to 
enrolment; a CPK retest > 3X ULN leads to exclusion. 
22. Subjects meeting criteria for contraindication for MRI – 
including the following: 
• History of severe claustrophobia impacting ability to 
perform MRI during the study, even despite mild 
sedation/treatment with as anxiolytic. 
• Subjects with metal implants, devices, paramagnetic 
objects contained within the body and excessive or metal 
containing tattoos. 
• Subjects unable to lie still within the environment of the 
MRI scanner or maintain a breath hold for the required 
period to acquire images, even despite mild 
sedation/treatment with an anxiolytic. 
23. Subject participated in a clinical research study involving a 
new chemical entity within 4 weeks of study entry.  
24. Known allergy to soy. 
Statistical 
Methods 
Descriptive statistics (mean, standard deviation, median, minimum, 
and maximum values) will be tabulated for the study population. 
Subject disposition, demographic and Baseline characteristics, extent 
of exposure and study termination/withdrawal information will be 
presented. Descriptive statistics will be presented for each of the 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 9 of 62  
CONFIDENTIAL 
evaluable safety and efficacy parameters for change from Baseline as 
well as value at each time point. Adverse event information will be 
summarized by age group and narratives were used in presentation of 
the data for safety monitoring. Serious adverse events (SAEs) will be 
summarized similarly and narratives presented. Clinical laboratory 
values will be summarized by time point, subject, and age group. 
Values and changes from baseline at each time point will be 
tabulated. 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 10 of 62  
CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice a day 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CAP-Fibroscan 
controlled attenuation parameter-Fibroscan 
CBC 
complete blood count 
CFR 
code of federal regulations 
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
diastolic blood pressure 
eCRF 
electronic case report form 
12-Lead ECG 
12- Lead Electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid 
EOS 
End-of-Study 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HbA1c 
hemoglobin A1c 
HOMA 
The Homeostasis Model Assessment 
IBD 
inflammatory bowel disease 
ICH 
International Conference on Harmonization 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
LFT 
Liver Function Test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI-PDFF 
MRI-Proton Density Fat Fraction 
NAFDL 
Nonalcoholic fatty liver disease 
NAFL 
Nonalcoholic fatty liver 
NASH 
Nonalcoholic Steatohepatitis 
PE 
physical exam 
PHI 
protected health information 
SAEs 
serious adverse events 
SBP 
systolic blood pressure 
SBTI 
soybean trypsin 
SOPs 
standard operating procedures 
SUSAR 
suspected adverse reaction 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
treatment-emergent adverse event 
TSH 
Thyroid Stimulating Hormone 


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 11 of 62  
CONFIDENTIAL 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 12 of 62  
CONFIDENTIAL 
TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE ..................................................2 
INVESTIGATOR SIGNATURE PAGE ...................................................................................3 
STATEMENT OF COMPLIANCE ...........................................................................................4 
SYNOPSIS .................................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................10 
TABLE OF CONTENTS .........................................................................................................12 
1 
INTRODUCTION ...........................................................................................................16 
2 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................20 
2.1 
Primary Objective ..................................................................................................20 
2.2 
Secondary Objective ..............................................................................................20 
2.3 
Primary Endpoint ...................................................................................................20 
2.4 
Secondary Endpoint ...............................................................................................20 
3 
INVESTIGATIONAL PLAN ..........................................................................................21 
3.1 
Overall Study Design and Plan ..............................................................................21 
3.2 
Screening/Visit 1 (up to Week -6, up to -42 Days) ................................................22 
3.2.1 
Screening/Visit 1 (up to Week -6, up to Days -42) ......................................22 
3.2.2 
Screen Failure ..............................................................................................23 
3.3 
Placebo Run-in Phase/Visit 2 (Week -2, Days -14) ...............................................23 
3.3.1 
Visit 2 (Week -2) .........................................................................................23 
3.4 
Treatment Phase (Week 0, Visit 3 – Week 12, Visit 8) .........................................24 
3.4.1 
Visit 3 (Week 0, Days 0±4) .........................................................................24 
3.4.2 
Visit 4 (Week 1, Days 7±4) .........................................................................25 
3.4.3 
Visit 5 (Week 2, Days 14±4) .......................................................................25 
3.4.4 
Visit 6 (Week 4, Days 28±4) .......................................................................26 
3.4.5 
Visit 7 (Week 8, Days 56±4) .......................................................................26 
3.4.6 
Visit 8 (Week 12, Days 84±4) .....................................................................27 
3.5 
End-of-Study (EOS) Phase (Visit 9, Week 16, Days 112±4)/Early Termination .28 
3.6 
Unscheduled Visit ..................................................................................................28 
3.7 
Self-Monitoring Fasting Blood Glucose and Patient Diaries ................................28 
3.8 
Schedule of Events .................................................................................................29 
4 
STUDY SUBJECT SELECTION ...................................................................................33 
4.1 
Inclusion Criteria ...................................................................................................33 
4.2 
Exclusion Criteria ..................................................................................................34 
4.3 
Subject and Trial Discontinuation .........................................................................35 
5 
STUDY TREATMENT (IMP) ........................................................................................37 
5.1 
Description of Investigational Drug.......................................................................37 


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
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CONFIDENTIAL 
5.1.1 
Packaging and Labeling ...............................................................................37 
5.1.2 
Storage and Handling ...................................................................................37 
5.2 
Randomization .......................................................................................................38 
5.3 
IMP Administration ...............................................................................................38 
5.3.1 
Week 0 to Week 12 (Visit 3 to Visit 8) .......................................................38 
5.4 
Dose Modifications ................................................................................................38 
5.5 
Measuring Subject Compliance .............................................................................38 
5.6 
Drug Accountability...............................................................................................39 
5.7 
Concomitant Medications and Supplements ..........................................................39 
5.8 
Behavioral Restrictions ..........................................................................................39 
6 
STUDY PROCEDURES AND ASSESSMENTS ...........................................................40 
6.1 
Informed Consent...................................................................................................40 
6.2 
Demographics, Medical History and Prior Medications ........................................40 
6.3 
Study Endpoints .....................................................................................................40 
6.4 
Efficacy Assessments.............................................................................................40 
6.5 
Safety Assessments ................................................................................................40 
6.5.1 
Weight and Height .......................................................................................40 
6.5.2 
Vital Signs ....................................................................................................40 
6.5.3 
Physical Examination...................................................................................41 
6.5.4 
12-Lead ECG ...............................................................................................41 
6.5.5 
Clinical Laboratory Tests .............................................................................41 
6.5.5.1 
Clinical Safety Laboratory Tests .......................................................41 
6.5.6 
Additional Bloodwork .................................................................................42 
6.5.7 
Fasting Blood Glucose and Insulin Monitoring ...........................................42 
6.5.8 
Pregnancy Test .............................................................................................42 
6.6 
Review and Documentation of Medications and Supplements .............................43 
7 
ADVERSE EVENTS AND SAFETY REPORTING......................................................44 
7.1 
Safety and Tolerability Assessments .....................................................................44 
7.2 
Definition of Adverse Event ..................................................................................44 
7.3 
Adverse Events of Special Interest ........................................................................44 
7.3.1 
Adverse Events of Hypoglycemia ...............................................................44 
7.4 
Definition of Serious Adverse Event .....................................................................44 
7.5 
Recording Adverse Events .....................................................................................45 
7.5.1 
Routine Reporting of Adverse Events .........................................................46 
7.5.2 
Reporting of Serious Adverse Events ..........................................................46 
7.5.2.1 
Pregnancy Reporting ..........................................................................47 
7.6 
Causality Assessment of Adverse Events ..............................................................47 
7.6.1 
Potential Adverse Events Associated with ORMD-0801 ............................48 


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
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7.7 
Adverse Event Severity Assessment ......................................................................48 
7.8 
Expectedness of Adverse Event .............................................................................48 
7.9 
Assessment of Adverse Event Outcome ................................................................49 
7.10 
Clinical Findings ....................................................................................................49 
8 
STATISTICAL METHODS ............................................................................................50 
8.1 
Sample Size ............................................................................................................50 
8.1.1 
Populations ...................................................................................................50 
8.2 
Safety Evaluation ...................................................................................................50 
8.2.1 
Adverse Events ............................................................................................50 
8.2.2 
Laboratory Evaluations ................................................................................51 
8.2.3 
Vital Signs ....................................................................................................51 
8.2.4 
12-lead ECG.................................................................................................51 
8.2.5 
Physical Examination...................................................................................51 
8.2.6 
Prior and Concomitant Medications and Supplements ................................51 
8.2.7 
Handling of Missing, Unused, or Spurious Data .........................................51 
8.3 
Efficacy Evaluation ................................................................................................52 
8.3.1 
Liver Fat Content .........................................................................................52 
8.3.2 
Handling of Missing or Spurious Data ........................................................52 
9 
DATA HANDLING AND RECORD KEEPING ...........................................................53 
9.1.1 
Electronic Data Capture ...............................................................................53 
9.2 
Quality Assurance and Database Lock ..................................................................53 
10 AMENDMENTS/MODIFICATIONS TO THE PROTOCOL .......................................53 
11 INVESTIGATOR OBLIGATIONS ................................................................................55 
11.1 
Regulatory Documentation ....................................................................................55 
11.2 
Protection of Human Subjects ...............................................................................55 
11.2.1 
Declaration of Helsinki ................................................................................55 
11.2.2 
Good Clinical Practice and Regulatory Compliance ...................................55 
11.2.3 
Institutional Review Board ..........................................................................55 
11.2.4 
Subject Informed Consent............................................................................56 
11.3 
Subject Confidentiality ..........................................................................................56 
11.4 
Case Report Forms .................................................................................................57 
11.5 
Source Documentation ...........................................................................................57 
11.6 
Retention of Records..............................................................................................57 
11.7 
Clinical Study Report .............................................................................................58 
12 STUDY ADMINISTRATION.........................................................................................58 
12.1 
Study Monitoring ...................................................................................................58 
12.2 
On-Site Audits .......................................................................................................59 
12.3 
Data Quality Assurance .........................................................................................59 


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
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CONFIDENTIAL 
12.4 
Publication Policy ..................................................................................................59 
12.5 
Insurance ................................................................................................................60 
12.6 
Disclosure and Confidentiality ..............................................................................60 
13 REFERENCES ................................................................................................................61 
 LIST OF IN-TEXT TABLES 
Table 1. Daily Schedule of Events from Screening Visit 1 through End-of-Study Visit 9 .....30


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 16 of 62  
CONFIDENTIAL 
1 INTRODUCTION 
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are global 
public health issues closely associated with the worldwide epidemics of diabetes and obesity.1-3 
NAFLD encompasses the spectrum of liver disease in patients with no significant alcohol 
consumption ranging from fatty liver to steatohepatitis and cirrhosis.1 Nonalcoholic fatty liver 
(NAFL) is characterized by the presence of liver infiltration of fat (hepatic steatosis) with no 
evidence of hepatocellular injury in the form of ballooning of hepatocytes or no evidence of 
cirrhosis.1 The risk for progression to cirrhosis and liver failure in these patients is minimal. 
NASH is defined by the presence of hepatic steatosis and inflammation with hepatocyte injury 
(ballooning) with or without cirrhosis.1 NASH can progress to cirrhosis, liver failure and 
occasionally liver cancer. 
NAFLD is now considered to be the commonest cause of chronic liver disease in developed 
countries with as high as 30% of the general population affected.2, 4 In newly identified cases of 
chronic liver disease in a US survey, 39% had NAFLD.2 A high prevalence of NASH among 
NAFLD cases has been reported2: up to 55% in patients with elevated aminotransferases5, 6, as 
high as 49% in morbidly obese patients7, 8, and 67% in a subset of patients with incident chronic 
liver disease.9  
Half a billion adults worldwide are estimated to be obese and 1.5 billion are overweight or 
obese.10, 11 Overall, about two-thirds of the population in the developed world have a BMI 
greater than 25 kg/m2.12 Primary NAFLD/NASH is associated with insulin resistance (IR) and its 
phenotypic manifestations. There are clear relationships between NAFLD and obesity13 and 
between NAFLD and diabetes independent of obesity.14 Systemic IR is considered to be the key 
risk factor for development of NAFLD.15  
The close relationship between NAFLD/NASH and type 2 diabetes mellitus (DM) leads to 
overlapping risk and complications and attendant economic burden for health care systems. 
Despite the high prevalence of NAFLD, no safe and effective treatment is currently available.16 
Management strategies for NAFLD/NASH rely primarily on non-pharmacologic measures. Since 
patients with NAFLD without steatohepatitis have excellent prognoses from a liver standpoint, 
treatments aimed at improving liver disease should be limited to those with NASH.1  
Life-style modifications are effective but adherence is difficult to maintain.17 Bariatric surgery 
can be performed in selective obese patients, but is too drastic to be the treatment of choice and 
thus it is not recommended for treating NASH.18 Vitamin E has been effective in treating 
nondiabetic NASH patients without cirrhosis.19 The long-term safety and efficacy of pioglitazone 
are not clear in NASH.20, 21 Metformin22, ursodeoxycholic acid, omega 3 fatty acids, and statins 
are not considered as therapy for NAFLD/NASH patients.1, 21 
 
TYPE 2 DIABETES and NAFLD/NASH 
Type 2 DM involves failure of the action and utilization of insulin within the body. Type 2 
sufferers have an endogenous resistance to insulin. The disease appears when they fail to 


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manufacture sufficient insulin levels to overcome this resistance. This relative lack of insulin 
eventually leads to chronic hyperglycemia. 
Traditionally, type 2 was known as “adult-onset diabetes” (with type 1 being referred to as 
“juvenile-onset” diabetes) as it generally struck adults, usually overweight, of age 45 and over. 
However, in recent years, the incidence of type 2 DM has skyrocketed—to the extent that it is 
now being termed a global “pandemic.” Type 2 DM is strongly correlated with obesity, and so 
this disproportionate increase is considered a reflection of the twin ills of modern life—
overeating/obesity and decreased physical activity. 
The 2014 CDC National Diabetes Statistics Report estimated that 29.1 million people or 9.3% of 
the US population have diabetes; 21 million diagnosed and 8.1 million undiagnosed.23 Another 
86 million (37% of US adults aged 20 years and older) people were estimated to suffer from pre-
diabetes, a condition that increases the risk of developing type 2 DM—the more common form 
of the disease—as well as heart disease and stroke. 
Comparable statistics may be found in both developed and developing countries around the 
world as the frequency of diabetes continues to rise. Global prevalence of diabetes is now 
estimated at more than 380 million, or about 8% of the worldwide adult population according to 
the International Diabetes Federation. Type 2 DM represents 85-95% of both present and future 
cases.24 
As noted above, the prevalence of NAFLD can be as high as 90–95% in obese individuals and up 
to 70% of patients with type 2 DM develop NAFLD.25 In addition, they share similarities in their 
risk factors, pathogenic mechanisms and complications. 
 
