Clinical trial NCT04616014
Conditions: Nonalcoholic Steatohepatitis (NASH)
Sponsor: Oramed, Ltd.
Start date: 2021-03-01; Completion date: 2022-09-15
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Study to Assess the Safety and Potential of Oral Insulin to Reduce Liver Fat Content in Type 2 Diabetes Patients with Nonalcoholic Steatohepatitis (NASH)

Detailed description:
An Open-Label Multi-Center Study to Assess the Safety and Potential of Oral Insulin to Reduce Liver Fat Content in Type 2 Diabetes Patients with Nonalcoholic Steatohepatitis (NASH)

Arms: arm 1: 16 mg QD, daily, in the morning (two capsules of ORMD--801, 8 mg each
Interventions: intervention 1: ORMD-0801 QD
Intervention descriptions: intervention 1: 16 mg, QD, two capsules, 8 mg each.

Protocol documents:
Prot_SAP_000.pdf: 
Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 1 of 59  
 
 
 
 
Clinical Study Protocol: ORA-D-N01B 
Study Title: 
An Open-Label Multi-Center Study to Assess the Safety and 
Potential of Oral Insulin to Reduce Liver Fat Content in Type 2 
Diabetes Patients with Nonalcoholic Steatohepatitis (NASH) 
Protocol Number: 
ORA-D-N01B 
EudraCT: 
2020-001046-19 
Study Phase:  
Phase 2 
Principal 
Investigator: 
 
Sponsor: 
Oramed Ltd. 
Mamila 20 
Jerusalem, 9414908, Israel 
Name of Sponsor 
Signatory: 
Miriam Kidron, PhD 
Chief Scientific Officer and Director 
Oramed Ltd. 
Protocol Version: 
1.3 
Date of Version: 
Version 1.2: June 24, 2020 
Version 1.1: May 3, 2020 
Version 1.3: March 30, 2021 
Original (Version 1.0): April 06, 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-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 2 of 59  
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE 
The undersigned has reviewed and approved Protocol No. ORA-D-N01B for issuance: 
 
  Miriam Kidron, PhD 
Chief Scientific Officer and Director 
Oramed Ltd. 
 
 
 
Signature 
 
Date 
 
 
 
 
Summary of Changes 
Protocol Number ORA-D-N01B 
Protocol Version 1.3 (March 30, 2021) 
 
The following table summarizes important changes to the protocol for study number 
ORA-D-N01B. These changes reflect modifications made to the protocol since protocol 
version 1.2 (dated May 3, 2020). Bold font is used as needed to highlight additions and 
strikethrough text is uses as needed to indicate deletions from protocol version 1.2. 
Section Numbers refer to locations of the revised information in Protocol Amendment 02 
(Version 1.3). 
 
ITEM 
# 
PROTOCOL 
ELEMENT 
(SECTION #) 
DESCRIPTION OF CHANGE 
1.   Header and Title 
Page 
x Changed protocol version from 1.2 to 1.3.  
x Changed protocol date from May 3, 2020 to March 
30, 2021.  
2.  
Synopsis and 
Sections 4.1 and 
4.2 
The following change is made to Inclusion Criterion #3:  
x 
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 > 6.5-11%28 or on treatment with at 
least one on treatment with metformin only or metformin in 
addition to and no more than two three of the following oral 
anti-diabetic medications, metformin, sulfonylurea, DPP-4 
inhibitors, oral GLP-1 receptor agonists (semaglutide), 
SGLT-2 inhibitor, or Thiazolidinediones (TZDs). 
 