INSULIN TREATMENT  
There is no known cure for diabetes. Treatment of the disease requires constant care and 
monitoring, along with some form of insulin or drug therapy coupled with diet and exercise.  
Patients with type 2 DM have generally been prescribed a diet and exercise program as well as 
oral medication in order to control blood glucose levels. However, diet and oral hyperglycemic 
agents have failed to provide a satisfactory control of type 2 DM in a progressively larger 
proportion of these patients. Therefore, there is now an increasing trend to treat type 2 diabetic 
patients with insulin as well, in order to avoid the potential complications from hyperglycemia. 
 
New Approaches To Insulin Therapy 
In the past decade, several major studies (DCCT, UKPDS and others) have focused attention on 
the need for strict control of glycemia to prevent and/or reduce the risk of both the specific 
microvascular and the less specific macrovascular complications.26,27 The mounting numbers of 
type 2 sufferers worldwide, coupled with the growing tendency to treat this form of diabetes with 
insulin therapy, means that there are currently millions of individuals, adults as well as children, 
who must inject themselves several times each day throughout their entire lives. Injections are 
painful, inconvenient, and frightening for many patients. Over time reluctance to carry out 
injections increases, and many patients become non-adherent to therapy. 


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In addition, the subcutaneous administration of insulin does not provide, in most cases, the fine 
continuous metabolic regulation that occurs normally with insulin secreted from the pancreas 
directly into the liver via the portal vein. 
An ideal solution for treating these diabetics would be to transplant healthy insulin producing 
cells (pancreatic islets) into the patient. However, direct transplantation has not yet been 
practical. The immune system of the recipient recognizes the cells as foreign and rejects them. 
The side effects of drugs necessary to suppress the immune system are too severe to justify their 
use in otherwise healthy patients. 
Consequently, research is underway to develop a new and different approach that would both 
improve the administration of insulin and provide a way by which the hormone can reach the 
liver in a physiological manner, namely, oral administration of insulin. 
 
ORAL ADMINISTRATION OF INSULIN 
Insulin injections are, intrinsically unpleasant and patients may cease to perform them, leading to 
a multitude of possible complications. In addition, subcutaneous injection is not the most 
physiologically efficient mode of insulin transfer to the body. Hence, the search for an oral form 
of insulin has been underway since Banting and Best’s discovery of insulin in 1922. Oral insulin 
would free patients of the pain and inconvenience of injections while providing a more 
physiologically advantageous route of administration.  
Proposed Mechanism 
Any attempt to develop an oral insulin modality must take into account two major obstacles that 
result from insulin’s biochemical characteristics as a polypeptide: 1) Its direct transfer across the 
mucosal barrier is restricted; 2) it is subject to degradation by the proteolytic enzymes located in 
the stomach and intestinal lumen.  
To overcome these barriers, Oramed has proposed a mechanism to prevent the digestion of the 
introduced hormone in the gastrointestinal tract and to facilitate its physiological absorption. 
After performance of a range of studies for optimization of co-factors to prevent the digestion of 
insulin, Oramed has identified the most efficacious formulation of encapsulated oral insulin. The 
proposed composition contains: (1) crystalline insulin, (2) EDTA as enhancer, (3) soybean 
trypsin (SBTI), and (4) omega 3-rich fish oil, in a coated capsule. These components are 
expanded upon in greater detail below. Each has a target function, which promotes the goals of 
our treatment modality. The chelating agent EDTA functions as an effective enhancer of the 
mixture. The SBTI prevents enzymatic degradation of the insulin by mucosal enzymes. 
Modality Components 
Insulin: 
Structure: 
Insulin is a polypeptide hormone produced by cells in the islets of Langerhans in the 
pancreas. Human insulin consists of two different peptide chains, the A (acidic) chain of 
21 amino acids and the B (basic) chain of 30 amino acids, connected by two disulfide 
bridges. The A chain contains a third disulfide bond.  


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Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
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The structure of insulin: The left-hand side of the panel is a space-filling model of the insulin monomer, 
believed to be biologically active. Carbon is green, hydrogen white, oxygen red, and nitrogen blue. On the 
right-hand side is a cartoon of the hexamer, believed to be the stored form. A monomer unit is highlighted 
with the A chain blue and the B chain cyan. Yellows denote disulfide bonds, and magenta spheres are 
zinc ions. 
Source: Created by Isaac Yonemoto.  Created with Pymol, Inkscape, and Gimp from NMR structure 1ai0 in the pdb. Ref: Chang, X., Jorgensen, 
A.M., Bardrum, P., Led, J.J. 
 
ORAL INSULIN FOR NAFLD/NASH 
The similarities between type 2 DM and NAFLD/NASH in risk factors, pathogenic mechanisms 
and complications suggest common approaches to therapeutic intervention. Recall that 70% of 
type 2 DM patients will develop NAFLD/NASH and that 85% of new cases of diabetes will be 
type 2 patients. The key component of insulin resistance shared by diabetes and NAFLD/NASH 
makes direct insulin intervention an attractive option. The oral insulin formulation has the 
potential advantage of first pass metabolism in the liver allowing local availability and 
concentration of insulin at the affected liver fat cells. 
 
ORAL INSULIN DEMONSTRATIONS OF EFFICACY IN TYPE 2 DIABETES 
Oramed’s research and development team has performed multiple studies on pigs and canines 
over the last decade. The studies were designed to optimize the composition and functionality of 
our oral insulin modality and to demonstrate its safety and efficacy for use in animals and 
humans.  
 
 
 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Primary Objective 
• To evaluate the safety of oral insulin in patients with nonalcoholic steatohepatitis 
(NASH) and type 2 DM. 
2.2 Secondary Objective 
• To assess whether oral insulin may be effective in reducing liver fat content and 
inflammation in patients with NASH and type 2 DM. 
2.3 Primary Endpoint 
• To evaluate safety of ORMD-0801 in patients with nonalcoholic steatohepatitis (NASH) 
and type 2 DM.  
2.4 Secondary Endpoint 
• To evaluate the effectiveness of ORMD-0801 in reducing liver fat content in patients 
with NASH and type 2 DM by measuring the final and baseline differences in the MRI-
PDFF. 
  
 
 


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Phase 2 Clinical Study 
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3 INVESTIGATIONAL PLAN  
3.1 Overall Study Design and Plan 
This is a double-blind, randomized, placebo-controlled, multi-center study using the oral 
ORMD-0801 insulin formulation in patients with NASH and confirmed type 2 DM. This 
exploratory multi-center study will enroll patients with NASH and type 2 DM between the ages 
of 18 and 70. Subjects will undergo a Screening Phase up to 42 days prior to the Treatment 
Phase, a Placebo Run-in Phase for 2 weeks, a Treatment Phase for 12 weeks and an End-of-
Study Phase 4 weeks after completion of the Treatment Phase. Approximately 36 subjects will 
be randomized in a 2:1 ratio to receive either 8 mg ORMD-0801, 1 capsule twice a day (once in 
the morning approximately 30 to 45 minutes prior to breakfast and no later than 10 AM, and 
once at night between 8 PM to Midnight and no sooner than 1 hour after dinner) or matching 
placebo.   
At Screening (Visit 1, up to week -6), subjects will sign the ICF and inclusion and exclusion 
criteria will be reviewed. Medical history, demographics (sex, age, race and ethnicity), and prior 
and concomitant medications will be recorded. Height and weight will be measured, and BMI 
will be calculated. Vital signs (SBP/DBP, heart rate and oral temperature), complete physical 
examination, 12-Lead ECG, clinical laboratory evaluations, serum pregnancy test for females of 
childbearing potential, blood lipids test, HbA1c, viral serology, CAP-Fibroscan and MRI-PDFF 
will be performed. For females of non-childbearing potential, FSH levels will be tested if results 
are not available. Adverse events will be monitored and recorded.  
After Screening, each subject will undergo a Placebo Run-in Phase (Visit 2, to Week -2). 
Concomitant medications will be reviewed. All subjects will receive the morning treatment 
(Run-in Placebo) in clinic, 1 bottle of placebo medication and subject diaries will be dispensed. 
Vital signs (SBP/DBP, heart rate and oral temperature) and weight will be collected. Fasting 
blood glucose and fasting insulin will be measured, urine pregnancy test will be performed for 
females of childbearing potential. Self-monitored fasting morning blood glucose (finger-stick) 
will be recorded in the patient diaries 3 days weekly in the morning. Adverse events will be 
monitored and recorded.  
Subjects will then undergo a Treatment Phase consisting of a treatment period of 12 weeks that 
will start at Visit 3 (Week 0) and outpatient visits at Weeks 1, 2, 4, 8, and 12 (final visit). At each 
visit, concomitant medication will be reviewed, weight will be measured, and sufficient quantity 
of medication will be dispensed to last until the next nominal clinic visit. Medication compliance 
check will be performed, self-monitored fasting morning blood glucose (finger-stick) will be 
recorded 3 days weekly in the morning and subjects’ diaries will be reviewed. Vital signs 
(SBP/DBP, heart rate and oral temperature) will be recorded. Adverse events will be monitored 
and recorded. ORMD-0801 morning treatment will be administered in clinic during Visits 3, 6 
and 7.  
At Visit 3, urine pregnancy test will be performed for females of childbearing potential. At Visit 
8, subjects will have HbA1c evaluations and MRI-PDFF performed. At Visits 3 and 8, a 
complete physical exam and CAP-Fibroscan will be performed. 


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At Visits 3 (baseline), 6, 7, and 8, patients will have clinical laboratory evaluations (serum 
chemistry, hematology) and blood lipids performed. Fasting blood glucose, insulin (also used for 
HOMA estimates) and adiponectin levels will be measured.  
The End-of-Study (EOS) Visit (Visit 9) will be conducted 4 weeks following the last scheduled 
treatment visit. Subjects concomitant medications will be reviewed, and weight will be 
measured. A complete physical exam and ECG will be performed and vital signs (SBP/DBP, 
heart rate and oral temperature) will be measured if deemed necessary by the investigator. 
Clinical laboratory evaluations [serum chemistry (including liver function tests (LFTs) and blood 
lipids) and hematology] will be performed. Fasting blood glucose, fasting insulin, HbA1c and 
adiponectin levels will be measured. Subject diaries will be collected and reviewed for self-
monitored fasting morning blood glucose. Adverse events will be monitored and recorded. 
Subjects who are discontinued early from the study will complete the EOS evaluations at the 
time of early discontinuation. 
3.2 Screening/Visit 1 (up to Week -6, up to -42 Days) 
At the Screening Visit, potential subjects will be given a detailed oral presentation describing the 
nature, purpose, risks, and requirements of the study and will receive detailed written 
information. Subjects will be given ample time to consider participation and ask questions which 
will be adequately addressed by site personnel. 
Once the subject is satisfied that he/she is willing to participate in the study, he/she will be asked 
to sign the study informed consent form (ICF) (refer to Section 11.1.4 for further detail regarding 
the ICF). The investigational site personnel obtaining written consent from the subject will also 
sign the form to confirm consent has been obtained.  
Once signed, the Investigator will retain the original ICF for the subject’s study records and 
provide the subject with a signed copy. The investigator will verify that informed consent has 
been obtained from each subject prior to enrollment into the study and prior to the subject 
undergoing any study-related procedures.  
Screening process will take place at Visit 1, up to 42 days prior to the treatment phase. Subjects 
will report to the clinic in the morning following a 10-hour fast. Screening activities after 
obtaining informed consent will be conducted and will consist of the following: 
3.2.1 Screening/Visit 1 (up to Week -6, up to Days -42) 
• Review inclusion and exclusion criteria; 
• Completion of medical and social history, including tobacco, alcohol, caffeine, and drug 
use; 
• Collection of demographic data (sex, age, race and ethnicity); 
• Review of prior and concomitant medication; 
• Complete physical examination (PE); 
• Height and weight will be measured, BMI will be calculated; 
• 12-lead electrocardiogram (ECG); 
• Measurement of vital signs (SBP/DBP, heart rate and oral temperature);  


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• Collection of fasted blood samples for clinical laboratory evaluations (see Section 6.5.5.1 
for a complete list of tests performed): 
o Serum Chemistry including liver function tests (LFTs), blood lipids, and Thyroid 
Stimulating Hormone (TSH); 
o Hematology;  
o HbA1c; 
o Viral serology (HCV-Ab, HBsAg, HBcore-total, HBs Ab, and anti-HIV Ab); 
o Serum pregnancy test (women of childbearing potential/WCBP only); 
• Serum FSH (to test for women in post menopause, if not available); 
• CAP - Fibroscan;  
• MRI-PDFF; 
• AE/SAE assessment. 
For subjects who meet eligibility criteria based on the Screening assessments, instruction will be 
provided on the following: 
• the use of adequate contraceptive methods (see Section 4.1) for the duration of the study 
(Screening through End-of-Study (Visit 9); 
• minimal use of concomitant medications during the study, if possible, and avoid 
prohibited medications as defined in Section 5.6; 
• maintenance of usual dietary habits and avoidance of drastic changes, such as a 
conversion to a vegetarian diet; 
• restraint from excessive alcohol use or binge drinking during the study, and restraint from 
drinking alcohol from 72 hours prior to all study visits; 
• restraint from excessive caffeine use (i.e., more than five cups of caffeinated beverages 
per day) during the study. 
3.2.2 Screen Failure 
A screen failure is defined as a subject who has signed the ICF, does not meet all the entry 
criteria outlined in Section 4 of this protocol. Note that this includes assessments through Visit 1 
(up to Days -42), prior to receiving IMP. 
The Investigator is responsible for keeping a record of all subjects screened for entry into the 
study and subsequently excluded. The reason(s) for exclusion will be recorded in the source 
documents and on the Screening log. 
3.3 Placebo Run-in Phase/Visit 2 (Week -2, Days -14)  
The Placebo Run-in Phase will consist of a 2-week period starting at Visit 2 (Week -2). Subjects 
will report to the clinic in the morning following a 10-hour fast prior to taking morning 
medication. The following procedures will be performed: 
3.3.1 Visit 2 (Week -2) 
• Review of concomitant medication; 
• Measurement of weight; 
• Urine pregnancy test (women of childbearing potential/WCBP only) prior to dosing; 


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• Dispense 1 bottle of placebo with instructions for administration. Subjects will receive 
placebo 8 mg (1 x 8 mg capsule) administered twice daily, once in the morning 
approximately 30 to 45 minutes prior to breakfast and no later than 10AM, and once at 
night between 8 PM to Midnight and no sooner than 1 hour after dinner; 
• Measurement of vital signs (SBP/DBP, heart rate and oral temperature); 
• Measurement of fasting blood glucose and fasting insulin for HOMA estimates; 
• Diaries will be dispensed for each week for subjects to self-monitor fasting morning 
blood glucose; 
• Self-monitored fasting morning blood glucose (finger-stick) recorded in the patient 
diaries 3 days weekly in the morning; 
• AEs/SAEs assessment; 
• Subjects will be administered morning placebo medication in clinic followed by a small 
snack after 30 to 45 minutes; 
• Remind subjects to arrive fasting for Visit 3 in 2 weeks. 
3.4 Treatment Phase (Week 0, Visit 3 – Week 12, Visit 8) 
The Treatment Phase will consist of a 12-week treatment period.  
3.4.1 Visit 3 (Week 0, Days 0±4) 
Subjects will report to the clinic in the morning following a 10-hour fast prior to taking morning 
medication. The following procedures will be performed: 
• Review of concomitant medication;  
• Complete physical examination;  
• Measurement of weight; 
• Collection of unused placebo medication;  
• Dispense 1 bottle of ORMD-0801 medication with instructions for administration. 
Subjects will receive either 8 mg ORMD-0801, 1 capsule twice a day (once in the 
morning approximately 30 to 45 minutes prior to breakfast and no later than 10 AM, and 
once at night between 8 PM to Midnight and no sooner than 1 hour after dinner) or 
matching placebo; 
• Perform medication compliance check; 
• Measurement of vital signs (SBP/DBP, heart rate and oral temperature) 
• Collection of fasted blood samples for clinical laboratory evaluations (see Section 6.5.5.1 
for a complete list of tests performed): 
o Serum Chemistry including liver function tests (LFTs) and blood lipids;  
o Hematology;  
• Urine pregnancy test (women of childbearing potential/WCBP only) prior to active 
dosing; 
• Measurement of fasting blood glucose and fasting insulin for HOMA estimates; 
• Review/Dispense diaries for each week for subjects to self-monitor fasting morning 
blood glucose; 
• Self-monitored fasting morning blood glucose (finger-stick) recorded in the patient 
diaries 3 days weekly in the morning; 
• Adiponectin test; 


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• CAP-Fibroscan; 
• AEs/SAEs assessment; 
• Subjects will be administered morning treatment dose in clinic followed by a small snack 
after 30 to 45 minutes; 
• Remind subjects to arrive for Visit 4 in 1 week. 
3.4.2 Visit 4 (Week 1, Days 7±4) 
Subjects will report to the clinic in the morning and the following procedures will be performed: 
• Review of concomitant medication;  
• Measurement of weight; 
• Collection of unused ORMD-0801 medication; 
• Dispense 1 bottle of ORMD-0801 medication with instructions for administration. 
Subjects will receive either 8 mg ORMD-0801, 1 capsule twice a day (once in the 
morning approximately 30 to 45 minutes prior to breakfast and no later than 10 AM, and 
once at night between 8 PM to Midnight and no sooner than 1 hour after dinner) or 
matching placebo;  
• Perform medication compliance check; 
• Measurement of vital signs (SBP/DBP, heart rate and oral temperature); 
• Review/Dispense diaries for each week for subjects to self-monitor fasting morning 
blood glucose; 
• Self-monitored fasting morning blood glucose (finger-stick) recorded in the patient 
diaries 3 days weekly in the morning; 
• AEs/SAEs assessment; 
• Remind subjects to arrive for Visit 5 in 1 week.  
3.4.3 Visit 5 (Week 2, Days 14±4) 
Subjects will report to the clinic in the morning following procedures will be performed: 
• Review of concomitant medication;  
• Measurement of weight; 
• Collection of unused ORMD-0801 medication; 
• Dispense 1 bottle of ORMD-0801 medication with instructions for administration. 
Subjects will receive either 8 mg ORMD-0801, 1 capsule twice a day (once in the 
morning approximately 30 to 45 minutes prior to breakfast and no later than 10 AM, and 
once at night between 8 PM to Midnight and no sooner than 1 hour after dinner) or 
matching placebo;  
• Perform medication compliance check; 
• Measurement of vital signs (SBP/DBP, heart rate and oral temperature); 
• Review/Dispense diaries for each week for subjects to self-monitor fasting morning 
blood glucose; 
• Self-monitored fasting morning blood glucose (finger-stick) recorded in the patient 
diaries 3 days weekly in the morning; 
• AEs/SAEs assessment; 


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• Remind subjects to arrive fasting for Visit 6 in 2 weeks. 
3.4.4 Visit 6 (Week 4, Days 28±4) 
Subjects will report to the clinic in the morning following a 10-hour fast prior to taking morning 
medication. The following procedures will be performed: 
• Review of concomitant medication;  
• Measurement of weight; 
• Collection of unused ORMD-0801 medication; 
• Dispense 2 bottles of ORMD-0801 medication with instructions for administration. 
Subjects will receive either 8 mg ORMD-0801, 1 capsule twice a day (once in the 
morning approximately 30 to 45 minutes prior to breakfast and no later than 10 AM, and 
once at night between 8 PM to Midnight and no sooner than 1 hour after dinner) or 
matching placebo;  
• Perform medication compliance check; 
• Measurement of vital signs (SBP/DBP, heart rate and oral temperature); 
• Collection of fasted blood samples for clinical laboratory evaluations (see Section 6.5.5.1 
for a complete list of tests performed): 
o Serum Chemistry including liver function tests (LFTs) and blood lipids;  
o Hematology;  
• Measurement of fasting blood glucose and fasting insulin for HOMA estimates; 
• Review/Dispense diaries for each week for subjects to self-monitor fasting morning 
blood glucose; 
• Self-monitored fasting morning blood glucose (finger-stick) recorded in the patient 
diaries 3 days weekly in the morning; 
• Adiponectin test; 
• AEs/SAEs assessment; 
• Subjects will be administered morning treatment dose in clinic followed by a small snack 
after 30 to 45 minutes; 
• Remind subjects to arrive fasting for Visit 7 in 4 weeks. 
3.4.5 Visit 7 (Week 8, Days 56±4) 
Subjects will report to the clinic in the morning following a 10-hour fast prior to taking morning 
medication. The following procedures will be performed: 
• Review of concomitant medication;  
• Measurement of weight; 
• Collection of unused ORMD-0801 medication; 
• Dispense 2 bottles of ORMD-0801 medication with instructions for administration. 
Subjects will receive either 8 mg ORMD-0801, 1 capsule twice a day (once in the 
morning approximately 30 to 45 minutes prior to breakfast and no later than 10 AM, and 
once at night between 8 PM to Midnight and no sooner than 1 hour after dinner) or 
matching placebo;  
• Perform medication compliance check; 


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• Measurement of vital signs (SBP/DBP, heart rate and oral temperature); 
• Collection of fasted blood samples for clinical laboratory evaluations (see Section 6.5.5.1 
for a complete list of tests performed): 
o Serum Chemistry including liver function tests (LFTs) and blood lipids; 
o Hematology;  
• Measurement of fasting blood glucose and fasting insulin for HOMA estimates; 
• Review/Dispense diaries for each week for subjects to self-monitor fasting morning 
blood glucose; 
• Self-monitored fasting morning blood glucose (finger-stick) recorded in the patient 
diaries 3 days weekly in the morning; 
• Adiponectin test; 
• AEs/SAEs assessment; 
• Subjects will be administered morning treatment dose in clinic followed by a small snack 
after 30 to 45 minutes; 
• Remind subjects to arrive fasting for Visit 8 in 4 weeks.  
3.4.6 Visit 8 (Week 12, Days 84±4) 
Subjects will report to the clinic in the morning following a 10-hour fast. The following 
procedures will be performed: 
• Review of concomitant medication;  
• Complete physical exam; 
• Measurement of weight; 
• Collection of unused ORMD-0801 medication; 
• Perform medication compliance check; 
• Measurement of vital signs (SBP/DBP, heart rate and oral temperature); 
• Collection of fasted blood samples for clinical laboratory evaluations (see Section 6.5.5.1 
for a complete list of tests performed): 
o Serum Chemistry including liver function tests (LFTs) and blood lipids;  
o Hematology;  
• Measurement of fasting blood glucose and fasting insulin for HOMA estimates; 
• Review/Dispense diaries for each week for subjects to self-monitor fasting morning 
blood glucose; 
• Self-monitored fasting morning blood glucose (finger-stick) recorded in the patient 
diaries 3 days weekly in the morning; 
• Adiponectin test; 
• HbA1c; 
• CAP-Fibroscan;  
• MRI-PDFF; 
• AEs/SAEs assessment; 
• Remind subjects to arrive fasting for Visit 9 in 4 weeks.  