The following change is made to Inclusion Criterion #9:  
x 
Females must have a negative urine pregnancy test result at 
screening, prior to the start of the run-in period, at initiation of 
active dosing and every 4 weeks till the end of the study. A 
negative urine and serum pregnancy test must be obtained 
prior to active dosing. Males and females of childbearing 
potential must use two methods of contraception (double 
Miriam Kidron
Digitally signed by Miriam 
Kidron 
Date: 2021.04.12 14:51:26 
+03'00'


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 3 of 59  
ITEM 
# 
PROTOCOL 
ELEMENT 
(SECTION #) 
DESCRIPTION OF CHANGE 
barrier method), one of which must be an acceptable a highly 
effective barrier method from the time of screening to the last 
study visit (22 weeks).  
Highly effective methods include:  
o 
combined (estrogen and progestogen 
containing) hormonal contraception (oral, 
intravaginal or transdermal) associated with 
inhibition of ovulation  
o 
progestogen-only hormonal contraception 
(oral, injectable or implantable) associated 
with inhibition of ovulation 
o 
intrauterine device (IUD)  
o 
intrauterine hormone-releasing system (IUS)  
o 
bilateral tubal occlusion  
o 
vasectomised partner (is the sole sexual 
partner of the WOCBP participating in the 
trial)  
o 
sexual abstinence 
Acceptable methods include: 
Double barrier methods of contraception include male 
condoms plus spermicide, diaphragm with spermicide plus 
male condom, cervical cap with spermicide plus male condom, 
or oral contraceptives. 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>40), b) 
who are surgically menopausal (surgical sterility defined by 
tubal occlusion, bilateral oophorectomy, bilateral 
salpingectomy or hysterectomy). 
 
The following change is made to Inclusion Criterion #12:  
x 
Glycaemia must be controlled (Glycosylated Hemoglobin 
A1C ≤8.5%) while any HbA1C increment should not 
exceed 1% during 6 months prior to enrolment). 
 
The following change is made to Inclusion Criterion #13: 
x 
Patients who are willing to participate in the study, have to 
have their own self-monitoring blood glucose devices. 
 
The following changes are made to Exclusion Criteria 
#14:  
x 
Treatment with anti-diabetic medications other than at least 
one and no - metformin and more than two three of the 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 4 of 59  
ITEM 
# 
PROTOCOL 
ELEMENT 
(SECTION #) 
DESCRIPTION OF CHANGE 
following medications: metformin, sulfonylurea, DPP-4 
inhibitors, oral GLP-1 receptor agonists (semaglutide), 
SGLT-2 inhibitors, or TZDs. 
 
The following changes are made to Exclusion Criteria 
#15: 
x 
Metformin, Fibrates and statins not provided on a stable dose 
in the last 6 months. 
3.  
Section 3.2.1 
The following updates were made to Screen Failure: 
Subjects previously screen failed on eligibility criteria that have 
been updated in a protocol amendment, may be re-screened 
under the amendment after re-consenting.    
 