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3.5 End-of-Study (EOS) Phase (Visit 9, Week 16, Days 112±4)/Early 
Termination  
The EOS Visit (Visit 9) will be conducted 4 weeks following the last scheduled treatment Visit. 
Subjects will report to the clinic in the morning following a 10-hour fast. The following procedures 
will be performed: 
• Review of concomitant medication; 
• Complete PE, only if the investigator deems it necessary; 
• Measurement of weight;  
• Collection of unused ORMD-0801 medication; 
• 12-Lead ECG, only if the investigator deems it necessary; 
• Measurement of vital signs (SBP/DBP, heart rate and oral temperature), only if the 
investigator deems it necessary;   
• Fasted blood samples will be collected for clinical laboratory evaluations (see 
Section 6.5.5.1 for a complete list of tests performed): 
o Serum Chemistry including liver function tests (LFTs) and blood lipids;  
o Hematology;  
• Measurement of fasting blood glucose and fasting insulin for HOMA estimates; 
• Review/Collect subject diaries for self-monitored fasting morning blood glucose; 
• HbA1c; 
• Adiponectin test; 
• AEs/SAEs assessment. 
Patients who are discontinued early from the study will complete the EOS evaluations at the time 
of early discontinuation. 
3.6 Unscheduled Visit  
A subject may be required to return to the clinic in the morning following a 10-hour fast for an 
Unscheduled Visit for a repeat measurement of fasting blood glucose and any necessary clinical 
safety laboratory assessments, if the investigator deems it necessary. AEs/SAEs assessment will 
also be performed.  
3.7 Self-Monitoring Fasting Blood Glucose and Patient Diaries 
All patients will self-monitor fasting morning blood glucose levels three (3) times weekly during 
the run-in and treatment period. Monitoring must be performed at the same time each designated 
day (± 10 minutes) prior any caloric intake. Patients will be required to record the values in a 
patient diary and bring the diary to each clinic visit. Information recorded for the fasting blood 
glucose will be reviewed by the clinical research coordinator for completeness and transcribed 
onto electronic case report form (eCRF). During the study, both fasting finger stick glucose and 
laboratory fasting plasma glucose will be obtained. 
If a fasting blood glucose measures greater than or equal to 270 mg/dL (15 mmol/L) during daily 
self-monitoring or during any in-clinic visit, the patient will be required to contact the clinic to 
report the value. The patient may be required to return for an unscheduled visit to the clinic for a 
repeat measurement of fasting blood glucose within one week after the original measurement. If 


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the patient is invited for an unscheduled visit, blood will be drawn and sent to lab for plasma 
glucose determination. If the repeat measurement is also greater than or equal to 270 mg/dL, the 
patient will be discontinued from treatment with study drug and offered rescue medication. The 
patient will continue to be seen for all remaining study visits, if possible. 
If a fasting blood glucose value is <70 mg/dL, the patient should drink 1 cup of orange juice or 
swallow 3-4 glucose tablets. The patient must check his blood sugar after 10 min and if the blood 
glucose level does not raise, the patient needs to drink another cup of orange juice or swallow 3-
4 glucose tablets. Blood sugar must be checked again after 10 minutes. The patient must call to 
report this event to the study site and record all blood glucose levels in the diary.  
If three or more fingerstick glucose values of <50 mg/dL (2.78 mmol/L) are observed within 12 
hours subsequent to administration of study drug without a reasonable explanation (such as 
increased physical activity and/or skipped meal), the patient will be discontinued from treatment 
with study drug and rescued with glucose administration (20g of glucose tablets) which will be 
available at all times at the study site. This information will be recorded in the patient’s diary and 
the patient will be instructed to contact the study site if this occurs. The patient will continue to 
be seen for all remaining study visits. 
Sites will instruct patients to immediately perform a finger stick glucose measurement if any 
symptoms occur that may be related to hypoglycemia (e.g., weakness, dizziness, shakiness, 
increased sweating, palpitations, or confusion), and to avoid delay in treating these symptoms.  
The measurements will be recorded in the patient diary. Patients will always carry glucose 
tablets with them and ingests 3-4 tablets if hypoglycemia occurs. 
Hypoglycemia and associated symptoms (e.g., weakness, dizziness, shakiness, increased 
sweating, palpitations, or confusion), have been associated with insulin administration, including 
ORMD-0801. 
3.8 Schedule of Events 
Table 1 below describes the daily schedule of events from Screening Visit 1 through End-of-
Study Visit 9.  
 


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 30 of 62  
CONFIDENTIAL 
Table 1: Daily Schedule of Events from Screening Visit 1 through End-of-Study Visit 9 
Assessments 
Screening 
Placebo 
Treatment 
Unscheduled Visit 
End-of-Study/ 
Early Termination 
Week 
up to -6 
-2 
0 
1 
2 
4 
8 
12 
Not Defined 
16 
Days 
Up to -42 
-14 
0±4 
7±4 
14±4 
28±4 
56±4 
84±4 
 
112±4 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Unscheduled 
9 
Written informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
Medical and social history 
(including tobacco, 
alcohol, caffeine, and 
drug use) 
X 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication1  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Demographics (sex, age, 
race and ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Complete physical 
examination 
X 
 
X 
 
 
 
 
X 
 
(X2) 
Height, Weight and BMI3 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy Test4 
X 
X 
X 
 
 
 
 
 
 
 
Treatment 
Administration5 
 
X5 
X5 
X 
X 
X5 
X5 
 
 
 
Dispense/Collect 
Medication6 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Medication compliance 
check 
 
 
X 
X 
X 
X 
X 
X 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
(X2) 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 31 of 62  
CONFIDENTIAL 
Assessments 
Screening 
Placebo 
Treatment 
Unscheduled Visit 
End-of-Study/ 
Early Termination 
Week 
up to -6 
-2 
0 
1 
2 
4 
8 
12 
Not Defined 
16 
Days 
Up to -42 
-14 
0±4 
7±4 
14±4 
28±4 
56±4 
84±4 
 
112±4 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Unscheduled 
9 
Vital signs7 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X2) 
Clinical laboratory 
evaluations8 
X 
 
X 
 
 
X 
X 
X 
(X2) 
X 
Fasting blood glucose and 
fasting Insulin9 
 
X 
X 
 
 
X 
X 
X 
(X2) 
X 
Self-monitored fasting 
morning blood glucose10 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense Diary/ Review 
Diary Data 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Adiponectin Test 
 
 
X 
 
 
X 
X 
X 
 
X 
HbA1c 
X 
 
 
 
 
 
 
X 
 
X 
Blood lipids: Total 
cholesterol, LDL, HDL, 
Triglycerides 
X 
 
X 
 
 
X 
X 
X 
 
X 
CAP-Fibroscan  
X 
 
X 
 
 
 
 
X 
 
 
MRI-PDFF 
X 
 
 
 
 
 
 
X 
 
 
Viral serology11   
X 
 
 
 
 
 
 
 
 
 
TSH and FSH12 
X 
 
 
 
 
 
 
 
 
 
AE/SAE assessment13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 32 of 62  
CONFIDENTIAL 
Table 1 Footnotes 
1 Prior and concomitant medications will be reviewed at Screening. Concomitant medications will be reviewed through Visits 2-9. 
2 Only if investigator deems necessary. 
3 Height measurement and BMI calculation will be performed at Screening only. Weight will be measured as indicated. 
4 Serum pregnancy test will be performed at Screening (Visit 1). Urine pregnancy test will be performed at Visit 2 and Visit 3. 
5 Blood samples taken prior to dosing in clinic and snack provided after 30-45 minutes at Visit 2, 3, 6, and 7. 
6 Study medication will be dispensed and collected at Visits 2-8 and collected at End-of-Study/Early Termination Visit.  
7 Vital signs (blood pressure, heart rate, oral temperature). Vital signs will be measured in the sitting position after at least 5 minutes of rest. 
8 Serum Chemistry: Sodium, Potassium, Glucose, BUN, Creatinine, BUN/Creatinine, Chloride, Calcium, Protein, Albumin, Globulin (total), A/G Ratio, SGOT 
(AST), SGPT (ALT), Bilirubin (total), Alkaline Phosphatase, CO2, Creatine Phosphokinase (CPK), Total cholesterol, LDL, HDL, Triglycerides, Thyroid 
Stimulating Hormone (TSH, screening only). Hematology: Hemoglobin, Hematocrit, RBC, WBC (total count and differential count), Platelets Count, Mean 
Platelet Volume (MPV), MCV, MCH, MCHC, RDW, Neutrophils (absolute value and %), Bands (ABS CNT), Bands, Lymphocytes (absolute value and %), 
Monocytes (absolute value and %), Eosinophils (absolute value and %), Basophils (absolute value and %), RBC Morphology. Urinalysis is not performed in this 
study.  
9 Fasting blood glucose and insulin will be used to determine Homeostasis Model Assessment (HOMA) estimates. During an Unscheduled Visit only fasting blood 
glucose will be collected, if investigator deems necessary. 
10 Self-monitoring (finger-stick) of fasting blood glucose will be required 3 days weekly in the morning, before breakfast, and recorded in patient diaries. 
11 HCV-Ab (hepatitis C virus antibody), HBsAg (surface antigen of the hepatitis B virus), HBcore-total (total hepatitis B core antibody), HBs Ab (hepatitis B 
surface antibody), anti-HIV Ab (human immunodeficiency virus antibody). 
12 Screening labs will include standard hematology, fasting serum chemistry, plus TSH. FSH will also be performed for women who are post-menopausal, if 
results are not available.  
13 Adverse events will be collected throughout the study beginning from the time the patient signs the consent form until the EOS (Visit 9) evaluations.  
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 33 of 62  
CONFIDENTIAL 
4 STUDY SUBJECT SELECTION 
4.1 Inclusion Criteria 
Each subject must meet all of the following criteria to be eligible for the study: 
Inclusion Criteria 
1. Male or female aged 18-70 years. 
2. BMI ≥25.  
3. Known type 2 DM according to American Diabetic Association (one of the three 
needed): Fasting Plasma Glucose ≥126 mg/dl or 2h postprandial (PG) following 75g 
OGTT ≥200 mg/dl or HbA1c > 6.5%28 or on treatment with metformin only or 
metformin in addition to no more than two of the following medications sulfonylurea, 
DPP-4 inhibitors, GLP-1 receptor agonists, Thiazolidinediones (TZDs). 
4. Diagnosis of NAFLD by non-invasive determination of hepatic steatosis grade S1, 
defined as hepatic steatosis>8%. by MRI- PDFF and CAP FibroScan ≥ 238 dB/m. 
5. Liver enzyme abnormalities: ULN≤5 times.  
6. Fibrosis score 1≤F≤3 as defined by FibroScan measurement (Liver stiffness 
measurement, LSM) of 6 ≤ LSM ≤ 12 kPa. 
7. Signature of the written informed consent. 
8. Negative serum pregnancy test at study entry for females of childbearing potential. 
9. Women of childbearing potential must have a negative urine pregnancy test result prior 
to the start of the run-in period and initiation if active dosing. Males and females of 
childbearing potential must use two methods of contraception (double barrier method), 
one of which must be an acceptable barrier method from the time of screening to the last 
study visit (22 weeks). Barrier methods of contraception include male condoms plus 
spermicide, diaphragm with spermicide plus male condom, and cervical cap with 
spermicide plus male condom. Acceptable methods of birth control include abstinence, 
oral contraceptives, surgical sterilization, vasectomy, the contraceptive patch, and the 
contraceptive ring. If a subject is not usually sexually active but becomes active, he or 
his partner should use medically accepted forms of contraception. Sperm donations will 
not be allowed for the duration of the study and for 90 days after the last dose of study 
drug. 
Females of non-childbearing potential are defined as postmenopausal who a) had more 
than 24 months since last menstrual cycle with menopausal levels of FSH (FSH Level > 
40), b) who are surgically menopausal (surgical sterility defined by tubal occlusion, 
bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
10. For hypertensive patients, hypertension must be controlled by stable dose of anti-
hypertensive medication for at least 2 months prior to screening (and the stable dose can 
be maintained throughout the study) with BP < 150/<95 mmHg. 
11. Patients previously treated with vitamin E (>400IU/day), Polyunsaturated fatty acid 
(>2g/day) or Ursodeoxycholic acid fish oil can be included if drugs are stopped at least 3 
months prior to enrolment and up to the end of the study. 
12. Glycaemia must be controlled (Glycosylated Hemoglobin A1C ≤8.5%) while any HbA1C 
increment should not exceed 1% during 6 months prior to enrolment). 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 34 of 62  
CONFIDENTIAL 
4.2 Exclusion Criteria 
Subjects who meet any of the following criteria must be excluded from the study: 
1. Patients with active (acute or chronic) liver disease other than NASH (e.g. viral hepatitis, 
genetic hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, alcohol liver 
disease, drug induced liver disease) at the time of enrolment. 
2. ALT or AST > 5 times ULN. 
3. Abnormal synthetic liver function (serum albumin ≤3.5gm%, INR >1.3). 
4. Known alcohol and/or any other drug abuse or dependence in the last five years. 
5. Weight >120 Kg (264.6 lbs.). 
6. Known history or presence of clinically significant, cardiovascular, gastrointestinal, 
metabolic (other than diabetes mellitus), neurologic, pulmonary, endocrine, psychiatric, 
neoplastic disorder or nephrotic syndrome. 
7. History or presence of any disease or condition known to interfere with the absorption, 
distribution, metabolism or excretion of drugs including bile salt metabolites (e.g. 
inflammatory bowel disease (IBD), previous intestinal (ileal or colonic) operation, 
chronic pancreatitis, celiac disease or previous vagotomy. 
8. Weight loss of more than 5% within 6 months prior to enrolment. 
9. History of bariatric surgery. 
10. Uncontrolled blood pressure BP ≥150/≥95. 
11. Non type 2 DM (type 1, endocrinopathy, genetic syndromes etc.). 
12. Patients with HIV. 
13. Daily alcohol intake >20 g/day (2 units/day) for women and >30 g/day (3 units/day) for 
men. 
14. Treatment with anti-diabetic medications other than metformin and more than two of the 
following medications sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, TZDs 
15. Metformin, fibrates, statins, not provided on a stable dose in the last 6 months. 
16. Patients who are treated with valproic acid, Tamoxifen, methotrexate, amiodarone. 
17. Chronic treatment with antibiotics (e.g. Rifaximin). 
18. Homeopathic and/or Alternative treatments. Any treatment must be stopped before the 
screening period.  
19. Uncontrolled hypothyroidism defined as Thyroid Stimulating Hormone >2X the upper 
limit of normal (ULN). Thyroid dysfunction controlled for at least 6 months prior to 
screening is permitted. 
20. Patients with renal dysfunction: eGFR< 40 ml/min. 
21. Unexplained serum creatinine phosphokinase (CPK) >3X the upper limit of normal 
(ULN). Patients with a reason for CPK elevation may have the measurement repeated 
prior to enrolment; a CPK retest > 3X ULN leads to exclusion. 
22. Subjects meeting criteria for contraindication for MRI – including the following: 
• History of severe claustrophobia impacting ability to perform MRI during the 
study, even despite mild sedation/treatment with as anxiolytic. 
• Subjects with metal implants, devices, paramagnetic objects contained within the 
body and excessive or metal containing tattoos. 
• Subjects unable to lie still within the environment of the MRI scanner or maintain 
a breath hold for the required period to acquire images, even despite mild 
sedation/treatment with an anxiolytic.  