4.  
Section 3.7 
The following updates were made to Self-Monitoring 
Fasting Blood Glucose and Patient Diaries: 
x 
Adverse events including hypoglycemia will be monitored 
from the self-monitoring blood glucose diary and recorded 
in the CRF. 
 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 5 of 59  
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) 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 6 of 59  
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-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 7 of 59  
Contents 
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE ...................................... 2 
INVESTIGATOR SIGNATURE PAGE ....................................................................... 5 
STATEMENT OF COMPLIANCE ............................................................................... 6 
SYNOPSIS ................................................................................................................... 10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 15 
1 
INTRODUCTION ............................................................................................... 17 
2 
STUDY OBJECTIVES ........................................................................................ 21 
2.1 
Primary Objectives ..................................................................................... 21 
2.2 
Secondary Objective .................................................................................. 21 
3 
INVESTIGATIONAL PLAN .............................................................................. 22 
3.1 
Overall Study Design and Plan .................................................................. 22 
3.2 
Screening/Visit 1 (up to week -6) .............................................................. 23 
3.2.1 
Screen Failure .................................................................................. 24 
3.3 
Run-in Phase/Visit 2 (to week -2) .............................................................. 24 
3.3.1 
Visit 2 (to week -2) .......................................................................... 24 
3.4 
Treatment Phase (week 0) .......................................................................... 24 
3.4.1 
Visits 3 (baseline), 6, 7, and 8 .......................................................... 25 
3.4.2 
Visits 3 (baseline), 5, 6, 7, and 8 ...................................................... 25 
3.4.3 
Visits 3 and 8 ................................................................................... 25 
3.4.4 
Visit 8 ............................................................................................... 25 
3.5 
End-of-Study (EOS) (Week 16)/Early Discontinuations ........................... 25 
3.6 
Unscheduled visit ....................................................................................... 26 
3.7 
Self-Monitoring Fasting Blood Glucose and Patient Diaries .................... 26 
3.8 
Schedule of Events ..................................................................................... 28 
4 
STUDY SUBJECT SELECTION........................................................................ 31 
4.1 
Inclusion Criteria ....................................................................................... 31 
4.2 
Exclusion Criteria ...................................................................................... 32 
4.3 
Subject and Trial Discontinuation ............................................................. 33 
5 
STUDY TREATMENT (IMP) ............................................................................ 35 
5.1 
Description of Investigational Drug ........................................................... 35 
5.1.1 
Packaging and Labeling ................................................................... 35 
5.1.2 
Storage and Handling ....................................................................... 35 
5.2 
IMP Administration ................................................................................... 36 
5.2.1 
Visit 3 to Visit 8 ............................................................................... 36 
5.3 
Dose Modifications .................................................................................... 36 
5.4 
Measuring Subject Compliance ................................................................. 36 
5.5 
Drug Accountability ................................................................................... 36 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 8 of 59  
5.6 
Concomitant Medications and Supplements .............................................. 37 
5.7 
Behavioral Restrictions .............................................................................. 37 
6 
STUDY PROCEDURES AND ASSESSMENTS ............................................... 38 
6.1 
Informed Consent ....................................................................................... 38 
6.2 
Demographics, Medical History and Prior Medications ............................ 38 
6.3 
Study endpoints .......................................................................................... 38 
6.4 
Efficacy Assessments ................................................................................. 38 
6.5 
Safety Assessments .................................................................................... 38 
6.5.1 
Weight and Height ........................................................................... 38 
6.5.2 
Vital Signs ........................................................................................ 38 
6.5.3 
Physical Examination ....................................................................... 39 
6.5.4 
12-Lead ECG ................................................................................... 39 
6.5.5 
Clinical Laboratory Tests ................................................................. 39 
6.5.6 
Fasting Blood Glucose and Insulin Monitoring ............................... 40 
6.5.7 
Pregnancy Test ................................................................................. 40 
6.6 
Review and Documentation of Medications and Supplements ................. 40 
7 
ADVERSE EVENTS AND SAFETY REPORTING .......................................... 42 
7.1 
Safety and Tolerability Assessments ......................................................... 42 
7.2 
Definition of Adverse Event ...................................................................... 42 
7.3 
Adverse Events of Special Interest ............................................................ 42 
7.3.1 
Adverse Events of Hypoglycemia ................................................... 42 
7.4 
Definition of Serious Adverse Event ......................................................... 42 
7.5 
Recording Adverse Events ......................................................................... 43 
7.5.1 
Routine Reporting of Adverse Events ............................................. 44 
7.5.2 
Reporting of Serious Adverse Events .............................................. 44 
7.6 
Causality Assessment of Adverse Events .................................................. 45 
7.6.1 
Potential Adverse Events Associated with ORMD-0801 ................ 46 
7.7 
Adverse Event Severity Assessment .......................................................... 46 
7.8 
Expectedness of Adverse Event ................................................................. 46 
7.9 
Assessment of Adverse Event Outcome .................................................... 47 
7.10 
Clinical Findings ........................................................................................ 47 
8 
STATISTICAL METHODS ................................................................................ 48 
8.1 
Sample Size ................................................................................................ 48 
8.1.1 
Populations ....................................................................................... 48 
8.2 
Safety Evaluation ....................................................................................... 48 
8.2.1 
Adverse Events ................................................................................ 48 
8.2.2 
Laboratory Evaluations .................................................................... 49 
8.2.3 
Vital Signs ........................................................................................ 49 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 9 of 59  
8.2.4 
12-lead ECG ..................................................................................... 49 
8.2.5 
Physical Examination ....................................................................... 49 
8.2.6 
Prior and Concomitant Medications and Supplements .................... 49 
8.2.7 
Handling of Missing, Unused, or Spurious Data ............................. 50 
9 
DATA HANDLING AND RECORD KEEPING ............................................... 51 
9.1 
Data Quality Assurance ............................................................................. 51 
9.2 
Case Report Forms ..................................................................................... 51 
9.3 
Source Documents ..................................................................................... 51 
9.4 
Direct Access to Source Data and Study Audits ........................................ 52 
9.5 
Study Monitoring ....................................................................................... 52 
9.6 
Study Close-Out ......................................................................................... 53 
9.7 
Archiving Study Records ........................................................................... 53 
10 AMENDMENTS/MODIFICATIONS TO THE PROTOCOL ........................... 53 
11 INVESTIGATOR OBLIGATIONS .................................................................... 54 
11.1 
Regulatory Documentation ........................................................................ 54 
11.2 
Protection of Human Subjects ................................................................... 54 
11.2.1 
Declaration of Helsinki .................................................................... 54 
11.2.2 
Good Clinical Practice and Regulatory Compliance ....................... 54 
11.2.3 
Institutional Review Board .............................................................. 54 
11.2.4 
Subject Informed Consent ................................................................ 55 
11.3 
Subject Confidentiality .............................................................................. 55 
11.4 
Retention of Records .................................................................................. 56 
11.5 
Clinical Study Report ................................................................................. 57 
12 STUDY ADMINISTRATION ............................................................................. 57 
12.1 
Publication Policy ...................................................................................... 57 
12.2 
Insurance .................................................................................................... 57 
12.3 
Disclosure and Confidentiality .................................................................. 57 
13 REFERENCES .................................................................................................... 58 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 10 of 59  
CONFIDENTIAL 
SYNOPSIS 
Title 
An Open-Label Multi-Center Study to Assess the Safety and Potential of 
Oral Insulin to Reduce Liver Fat Content in 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: Two capsules of 8 mg each  
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 Up to 40 patients with NASH and Type 2 DM will be enrolled in this 
multi-center study.  
Study Design 
This is an open, 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, Placebo run-in, Treatment Phase and End-of-
Study Phase.  
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 as liver function 
tests. 
Summary of 
Assessments 
Safety Assessments:  
Safety will be assessed by monitoring adverse events including 
hypoglycemia, physical exam, vital signs (blood pressure heart rate and 
oral temperature), ECG and clinical laboratory assessments.   
Efficacy Assessments:  