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Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 35 of 62  
CONFIDENTIAL 
23. Subject participated in a clinical research study involving a new chemical entity within 4 
weeks of study entry. 
24. Known allergy to soy. 
4.3 Subject and Trial Discontinuation 
Subjects may choose to withdraw from this study at any time for any reason without penalty of 
jeopardizing their health care or loss of benefits to which the subject is otherwise entitled.   
Within the provisions of informed consent and good clinical judgment with respect to safety, 
every attempt will be made to have subjects complete the study. The following are reasons to 
terminate a subject’s participation in the study:  
1. Subject experiences an AE that in the judgement of the Investigator poses a significant 
risk to the subject for continued participation in the study. 
2. Subject uses any medication that in the judgment of the Investigator poses a significant 
risk to the subject for continued participation in the study or that will interfere with the 
interpretation of the results of the study. 
3. Subject becomes pregnant. 
4. Significant protocol violation or noncompliance on the part of the subject or the 
Investigator.  
5. Intercurrent illness that requires treatment that is not consistent with the protocol 
requirements, or intercurrent illness or the associated treatment that in the judgment of 
the Investigator poses a significant risk to the subject for continued participation in the 
study.  
6. Subject wishes to withdraw for any reason.  
7. Sponsor elects to end the study, or the Investigational Site elects to end the study at their 
site.  
8. Any other reason that in the judgment of the Investigator poses unacceptable risk to the 
subject. 
Subjects who withdraw from the study prior to treatment may be replaced. Subjects who are 
withdrawn and have received at least one treatment will not be replaced. Subjects who 
discontinue study drug treatment will not be replaced. 
Except in cases of emergency, the Investigator should consult with the Sponsor and the Medical 
Monitor before removing the subject from the study. In some circumstances it may be necessary 
to temporarily interrupt treatment as a result of AEs that may have an unclear relationship to the 
IMP. The Investigator should obtain approval from the Sponsor and Medical Monitor before 
restarting IMPs that were temporarily discontinued for an AE. 
In the event that a subject discontinues the study prior to completion, the date the subject is 
withdrawn and the reason for discontinuation will be recorded in the source documents and 
eCRF. Although a subject will not be obliged to give his/her reason for withdrawing 
prematurely, the Investigator will make a reasonable effort to obtain the reason while fully 
respecting the subject’s rights.   
All subjects who are randomized and treated (i.e., received any amount of IMP) will be included 
in the safety analyses. Thus, every effort will be made to contact any subject who fails to attend 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 36 of 62  
CONFIDENTIAL 
any follow-up appointments/contacts, in order to ensure that he/she is in satisfactory health. If a 
subject withdraws from the study as a result of meeting discontinuation criteria after the start of 
IMP administration, reasonable efforts should be made to have the subject return for the early 
withdrawal evaluations (Section 3.5). Any subject withdrawn due to a suspected IMP related AE 
should be followed until resolution or stabilization of the event. 
If a subject becomes pregnant, IMP will be discontinued immediately, and the subject will be 
referred to an obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling. The subject will be followed until delivery or other termination of 
pregnancy for outcome. 
Subjects may choose to withdraw authorization to use and disclose their PHI as defined by the 
HIPAA. Such withdrawal of authorization must be made to the Investigator in writing. Any PHI 
collected by the Investigator prior to the date of such withdrawal will continue to be used and 
disclosed. 
The Sponsor has the right to terminate this study, and the Investigator/Investigational Site has the 
right to close the site, at any time, although this should occur only after consultation between 
involved parties. The Investigator or representative will notify the IRB in writing of a premature 
termination of a study or closure of Investigational Site or of a temporary halt of the study, 
including the reason of such an action and will send a copy of the notification to the Sponsor.   
Events that may trigger premature termination of a study or closure of an Investigational Site 
include, but are not limited to, a new toxicity finding, a request to discontinue the trial from a 
regulatory authority, non-compliance with the protocol, GCP violations, slow recruitment/low 
enrollment, or change in development plans for the IMP. 
If either of the criteria listed below is met, enrollment of new subjects and dosing of ongoing 
subjects will be temporarily stopped. The Investigator, Sponsor, and the Medical Monitor will 
discuss whether a lower dose or any additional treatment guidelines should be implemented, or if 
the trial should be permanently stopped. Any proposed changes to the protocol to address such 
findings will be submitted for review and approval by the IRB and U.S. Food and Drug 
Administration (FDA) prior to re-starting the trial. 
1. A death within 30 days after IMP administration where there is a reasonable possibility 
that the drug caused the event; 
2. Two Grade 4 AEs where there is a reasonable possibility that the IMP caused the events. 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 37 of 62  
CONFIDENTIAL 
5 STUDY TREATMENT (IMP) 
5.1 Description of Investigational Drug 
Active: 
Code name: ORMD-0801 
Dosage form: 1 soft gelatin capsule administered BID (1 capsule in the morning and 1 capsule at 
night)  
Strength: 8 mg insulin per capsule  
Description: API (recombinant human insulin USP), in Oramed’s proprietary formulation [SBTI, 
disodium EDTA, fish oil, aerosil, and TWEEN 80] in capsules. 
 
Placebo control: 
Fish oil in capsules, identical in appearance to ORMD-0801, administered BID (one capsule in 
the morning, prior to breakfast and one capsule at night), daily. 
  
5.1.1 Packaging and Labeling 
All study medication will be shipped in bulk. Sufficient study medication will be distributed to 
cover the time between visits. The Investigational Site pharmacist will be responsible for 
dispensing the appropriate treatment period study treatment based on the randomization 
schedule.   
Study medication will be dispensed to the site with instructions for when treatment can be 
administered.  
The treatment packages will be labeled with the following information: 
 Study number 
 Patient ID 
 Bottle ID 
 Dosage Form/Content 
 Directions for use, including route of administration 
 Number of capsules in package 
 Storage conditions 
 Instructions to “keep out of reach of children” 
 Caution: New Drug – Limited by Federal (or United States) law to investigational use.  
 Name of Sponsor  
A label with the identical information will be made available for drug accountability purposes. 
5.1.2 Storage and Handling 
All IMP must be kept in an appropriate, secure area to prevent unauthorized access. All IMP is to 
be shipped under refrigerated conditions and stored at controlled temperature (36 to 46°F; 2 to 
8°C). Excessive humidity should be avoided. Storage conditions will be monitored, and 
appropriate monitoring logs maintained as source data. Deviations from the established 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 38 of 62  
CONFIDENTIAL 
temperature, as well as the occurrence of excessive humidity, should be documented, and the 
Sponsor should be notified.  
IMP should be handled, using proper procedures as defined by Investigational Site standard 
operating procedures (SOPs) for Investigational Drugs. IMP will be returned or destroyed 
according to instructions provided by Oramed Ltd. Drug destruction procedures and 
documentation must be retained at the site. 
Investigator will be supplied with a sufficient amount of study medication in order to provide 
each subject with sufficient treatment. Site will document their inspection of shipments of study 
medication and notify the Sponsor of any breakage, shortage, or other adverse shipment events.  
5.2 Randomization 
This is a double-blind, randomized, placebo-controlled study. Adult male and female subjects 
with NASH and type 2 DM will be competitively enrolled at all study sites. Approximately 36 
subjects will be randomized in a 2:1 ratio to either ORMD-0801 8 mg BID or to matching 
placebo.  
Integrium, LLC will generate and implement the randomization procedures for this trial. A 
computer-generated randomization schedule will be used for assigning the treatment groups. The 
Investigational Site pharmacist will follow this randomization schedule to dispense the 
appropriate study treatment. 
5.3 IMP Administration 
5.3.1 Week 0 to Week 12 (Visit 3 to Visit 8) 
The treatment regimen will consist of a soft gelatin capsule containing 8 mg insulin, and 75 mg 
SBTI. Sufficient quantity of medication will be dispensed to last until the next nominal clinic 
visit. ORMD-0801 morning treatment will be administered in clinic during Visits 3, 6 and 7. 
Subjects will receive either 8 mg ORMD-0801, 1 capsule twice a day (once in the morning 
approximately 30 to 45 minutes prior to breakfast and no later than 10 AM, and once at night 
between 8 PM to Midnight and no sooner than 1 hour after dinner) or matching placebo. 
At Visits 2 (Placebo Run-in), 3, 6, and 7 blood samples and weights will be taken prior to 
morning dosing in clinic, followed by a small snack after 30 to 45 minutes. 
5.4 Dose Modifications 
This study does not include any planned dose modifications. Subjects will be administered IMP 
orally at the assigned dose level unless discontinuation criteria as defined in Section 4.3 are met. 
5.5 Measuring Subject Compliance 
Dosing compliance will be assessed through a count of unused study medication during clinic 
Visit 3 to Visit 8.   


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 39 of 62  
CONFIDENTIAL 
5.6 Drug Accountability 
In accordance with current GCP, the Investigational Site will account for all IMP supplies.  
Details of receipt, storage, administration, and return or destruction will be recorded in the 
Investigational Drug accountability record according to the SOP of the Investigational Site.  
Copies of the Investigational Drug accountability record will be provided to the Sponsor. 
IMP will only be dispensed to subjects enrolled in this protocol, and only as directed by this 
protocol. Administration of IMP will be accurately recorded in each subject’s source documents 
and eCRF. Study participants will be dispensed sufficient quantities of study treatment to last 
until the next nominal clinic visit. Study participants will be asked to return all unused study 
medication for accountability at each clinic visit. Compliance with study medication is 
monitored and recorded by site personnel by counting the remaining study medication. 
At the conclusion of the study, study drug supplies (including partially used packages) will be 
returned or destroyed according to instructions provided by Oramed Ltd. Drug destruction 
procedures and documentation must be retained at the site. 
5.7 Concomitant Medications and Supplements 
All prior medications and supplements taken within 30 days prior to the first dose of IMP and 
concomitant medications and supplements will be recorded in the subject’s source 
documentation and in the eCRF. 
Any concomitant medication use will be evaluated on a case-by-case basis by the Investigator. 
If a subject requires the use of any medications, the Investigator will contact the Sponsor and the 
Medical Monitor to discuss the subject’s continued participation in the study. In the event of an 
emergency, subjects will be treated at the discretion of the Investigator according to acceptable 
community standards of medical care.   
5.8 Behavioral Restrictions 
Subjects should arrive following a minimum 10-hour fast and must not take any food prior to 
scheduled dosing as described in the study design. Water intake will be unrestricted. All subjects 
will continue with their regular diet. 
Excessive caffeine use (i.e., more than five cups of caffeinated beverages per day) will not be 
allowed from Screening through Visit 8. Excessive alcohol use or binge drinking will be 
discouraged during the study, and alcohol will be prohibited 72 hours prior to each visit. Subject 
should not use any recreational or illicit drugs throughout the study. 
Subjects will also be asked to refrain from any unusual or unaccustomed vigorous exercise 
during the course of the study. 
 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 40 of 62  
CONFIDENTIAL 
6 STUDY PROCEDURES AND ASSESSMENTS 
6.1 Informed Consent 
According to the ICH guideline for GCP (E6) and all institutional local, state, and federal laws, 
the Investigator will obtain and document informed consent for each subject screened for this 
study. All subjects will be informed in writing of the nature of the protocol and Investigational 
Drug, its possible hazards, and their right to withdraw at any time, and will voluntarily sign a 
form (ICF) indicating their consent to participate in the study prior to the initiation of study 
procedures. The subject’s medical record should contain written documentation indicating that 
informed consent was obtained. The ICF must be reviewed and approved by the Investigator’s 
designated IRB and by Oramed Ltd. designee prior to its use. Refer to Section 11.1.4 for further 
details regarding informed consent. 
6.2 Demographics, Medical History and Prior Medications 
At Screening, demographics (sex, age, race and ethnicity), a complete medical history and social 
history, including smoking, caffeine, alcohol, and drug use, will be collected by subject 
interview. Medications and supplements, recent blood donations, illnesses, and participation in 
other Investigational Drug trials or clinical trials will also be recorded. 
6.3 Study Endpoints 
The primary endpoint of this trial will evaluate safety of ORMD-0801 in patients with 
nonalcoholic steatohepatitis (NASH) and type 2 DM.  
Secondary endpoint will evaluate the effectiveness of ORMD-0801 in reducing liver fat content 
in patients with NASH and type 2 DM by measuring the final and baseline differences in the 
MRI-PDFF. 
6.4 Efficacy Assessments 
Fat content in the liver will be assessed by measuring the final and baseline differences in the 
MRI-PDFF results. Images generated from the MRI-PDFF scans will be submitted for central 
reading.  
6.5 Safety Assessments 
6.5.1 Weight and Height 
Height will be measured, and BMI will be calculated at Screening only with the subject wearing 
no shoes. Weight will be measured at all visits in fasting conditions when possible (on visits 
when subject is required to fast). The subject will be clothed while being weighed, but should 
remove shoes, coats, jewelry and other accessories (refer to Table 1). 
6.5.2 Vital Signs 
Vital signs, including seated systolic/diastolic blood pressure (SBP/DBP), heart rate and oral 
temperature, will be recorded where indicated in Table 1. Vital signs will be measured after the 
subject has been sitting for at least 5 minutes in a quiet environment and prior to any blood draw 


Oramed Ltd. 
 
Protocol No.: ORA-D-N02 
Phase 2 Clinical Study 
Final; Version 2; Dated: August 25, 2020 
Page 41 of 62  
CONFIDENTIAL 
that occurs at the same time point. The recorded seated SBP/DBP value will be the mean of two 
measurements taken 2 minutes apart and always using the non-dominant arm. 
6.5.3 Physical Examination 
A complete physical examination will be performed at Screening and Visits 3 and 8 (refer to 
Table 1). At the Investigator’s discretion, an additional physical exam may be performed during 
the End-of-Study/Early Termination (Visit 9). The physical examination will include the 
following organ or body system assessments: skin; head, eyes, ears, nose, and throat; thyroid; 
lungs; cardiovascular; abdomen (liver, spleen); lymph nodes; and extremities, as well as an 
abbreviated neurological examination. 
6.5.4 12-Lead ECG 
A 12-lead ECG will be performed at Screening as indicated in Table 1. At the Investigator’s 
discretion, an additional ECG may be performed at the End-of-Study/Early Termination (Visit 
9). The 12-lead ECG will be recorded after the subject has been resting at least 5 minutes in the 
supine position in a quiet environment. ECGs will be read for QT and QTc (Fridericia's) 
intervals and clinically significant abnormalities. 
6.5.5 Clinical Laboratory Tests 
Blood for clinical safety laboratory assessments will be collected and processed using standard 
procedures at Screening and on Visits 3, 6, 7, 8 and 9 and on any unscheduled visit if the 
investigator deems it necessary, as indicated in Table 1. A local laboratory will perform all 
clinical laboratory tests. In the event of abnormal clinical laboratory values, the Investigator will 
make a judgment whether or not the abnormality is clinically significant. 
6.5.5.1 Clinical Safety Laboratory Tests 
The clinical safety laboratory tests will include the following hematology and serum chemistry 
tests: 
• Hematology 
o Hemoglobin 
o Hematocrit 
o RBC 
o WBC (total count and differential count) 
o Platelets Count 
o Mean Platelet Volume (MPV) 
o MCV 
o MCH 
o MCHC 
o RDW 
o Neutrophils (absolute value and %) 
o Bands (ABS CNT) 
o Bands  
o Lymphocytes (absolute value and %) 
o Monocytes (absolute value and %) 
o Eosinophils (absolute value and %) 


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o Basophils (absolute value and %) 
o RBC Morphology 
 
• Serum Chemistry 
o Sodium 
o Potassium 
o Glucose  
o BUN 
o Creatinine 
o BUN/Creatinine 
o Chloride 
o Calcium 
o Protein 
o Albumin 
o Globulin (total) 
o A/G Ratio 
o SGOT (AST) 
o SGPT (ALT) 
o Bilirubin (total) 
o Alkaline Phosphatase 
o CO2 
o Creatine Phosphokinase (CPK) 
o Blood lipids: Total cholesterol, LDL, HDL, Triglycerides 
o Thyroid stimulating hormone (TSH, screening only) 
Urinalysis is not performed in this study.  
6.5.6 Additional Bloodwork 
In addition to the blood tests listed above, viral serology (HCV-Ab, HBsAg, HBcore-total, HBs 
Ab, and anti-HIV Ab), HbA1c, and adiponectin will be measured as indicated in Table 1. 
Adiponectin samples will be shipped to a Central Laboratory in Israel.  
6.5.7 Fasting Blood Glucose and Insulin Monitoring 
During the study, both fasting finger stick glucose and laboratory fasting plasma glucose 
will be obtained at time points stated in Table 1. Fasting blood insulin will be used to 
determine HOMA estimates.  
6.5.8 Pregnancy Test 
A serum pregnancy test will be performed for WCBP at Screening (Visit 1). A urine pregnancy 
test will be performed for WCBP at Visit 2 and Visit 3 (refer to Table 1). 
FSH testing (if not available) to confirm menopause will be performed at Screening for women 
who have had more than 24 months since their last menstrual cycle, who are younger than 55 
years old, and who are not surgically menopausal. 


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6.6 Review and Documentation of Medications and Supplements 
All medications or supplements subjects are taking or have taken within 30 days prior to Visit 1 
through Visit 9 will be recorded in the subject’s medical record and the eCRF.  
All medications and supplements (other than IMP) taken by the subject after Visit 1 through 
Visit 8 assessments will be considered “concomitant” medications and supplements.  
Medications and supplements taken prior to Visit 1 that are no longer being taken at Visit 1 will 
be considered “prior” medications and supplements. 
Medications and supplements should be recorded according to the generic name when possible.  
The use of concomitant medications and supplements should be limited to those that are 
medically necessary. Any medication or supplement used should have an indication recorded, 
and for concomitant medications and supplements, this indication must be represented as either 
for the treatment of an AE, for the management of a pre-existing condition, or for prophylaxis.  
Dosage increases for any concomitant medication or supplement should be noted and the reason 
for the dosage increase recorded as an AE (assumes worsening condition). The side effects of 
concomitant medications will be recorded as AEs.  
Any subject whose condition becomes disqualifying during the course of the study may be 
treated for that condition. If the condition is suspected during Screening, the subject should not 
be enrolled. Treatment of the condition should be instituted according to the 
Investigator’s/attending physician's judgment.  
Medications that have no treatment intent but rather are part of supportive routine care such as 
local anesthetics, intravenous solutions to maintain fluid balance and keep access open, 
medications used for prophylaxis, and narcotics for postsurgical pain must also be recorded in 
the subject’s medical record and eCRF. 
 
 


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7 ADVERSE EVENTS AND SAFETY REPORTING 
Information about all adverse events, whether volunteered by the patient, discovered by 
Investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded on the Adverse Event Case Report Form and followed-up 
as appropriate. 
Medical conditions present at study entry are considered pre-existing conditions and will be 
documented as medical history in the study source and eCRF documents. All adverse events, 
including worsening of pre-existing conditions, must be reported and documented as described 
below. 
7.1 Safety and Tolerability Assessments 
Volunteered, observed, and elicited reports of adverse events must be recorded. This includes 
adverse events the patient reports spontaneously, those the Investigator observes, and those the 
study staff elicits in response to open-ended questions during study visits. 
Each adverse event will be assessed by the Investigator with regard to seriousness, severity, and 
relatedness to the study treatment for recording in the eCRF. 
7.2 Definition of Adverse Event  
An adverse event is any untoward medical event that occurs in a patient or patient administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (including 
abnormal laboratory findings), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
7.3 Adverse Events of Special Interest 
7.3.1 Adverse Events of Hypoglycemia 
The CTCAE (version 5.0) criteria for mild, moderate, and severe hypoglycemia based on blood 
glucose will be used, as shown below: 
Mild: < 70 – 55 mg/dL (< 3.8 - 3.0 mmol/L) 
Moderate: < 55 – 40 mg/dL (< 3.0 - 2.2 mmol/L) 
Severe: < 40 – 30 mg/dL (< 2.2 - 1.7 mmol/L) 
Life Threatening: < 30 mg/dL (< 1.7 mmol/L) 
7.4 Definition of Serious Adverse Event  
International Conference on Harmonization (ICH) Guidelines define a serious adverse event 
(SAE) as any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening.  


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• Requires or prolongs existing hospitalization.  
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Important medical events that may not result in death, be life-threatening or require 
hospitalization, but that may jeopardize the patient or require medical intervention to 
prevent one of the above outcomes, should also be considered serious when based upon 
the Investigator’s medical judgment.  
Events not to be reported as SAEs are the following:  
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition. 
• Treatment, including hospitalization, which was elective or pre-planned for a pre-existing 
condition that is unrelated to the indication under study and did not worsen. 
• Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
aforementioned definitions of “serious” and not resulting in hospital admission. 
7.5 Recording Adverse Events 
All adverse events experienced during the trial, regardless of relationship to study medication, 
must be recorded on the Adverse Event eCRF from the time of patient consent until completion 
of patients End-of-Study Visit (Visit 9). All serious adverse events will be collected through 
Visit 9. The Investigator must continue to follow all non-serious events possibly related to the 
study medication and all serious adverse events until they resolve or until the Investigator 
assesses them in writing as chronic or stable.  
Regardless of relationship to study medication, the event must be recorded on the Adverse Event 
eCRF. Adverse event documentation should include the following information: 
• Standard medical terminology for the AE  
• Description of adverse event 
• Date and time of onset 
• Date and time of resolution of the adverse event  
• Whether or not the event is ongoing 
• Severity of the event  
• Relationship between the adverse event and the investigational product 
• Description of any actions taken (e.g., medications, treatments) 
• Outcome of the AE 
• Whether or not the effect was serious and/or unanticipated 
Whenever possible, a diagnosis should be given when signs and symptoms are due to common 
etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported 
as "upper respiratory infection"). For the purposes of this study, hypoglycemic events will be 
considered adverse events and should be recorded in source and eCRF records.  
When a diagnosis is not available, each adverse event should be reported separately. For 
example, “nausea and vomiting” should be split into two separate events. 


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7.5.1 Routine Reporting of Adverse Events 
All AEs, whether or not associated with the IMP that are observed by the Investigator, other 
Investigational Site personnel, or those reported by the subject will be recorded in the subject’s 
source documentation and on the AE page of the eCRF. Copies of the SAE eCRF pages or an 
SAE listing generated based on the eCRF pages will be submitted to the Sponsor at regularly 
scheduled intervals to allow the Sponsor to meet expedited regulatory reporting requirements 
under 21 CFR 312.32 and regular regulatory reporting requirements under 21 CFR 312.33.  
For each AE, the following information will be entered in the eCRF: 
• Medical diagnosis of the event in standard medical terminology (if a medical diagnosis 
cannot be determined, a description of each sign or symptom characterizing the event); 
• Date of onset of any new AE or worsening of a previously observed AE. For the days 
when the subject is in the clinic (Visit 2 to Visit 9), the time (based on a 24-hour clock) of 
onset should be recorded if available; 
• Date of resolution of the event (or confirmation ongoing). For the days when the subject 
is in the clinic (Visit 2 to Visit 9), the time (based on a 24-hour clock) of resolution 
should be recorded if available; 
• Whether the event is serious (per definition in Section 7.4), and if so, the reason it is 
considered serious; 
• Severity of AE (per definition in Section 7.7); 
• Assessment of the attributability of the AE to the IMP [per definition in Section 7.5];  
• Expectedness of AE (per definition in Section 7.8); 
• Action taken in treating the AE (including concomitant medications or therapies 
administered) and/or change in the IMP administration or dose (including whether the 
IMP was temporarily interrupted or discontinued); 
• Outcome of AE (per definition in Section 7.9).   
7.5.2 Reporting of Serious Adverse Events 
In accordance with Federal regulations, Investigators will be notified of the occurrence of 
serious, unexpected and related adverse events. 
The Investigator must report all serious adverse events to Sponsor or delegate within 24 hours of 
the site being notified of the event. Investigators must also report these events to the Institutional 
Review Board (IRB) in accordance with the IRB’s reporting guidelines, within the IRB specified 
timeframe, or no later than 48 hours after knowledge of the event. 
For submission of these events to the Israeli Regulatory Agency- the Sponsor will follow FDA 
regulations 21 CFR 312.32. If the event is determined to meet the requirements of IND Safety 
Reporting, then expedited reporting requirements to the FDA will be followed. The Sponsor may 
need to issue an Investigator notification, to inform all Investigators involved in any study with 