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 11 of 59  
CONFIDENTIAL 
Efficacy will be assessed by measuring the final and baseline differences in 
fat content obtained from MRI and Fibroscan results.  
Duration of 
Participation 
Screening Phase: up to 42 days prior to enrolment 
Placebo run-in Phase: 2 weeks  
Treatment Phase: 12 weeks 
End-of-Study (EOS): After completion of 4 weeks after end of treatment 
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 > 
6.5-11%28 or on treatment with at least one  and no more than three 
of the following oral anti diabetic medications metformin, 
sulfonylurea, DPP-4 inhibitors, oral GLP-1 receptor agonists 
(semaglutide), SGLT-2 inhibitor, orThiazolidinediones (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 pregnancy test at study entry for females of childbearing 
potential. 
9. Females must have a negative urine pregnancy test result at 
screening, prior to the start of the run-in period, at initiation of active 
dosing and every 4 weeks till the end of the study. A negative urine 
and serum pregnancy test must be obtained prior to active dosing. 
Males and females of childbearing potential must use two methods 
of contraception, one of which must be a highly effective method 
from the time of screening to the last study visit (22 weeks).  
Highly effective methods include:  
o combined (estrogen and progestogen containing) hormonal 
contraception (oral, intravaginal or transdermal) associated 
with inhibition of ovulation  
o progestogen-only hormonal contraception (oral, injectable or 
implantable) associated with inhibition of ovulation 
o intrauterine device (IUD)  
o intrauterine hormone-releasing system (IUS)  
o bilateral tubal occlusion  
o vasectomised partner (is the sole sexual partner of the 
WOCBP participating in the trial)  
o sexual abstinence 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 12 of 59  
CONFIDENTIAL 
Acceptable methods include: 
Double barrier methods of contraception include male condoms 
plus spermicide, diaphragm with spermicide plus male condom, 
cervical cap with spermicide plus male condom. 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>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. 
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. 
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. 


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Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 13 of 59  
CONFIDENTIAL 
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 at least one and 
no  more than three of the following medications: metformin, 
sulfonylurea, DPP-4 inhibitors, oral GLP-1 receptor agonists 
(semaglutide), SGLT-2 inhibitors, or TZDs 
15. Fibrates and 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: 
x History of severe claustrophobia impacting ability to perform 
MRI during the study, even despite mild sedation/treatment 
with as anxiolytic. 
x Subjects with metal implants, devices, paramagnetic objects 
contained within the body and excessive or metal containing 
tattoos. 
x 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 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 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 14 of 59  
CONFIDENTIAL 
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-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 15 of 59  
CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
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 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
diastolic blood pressure 
ECG 
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 
ULN 
upper limit of normal 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 16 of 59  
CONFIDENTIAL 
WHO 
World Health Organization 
  
 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 17 of 59  
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 
manufacture sufficient insulin levels to overcome this resistance. This relative lack of insulin 
eventually leads to chronic hyperglycemia. 


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Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 18 of 59  
CONFIDENTIAL 
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. 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 19 of 59  
CONFIDENTIAL 
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.  


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 20 of 59  
CONFIDENTIAL 
 
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.  
 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 21 of 59  
CONFIDENTIAL 
2 STUDY OBJECTIVES 
2.1 Primary Objectives 
x To evaluate the safety of oral insulin in patients with nonalcoholic steatohepatitis 
(NASH) and type 2 DM. 
2.2 Secondary Objective 
x To assess whether oral insulin may be effective in reducing liver fat content and 
inflammation in patients with NASH and type 2 DM. 
 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 22 of 59  
CONFIDENTIAL 
3 INVESTIGATIONAL PLAN  
3.1 Overall Study Design and Plan 
This is an open, 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 40 
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 enrolment for 2 weeks, a treatment phase for 12 weeks 
and an end-of-study phase after completion of 4 weeks, after end of treatment.  
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, urine 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, ORMD-0801 morning 
treatment will be administered in clinic, 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.  
At Visit 3, urine and serum pregnancy test will be performed for females of childbearing 
potential. Additional urine serum pregnancy test will be performed for females of childbearing 
potential at visits 6, 7 and 8. At Visit 8, subjects will have HbA1c evaluations and MRI-PDFF 
performed. At Visits 3 and 8, a complete physical exam and fibroscan will be performed. 
The end of the 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 evaluation will be performed. Fasting blood glucose, fasting insulin, HbA1c,  


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
Page 23 of 59  
CONFIDENTIAL 
blood lipids and adiponectin levels will be measured. Urine serum pregnancy test will be 
performed for females of childbearing potential. 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) 
Screening process will take place at Visit 1, up to 42 days prior to enrolment. Screening activities 
will consist of the following: 
 