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the same drug (or therapy) that this serious unexpected suspected adverse reaction (SUSAR) has 
occurred.  
Investigator Reporting Procedures 
The PI or other study personnel must immediately (within 24 hours) inform Sponsor 
representative of any AE considered serious (as defined above) or otherwise medically 
significant. Notification should be via email or facsimile transmission of a written report signed 
by the PI. Notification must include the PI’s assessment as to whether the event was or was not 
related to the use of the study medication.  
Medical Monitor: 
 
Carmen Margaritescu, MD 
Safety Office, Integrium, LLC 
Office: 714-210-6665  
Cellular: 714-328-7083 
Email: carmen.margaritescu@integrium.com 
The Principal Investigator must also promptly inform the governing IRB of the serious adverse 
event per the governing IRB’s requirements. 
The CRO will notify Oramed within 24 hours of receipt. Any SAE that occurred within 30 days 
after last dose will be followed and reported as above. 
7.5.2.1 Pregnancy Reporting 
If the subject or partner of a subject participating in the study becomes pregnant during the study 
or within 30 days or discontinuing study medication, the Investigator should report the 
pregnancy to Oramed within 24 hours of being notified. The Exposure In-Utero form to the 
Investigator for completion. 
The subject or partner should be followed by the Investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
the Sponsor. At the completion of the pregnancy, the investigator will document the outcome of 
the pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification as 
an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
7.6 Causality Assessment of Adverse Events 
For all AEs, the Principal Investigator will provide an assessment of causal relationship to the 
study medication. The causality assessment must be recorded in the subject’s source documents 
and, on the AE eCRF. Causal relationship will be classified according to the following criteria: 
 
1. Unrelated: The event is clearly due to causes other than the active study drug. 
2. Unlikely: The event is doubtfully related to active study drug.  The event was most likely 
related to other factors such as the patient’s clinical state, concomitant drugs or other 
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3. Possible: The event follows a reasonable temporal sequence from the time of active study 
drug administration but could have been produced by other factors such as the patient’s 
clinical state, therapeutic interventions or concomitant drugs. 
4. Probable: The event follows a reasonable temporal sequence from the time of active 
study drug administration and follows a known response pattern to the drug. The toxicity 
cannot be reasonably explained by other factors such as the patient’s clinical state, 
therapeutic interventions or concomitant drugs. 
5. Definite: The event follows a reasonable temporal sequence from the time of active study 
drug administration, follows a known response pattern to the drug, cannot be reasonably 
explained by other factors such as the patient’s condition, concomitant drugs or 
therapeutic interventions, AND either occurs immediately following active study drug 
administration, improves on stopping the study drug, or reappears on re-exposure. 
 
7.6.1 Potential Adverse Events Associated with ORMD-0801 
Hypoglycemia and associated symptoms (e.g., weakness, dizziness, shakiness, increased 
sweating, palpitations, or confusion), have been associated with insulin administration, including 
ORMD-0801.  Animal reproductive studies have not been conducted with ORMD-0801. It is not 
known whether ORMD-0801 can cause fetal harm when administered to a pregnant woman. It is 
also not known whether this product is excreted in human milk. Pregnant or breastfeeding 
women are excluded from this study. 
Long-term animal studies have not been completed to assess whether ORMD-0801 impairs 
fertility.  
7.7 Adverse Event Severity Assessment 
The Principal Investigator will provide an assessment of the severity of each adverse reaction by 
recording a severity rating on the appropriate AE reporting page of the subject’s eCRF. Severity 
will be assessed according to the following scale: 
Mild – events are usually transient and easily tolerated, requiring no special treatment and causing 
no disruption of the subject’s normal daily activities. 
Moderate – events introduce a low level of inconvenience or concern to the subject and may 
interfere with daily activities but are usually improved by simple therapeutic measures. Moderate 
experiences may cause some interference with functioning. 
Severe – events interrupt the subject’s normal daily activities and generally require systemic drug 
therapy or other treatment. They are usually incapacitating. 
7.8 Expectedness of Adverse Event 
An unexpected AE is defined in 21 CFR 312.32(a) as follows: 
An AE is considered “unexpected” if it is not listed in the IB or is not listed at the specificity 
or severity that has been observed; or, if an IB is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the 
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7.9 Assessment of Adverse Event Outcome 
Outcome of AEs will be defined according to ICH Topic E2B, ICH Guideline. 
• Recovered/Resolved: The subject has recovered fully from the AE without any 
remaining effects or impairment. 
• Recovered/Resolved with Sequelae: The subject has recovered, but with an after effect 
possibly due to disease or treatment. 
• Not Recovered/Not Resolved: The condition is still present. 
• Fatal: Fatal should only be used when death is possibly related to the AE. 
• Unknown: The primary outcome is not known at the time of the final assessment. If an 
outcome for an AE is not available at the time of the initial report, follow-up will proceed 
until an outcome is known or followed up to the Final Study Visit. Any subject with a 
possible IMP-related AE at the Final Study Visit will be followed until resolution or 
stabilization of the event. Further, any SAE, whether or not related to IMP (active or 
Placebo), that occurs within 30 days following the last dose of IMP will be followed until 
resolution or stabilization of the event. 
7.10 Clinical Findings 
Any significant clinical findings at Visit 9 will be followed until the condition returns to pre-
study status, stabilizes, or can be explained as not being IMP related. If the clinical finding is 
reported as an AE (per the criteria outlined in Section 7.2), the follow-up procedures for AEs 
defined above will apply. 
 
 


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8 STATISTICAL METHODS 
This section describes the statistical methods to be used for the analysis and reporting of data 
collected under Protocol No. ORA-D-N02. Additional details will be provided in the statistical 
analysis plan. 
8.1 Sample Size 
Up to 36 patients with NASH and Type 2 DM will be randomized to complete approximately 30 
in this multi-center exploratory study. Subjects will be enrolled at 2 sites in Israel and 3 sites in 
the USA. 
The treatment regimen will consist of a soft gelatin capsule containing 8 mg insulin, and 75 mg 
SBTI. Patients will take one capsule in the morning and one capsule at night, daily, or matching 
placebo, based on their randomized schedule.   
The size of the study population was determined by reviewing the literature for pilot studies and 
was found to be sufficient to show trends of reducing liver fat content by MRI-PDFF images and 
CAP-Fibroscan. This study is not powered for statistical significance.   
8.1.1   Populations 
Safety Population: All subjects who receive at least one dose of IMP will be included in the 
safety population. 
Intention to Treat: All subjects who received treatment were included in the Intention to Treat 
population. 
8.2 Safety Evaluation 
8.2.1 Adverse Events 
AEs will be coded using the most current version of MedDRA. The severity of AEs will be 
graded according to NCI CTCAE version 4.03. AEs will be regarded as “pretreatment” if they 
occur during the Placebo Run-in Phase. TEAEs are defined as any AE that starts or increases in 
severity after the first dose of IMP at Visit 3. 
The incidence of TEAEs will be tabulated by MedDRA preferred term, system organ class, 
treatment group, severity, and assigned relationship to IMP. The incidence for each TEAE will 
be provided as the total number of subjects that experienced the TEAE, as well as the percentage 
of the population that this represents. If a TEAE is reported more than once for a given subject, 
the greatest severity and the worst-case attribution will be presented in the summary tables. 
TEAEs will be listed for individual subjects, along with information regarding onset and end 
dates, onset time where available, severity, seriousness, relationship to IMP, action taken, and 
outcome. A similar listing will be prepared for the pretreatment AEs.   
Pretreatment AEs and TEAEs that lead to withdrawal from the study will be separately listed and 
summarized. Similarly, separate tabulations and listings will be prepared for pretreatment and 
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Descriptive statistics will be generated as appropriate (i.e., frequency for categorical data).  
Inferential statistical analysis comparing the AE data between Active treatment and Placebo is 
not planned. 
8.2.2 Laboratory Evaluations 
Individual clinical safety lab (hematology, serum chemistry and serology) values will be listed 
by visit and summarized using descriptive statistics as appropriate (i.e., mean, median, range, 
and standard deviation for continuous data and frequency for categorical data). Individual change 
from baseline (Screening) in laboratory values will be calculated and summarized descriptively. 
Shift tables from baseline (Screening) to post-dose (Visit 8) will also be produced for the 
laboratory assessments based on the categories of Low, Normal, and High. A clinically 
significant change from baseline will be recorded as an AE if deemed appropriate by the 
Investigator. 
8.2.3 Vital Signs 
Individual vital sign measurements (seated SBP/DBP, heart rate and oral temperature) will be 
listed by measurement time and summarized using descriptive statistics as appropriate (i.e., 
mean, median, range, and standard deviation). Individual change from baseline (screening) in 
vital sign measurements will be calculated and summarized descriptively. A clinically significant 
change from baseline will be recorded as a TEAE if deemed appropriate by the Investigator. 
8.2.4 12-lead ECG 
Individual 12-lead ECG assessments will be listed by visit and summarized using descriptive 
statistics as appropriate (i.e., mean, median, range, and standard deviation for continuous data 
and frequency for categorical data).   
8.2.5 Physical Examination 
Individual physical examination findings will be listed by visit. A clinically significant change 
from baseline (Screening) will be recorded as an AE if deemed appropriate by the Investigator. 
8.2.6 Prior and Concomitant Medications and Supplements 
Medications and supplements will be coded using the most current version of the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system.   
All medications and supplements (other than IMP) taken by the subject from Visit 2 through 
Visit 8 will be considered “concomitant” medications and supplements. Medications and 
supplements taken prior to Visit 2 that are no longer being taken at the time of Visit 2 will be 
considered “prior” medications and supplements.   
Concomitant medications and supplements will be listed for individual subjects. A similar listing 
will be prepared for prior medications and supplements taken within 30 days prior to the first 
dose of IMP. The incidence of these prior and concomitant medications and supplements will be 
summarized. 
8.2.7 Handling of Missing, Unused, or Spurious Data 
Descriptive statistics and listings will be provided for all data. No substitution of missing data 
will be used in any calculations. Data points that appear to be spurious will be investigated and 


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will not be excluded from the listings. Influential cases will be handled in an appropriate 
statistical manner. 
8.3 Efficacy Evaluation 
8.3.1 Liver Fat Content 
The analysis of liver fat content will be an Analysis of Covariance (ANCOVA) with treatment, 
country and site as effects and baseline value as a covariate.  
8.3.2 Handling of Missing or Spurious Data 
Multiple Imputation Methods will be used as a supportive analysis to account for missing data. 
Missing or spurious data will be imputed. Imputed values are drawn for a distribution (that can 
be different for each missing entry). This step results in m complete data sets. Each of the m 
completed data sets will be analyzed. This step results in m analyses. The results for the m 
analyses will be pooled into a final result. The details of how the missing or spurious values were 
imputed will be documented. 
 
 


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9 DATA HANDLING AND RECORD KEEPING 
All data required by the study protocol will be collected in a validated database according to 
the CRO’s SOPs. 
9.1.1 Electronic Data Capture 
Data from the source documents will be entered into the EDC system by authorized 
Investigational Site personnel. Data Management staff, using both electronic and manual checks, 
will systematically check the data. Errors or omissions will result in queries (which can be issued 
by the Study Monitor or Data Management staff), which will be presented to the Investigational 
Site within the EDC system. The Investigational Site will resolve the queries within the EDC 
system. The Study Monitor and Data Management staff will review the responses as part of the 
query resolution process. The EDC system will track the queries with the corresponding 
responses. 
Medications and supplements entered into the database will be coded in the EDC system using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. AEs and Medical History will be coded in the EDC system using 
MedDRA terminology.  
Laboratory samples will be processed by local laboratories. Results will be reported to Integrium 
and imported into the database. 
9.2 Quality Assurance and Database Lock 
A 100% critical variable review of all key safety and secondary endpoint data in the database 
will be performed. Following this review, a data quality control audit or a random sample equal 
to 10% of subjects, with a minimum of 5 subjects will be performed. 
When the database has been declared to be complete and accurate, the database will be locked. 
Any changes to the database after that time can only be made by joint written agreement between 
the Sponsor, the Investigator, Integrium, and the study biostatistician. 
 
10 AMENDMENTS/MODIFICATIONS TO THE PROTOCOL 
The Investigator will ensure that the study is conducted in accordance with the procedures and 
evaluations described in this protocol. As the study progresses it may become necessary to 
change or modify parts of the protocol. The Sponsor or designee is responsible for submitting 
protocol amendments to the appropriate government regulatory authorities. The Investigator is 
responsible for submitting protocol amendments to the appropriate IRB. Approval by the IRB 
must be obtained before changes are implemented.   
When an emergency occurs that requires a departure from the protocol for an individual, a 
departure will be only for that subject. The Investigator or other physician in attendance in such 
an emergency will, if circumstances and time permit, contact the Medical Monitor immediately 
by telephone. Such contacts will be made as soon as possible to permit a decision as to whether 


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or not the subject (for whom the departure from protocol was affected) is to continue in the 
study. The eCRF and source documents will completely describe the departure from the protocol 
and state the reasons for such departure. In addition, the IRB will be notified in writing of such 
departure from protocol. 
 