Visit 1 (up to week -6) 
x Informed consent 
x Medical history  
x Concomitant medication 
x Complete Physical examination (PE)  
x Weight and height  
x ECG 
x Vital signs (blood pressure, heart rate, oral temperature). Vital signs will be measured in 
the sitting position after at least 5 minutes of rest.  
x Urine pregnancy test 
x Females of non-childbearing potential FSH levels will be tested if results not available. 
x Clinical laboratory evaluations 
o Chemistry: Electrolytes, Blood Urea Nitrogen (BUN), international normalized 
ratio (INR), creatinine, glucose level, liver function tests (LFT) including 
transaminases (ALT, AST), albumin, and alkaline phosphatases, creatine 
phosphokinase (CPK), Bilirubin 
o Hematology: Complete blood count (CBC)  
o Thyroid Stimulating Hormone (TSH) 
o HbA1C 
o Blood lipids: Total cholesterol, LDL, HDL, Triglycerides 
o Viral serology:  HCV-Ab, HBsAg, HBcore-total, HBs Ab, anti-HIV Ab 
x CAP - Fibroscan  
x MRI-PDFF 
x 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; 


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Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
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CONFIDENTIAL 
• 
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. 
 
3.2.1 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. 
Subjects previously screen failed on eligibility criteria, may be re-screened after re-consenting at 
the discretion of the treating physician.    
3.3 Run-in Phase/Visit 2 (to week -2)  
The run-in phase will consist of 2 weeks period starting at visit (Visit 2) week -2  
3.3.1 Visit 2 (to week -2) 
x Concomitant medication 
x Weight 
x Morning placebo administration (run-in placebo) 
x Vital Signs 
x Urine pregnancy test 
x Fasting blood glucose and fasting Insulin 
x Self-monitored fasting morning blood glucose (finger-stick) recorded in the patient 
diaries 3 days per week in the morning. 
x Dispense 1 bottle of Placebo - Patients will take 2 capsules daily of Placebo in the 
morning, 30 to 45 minutes prior to breakfast and no later than 10 AM for 2 weeks. 
x AEs/SAEs assessmentAEs/SAEs assessment 
3.4 Treatment Phase (week 0) 
The Treatment Phase will consist of a treatment period of 12 weeks that will start at Visit 3 (week 
0) and outpatient Visits 3 (baseline) and visits at week 1, 2, 4, 8, and 12 (final visit).  
At each visit patients will have: 
x Concomitant medication 
x Weight 
x Morning treatment administration of oral ORMD-0801 insulin formulation  
x Medication Compliance check. 
x Urine pregnancy test at visit 3 prior to active dosing and at visits 6, 7, 8 and 9. 
x Serum pregnancy test at visit 3 prior to active dosing 


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Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
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CONFIDENTIAL 
x Vital signs (blood pressure, heart rate, oral temperature). Vital signs will be measured in 
the sitting position after at least 5 minutes of rest. 
x Self-monitored fasting morning blood glucose (finger-stick) of fasting blood 
x AEs/SAEs assessment 
 
3.4.1 Visits 3 (baseline), 6, 7, and 8 
x At Visits 3 (baseline), 6, 7, and 8, patients will have:  
x Clinical laboratory evaluations (chemistry, hematology) 
x Fasting blood glucose and insulin (also used for HOMA estimates)1  
x Adiponectin 
x Blood lipids: Total cholesterol, LDL, HDL, Triglycerides 
 
3.4.2 Visits 3 (baseline), 5, 6, 7, and 8 
x Return capsules - check compliance 
x At visit 3 and 5 - Dispense 1 bottle of ORMD-0801  
x At visits 6 and 7 – dispense 2 bottles of ORMD-0801 
x Patients will take 2 capsules daily of ORMD-0801 in the morning, 30 to 45 minutes prior 
to breakfast and no later than 10 AM for 12 weeks. 
 
3.4.3 Visits 3 and 8 
At Visits 3 and 8 patients will have: 
x Complete PE 
x Fibroscan 
 
3.4.4 Visit 8 
At visit 8 Patients will have: 
x HbA1C 
x MRI-PDFF 
3.5 End-of-Study (EOS) (Week 16)/Early Discontinuations  
The EOS Visit (Visit 9) will be conducted 4 weeks following the last scheduled treatment Visit. 
Patients will complete the following EOS evaluations: 
x Concomitant medication 
x Complete PE, only if the investigator deems it necessary. 
x Weight 
x ECG, only if the investigator deems it necessary. 
x Vital signs (blood pressure, heart rate, oral temperature) will be measured in the sitting 
position after at least 5 minutes of rest, only if the investigator deems it necessary.   
 