 


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11 INVESTIGATOR OBLIGATIONS 
11.1 Regulatory Documentation 
Before the trial starts, Essential Documents as defined in ICH E6, will be generated and placed in 
both the Investigator’s and Sponsor’s files. Additional Essential Documents will be added to 
both files as new information becomes available and at the completion or termination of the trial 
as defined in ICH E6. 
11.2 Protection of Human Subjects 
11.2.1 Declaration of Helsinki  
The Investigator will conduct this study in accordance with the Declaration of Helsinki (1964) 
including all amendments up to and including the October 2013 revision. 
11.2.2 Good Clinical Practice and Regulatory Compliance 
The Investigator will conduct this study in accordance with the principles of GCP (current ICH 
guidelines) and the requirements of all local regulatory authorities regarding the conduct of 
clinical trials and the protection of human subjects. 
The study will be conducted as described in the approved protocol, with amendments and in 
accordance with the obligations of clinical Investigators set forth in the Form FDA 1572 and in 21 
CFR 50, 54, 56 and 312. 
11.2.3 Institutional Review Board  
The Investigator is responsible for the submission of the protocol, ICF, and other written 
materials (such as advertisements and diaries), along with relevant supporting data (e.g., IB), to 
the appropriate IRB for review and approval before the study can be initiated. The Investigator is 
also responsible for submitting amendments to the protocol and ICF to the IRB for review and 
approval prior to implementation of the change. The Investigator is responsible for providing the 
Sponsor with a letter documenting the IRB approval prior to initiation of the study or 
implementation of the changes, respectively.  
The Investigator will not have authority to implement any deviation or change to the protocol 
without prior review and documented approval/favorable opinion from the IRB of an 
amendment, except where necessary to eliminate an immediate hazard to study subjects. Any 
significant deviation from the approved protocol will be documented in the source documents 
and eCRF.  
Any deviation or change to the protocol required to eliminate an immediate hazard prior to 
obtaining IRB approval/favorable opinion, will be submitted as soon as possible to:  
• IRB for review and approval/favorable opinion.  
• The Sponsor via appropriate designees. 
• Regulatory Authorities, if required by local regulations.  
Documentation of IRB approval signed by the chairperson or designee of the IRB will be provided 
to the Sponsor via appropriate designees.  


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If an Amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the ICF will be revised and submitted to the IRB for review and approval/favorable 
opinion; (2) the revised ICF will be used to obtain consent from subjects currently enrolled in the 
study if they are affected by the Amendment; and (3) the new ICF will be used to obtain consent 
from any new subjects prior to enrollment. 
The Investigator is responsible for informing the IRB of all reportable AEs. IND Safety Reports 
provided by the Sponsor to the Investigator will be promptly forwarded to the IRB by the 
Investigator. Updates to the IB provided by the Sponsor to the Investigator will be submitted to 
the IRB by the Investigator. 
The Investigator is also responsible for informing the IRB of the progress of the study and for 
obtaining annual IRB renewal. The Investigator must inform the IRB when the study is 
completed or terminated. After completion or termination of the study, the Investigator will 
submit the final clinical study report to the IRB.  The structure and content of the report will 
meet that described in Structure and Content of Clinical Study Reports E3 (ICH Harmonized 
Tripartite Guideline, dated November 30, 1995).  
11.2.4  Subject Informed Consent 
The Investigator must comply with informed consent regulations (21 CFR Part 50) and relevant 
state regulations (i.e., California Bill of Rights for California patients).   
The ICF will clearly describe the nature, scope, and potential risks and benefits of the study, in a 
language that the subject understands. The ICF will conform to all the requirements for informed 
consent according to ICH GCP and US FDA guidelines (21 CFR 50) and will include any 
additional elements required by the Investigator’s institution or local regulatory authorities. The 
ICF will adhere to the ethical principles that have their origin in the Declaration of Helsinki.   
Prior to the beginning of the study, the Investigator will obtain the IRB’s written 
approval/favorable opinion of the written ICF. The IRB approved ICF will be given to each 
prospective participant. The subjects will be given adequate time to discuss the study with the 
Investigator or site staff and to decide whether or not to participate. Each subject who agrees to 
participate in the trial and who signs the ICF will be given a copy of the signed, dated, and 
witnessed document. The original signed ICF will be retained by the Investigator in the study 
files. 
The ICF and any other information provided to subjects will be revised whenever important new 
information becomes available that is relevant to the subject's consent, and the Investigator will 
obtain the IRB’s written approval/favorable opinion prior to the use of the revised documents. 
The Investigator, or a person designated by the Investigator, will fully inform the subject of all 
pertinent aspects of the study and of any new information relevant to the subject's willingness to 
continue participation in the study. Subjects will read and sign any and all revised ICFs.  
11.3 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects’ state of 
health will be regarded as confidential. This is detailed in the ICF provided to the subject. An 
agreement for the use or disclosure of any such information (PHI) will be obtained from the 
subject in writing (HIPAA authorization) prior to performing any study-related procedures.  


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Disclosure of subject medical information obtained as a result of this study to third parties other 
than those noted below is prohibited.   
Medical information resulting from a subject’s participation in this study may be given to the 
subject’s personal physician or to the appropriate medical personnel responsible for the subject’s 
welfare. Data generated as a result of this study are to be available for inspection on request by 
FDA or other government regulatory agency auditors, the Sponsor (or designee), and the IRB.   
The information developed in this clinical study will be used by the Sponsor in the clinical 
development of the IMP and therefore may be disclosed by the Sponsor as required for 
disclosure as a public company to other clinical investigators, to other pharmaceutical 
companies, to the FDA, and to other government agencies. All reports and communications 
relating to subjects in this study will identify each subject only by their initials and subject 
number.   
11.4 Case Report Forms 
All data required by the study protocol will be recorded in the eCRF. Data from the source 
documents will be entered into the EDC system by authorized Investigational Site personnel. 
The eCRF will be updated at the time of each subject visit. Results of tests performed outside 
the Investigational Site will be entered as soon as available to the Investigational Site. The 
Principal Investigator must verify that all data entries in the eCRF are accurate and correct by 
signing the subject’s eCRF investigator signature screen. 
11.5 Source Documentation 
All data entered in the eCRF must be verifiable against source documentation. Source 
documents may include, but are not limited to, a subject’s medical record, hospital charts, clinic 
charts, the Principal Investigator’s study files, as well as the results of diagnostic tests.   
11.6 Retention of Records 
The Investigator has the responsibility of maintaining a comprehensive and centralized filing 
system containing all study-related documentation. These files must be available for inspection 
by the Sponsor or designee, the IRB, and regulatory authorities (i.e., FDA or international 
regulatory authorities) at any time and should consist of the Essential Documents as defined in 
ICH E6, which include, but are not limited to, the following elements: 
• Subject files, containing the completed eCRFs, supporting source documentation from 
the medical record, including laboratory data, and the signed ICF;  
• Regulatory files, containing the protocol with all amendments and Sponsor and 
Investigator signature pages, copies of all other regulatory documentation, and all 
correspondence between the site and the IRB and Sponsor; and  
• Drug accountability files, including a complete account of the receipt and disposition of 
the IMP (active and Placebo). 
The Investigator will retain all study records for at least 2 years after the last approval of a 
marketing application in an ICH region (i.e., United States, Europe, or Japan), and until there are 


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no pending or contemplated marketing applications in an ICH region. If no application is filed or 
if the application is not approved for such indication, the Investigator will retain all study records 
for at least 2 years after the investigation is discontinued and regulatory authorities have been 
notified. The Sponsor will provide written notification when it is appropriate for the Investigator 
to discard the study-specific documents referenced above. 
The Investigator will notify the Sponsor prior to destroying any study records. Should the 
Investigator wish to assign the study records to another party or move them to another location, 
the Sponsor will be notified in writing in advance. 
If the Investigator cannot guarantee this archiving requirement at the Investigational Site for any 
or all of the documents, special arrangements will be made between the Investigator and the 
Sponsor for storage. If source documents are required for continued care of the subject, 
appropriate copies for storage off site will be made. 
11.7 Clinical Study Report 
After completion or termination of the study, a clinical study report will be prepared. The 
structure and content of the report will meet that described in Structure and Content of Clinical 
Study Reports E3 (ICH Harmonized Tripartite Guideline, dated November 30, 1995). The 
Principal Investigator must verify that all information and data in the clinical study report is 
accurate and correct by signing the clinical study report.   
 
12 STUDY ADMINISTRATION 
12.1 
Study Monitoring 
This study will be monitored by the Sponsor or designee to evaluate the progress of the study, to 
verify the accuracy and completeness of the eCRFs, to assure that all protocol requirements, 
applicable laws and/or regulations, and Investigator’s obligations are being fulfilled, and to 
resolve any inconsistencies in the study records.  
The Investigator will allow the Study Monitor to periodically review, at mutually convenient 
times during the study and after the study has been completed, all eCRFs and office, hospital, 
and laboratory records supporting the participation of each subject in the study.   
The Study Monitor will compare the eCRF data against source documentation in order to verify 
its accuracy and completeness. The Investigator and Investigational Site staff will collaborate 
with the Study Monitor to resolve any identified data discrepancies in a timely manner.   
The Study Monitor will record any protocol deviations identified, including, but not limited to, 
subjects that were enrolled even though they did not meet all eligibility criteria, subjects who 
took concomitant medications specifically prohibited by the protocol, subjects who received the 
wrong study treatment or incorrect dose, and subjects who failed to comply with the protocol-
defined dietary restrictions. The Investigator and Investigational Site staff will collaborate with 
the Study Monitor to identify the reason for each protocol deviation.   


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The Study Monitor will compare the Investigational Site study treatment accountability record 
against the study treatment inventory (unused and used) at the site. The Investigator and 
Investigational Site staff will collaborate with the Study Monitor to resolve any identified 
discrepancies in a timely manner. 
Each issue identified during study monitoring visits will be documented and reported to both 
the Sponsor and the Investigator. 
12.2 
On-Site Audits 
The FDA, or other regulatory authorities, may request access to all study records for 
inspection and copying. The Principal Investigator and Investigational Site staff will 
cooperate with the inspectors and allow access to all source documents supporting the eCRFs 
and other study-related documents. The Investigator will immediately notify the Sponsor 
when contacted by any regulatory authority for the purpose of conducting an inspection.  
The Sponsor or designee may also request to visit the Investigator’s site to conduct an audit of 
the study. Prior to initiating this audit, the Investigator will be contacted by the Sponsor to 
arrange a convenient time for this visit. The Principal Investigator and Investigational Site 
staff will cooperate with the auditors and allow access to all source documents supporting the 
eCRFs and other study-related documents.  
12.3 Data Quality Assurance 
All eCRFs must be completed by authorized Investigational Site personnel who have 
undergone eCRF training. Data will be entered into the eCRF as information becomes 
available on a visit-by-visit basis. All data recorded on the eCRFs must be supported by 
source documentation. The Principal Investigator must verify that all data entries in the eCRF 
are accurate and correct by electronically signing and dating the eCRF. 
All eCRF corrections must be made by the Principal Investigator or authorized Investigational 
Site personnel. The Principal Investigator must authorize changes to the recorded data, and 
this authorization must be documented in the source documents.  
Refer to Section 9 for further details regarding Data Management quality assurance, including 
query generation and resolution, final data review, and database lock. 
12.4 Publication Policy 
All information and data obtained in the course of the study are the property of the Sponsor and 
are considered confidential. To avoid disclosures that could jeopardize proprietary rights, the 
institution and/or the Investigator agree to certain restrictions on publications (e.g., abstracts, 
speeches, posters, manuscripts, and electronic communications), as detailed in the clinical trial 
agreement. 
The publication or presentation of any study results shall comply with all applicable privacy 
laws, including, but not limited to, HIPAA or equivalent. 


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12.5 Insurance 
The sponsor has liability insurance at industry standard levels for a study of this size. This 
insurance provides coverage for damage to research subjects through injury or death caused by 
the study subject to the terms of the insurance policy. 
12.6 Disclosure and Confidentiality 
By signing the protocol, the Investigator agrees to keep all information provided by the Sponsor 
and Integrium in strict confidence and to request similar confidentiality from his/her staff and the 
IRB.  Study documents provided by the Sponsor and Integrium (protocols, IBs, eCRFs, and other 
material) will be stored appropriately to ensure their confidentiality. The information provided 
by the Sponsor and Integrium to the Investigator may not be disclosed to others without direct 
written authorization from the Sponsor and Integrium, except to the extent necessary to obtain 
informed consent from subjects who wish to participate in the study. 
 
 


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