1 HOMA = The Homeostasis Model Assessment 


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Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
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CONFIDENTIAL 
x Clinical laboratory evaluations (chemistry, hematology) 
x Fasting blood glucose 
 
and fasting Insulin 
x Blood lipids: Total cholesterol, LDL, HDL, Triglycerides 
x Adiponectin 
x HbA1C 
x Urine pregnancy test 
x 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  
The patient 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 CRF’s. During the study, both fasting finger stick glucose and laboratory fasting plasma 
glucose will be obtained. Adverse events including hypoglycemia will be monitored from the self-
monitoring blood glucose diary and recorded in the CRF. 
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 
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 patients 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 


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Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
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CONFIDENTIAL 
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. 
 


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Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
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CONFIDENTIAL 
3.8 Schedule of Events 
Table 1 below describes the daily schedule of events from Screening Visit 1 through End of the Study Visit 9.   
 
Table 1: Daily Schedule of Events from Screening Through Visit 9 
Assessments 
Screening 
Placebo 
 
Treatment 
 
Un Scheduled 
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 
Un 
Scheduled  
9 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Collection of 
Demographics  
X 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
medication  
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Complete 
physical 
examination 
X 
 
X 
 
 
 
 
X 
 
(X1 ) 
Height and weight 
and BMI 
X 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urine pregnancy 
X 
X 
X 
 
 
X 
X 
X 
 
X 
Serum pregnancy 
 
 
X 
 
 
 
 
 
 
 
FSH3 
X 
 
 
 
 
 
 
 
 
 
Morning treatment 
in clinic  
 
X 
X 
X 
X 
X 
X 
X 
 
 


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Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
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CONFIDENTIAL 
Medication 
dispensing 
 
X 
X 
 
X 
X 
X 
 
 
 
Medication 
compliance check 
 
 
X 
X 
X 
X 
X 
X 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
(X1 ) 
Vital signs4 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X1 ) 
Clinical laboratory 
evaluations5 
X 
 
X 
 
 
X 
X 
X 
(X1 ) 
X 
Fasting blood 
glucose and 
fasting Insulin6 
 
X 
X 
 
 
X 
X 
X 
(X1 ) 
X 
Self-monitored 
fasting morning 
blood glucose7 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Adiponectin 
 
 
X 
 
 
X 
X 
X 
 
X 
HbA1C 
X 
 
 
 
 
 
 
X 
 
X 
Blood lipids: Total 
cholesterol, LDL, 
HDL, 
Triglycerides 
X 
 
X 
 
 
X 
X 
X 
 
X 
Fibroscan Test 
X 
 
X 
 
 
 
 
X 
 
 
MRI PDFF 
 
X 
 
 
 
 
 
 
X 
 
 
Viral serology8   
X 
 
 
 
 
 
 
 
 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
AE/SAE 
assessment9 
X 
X---------------------------------------------------------------------------------------------------------------> 
1Only if investigator deems necessary 
2Blood samples taken prior to dosing in clinic and snack provided after 30-45 minutes at V2, 3, 6, 7, and 83Vital signs (blood pressure, heart rate, oral temperature). Vital signs will be 
measured in the sitting position after at least 5 minutes of rest.  
3For females of non-childbearing potential, FSH levels will be tested if results are not available 
4Vital signs (blood pressure, heart rate, oral temperature). Vital signs will be measured in the sitting position after at least 5 minutes of rest. 
5Chemistry and hematology: electrolytes, Blood Urea Nitrogen (BUN), international normalized ratio (INR), creatinine, glucose, bilirubin, Liver Function Tests (LFTs) and Complete 
Blood Count (CBC) 
6Fasting blood glucose and insulin will be used to determine Homeostasis Model Assessment (HOMA) estimates. 


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Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
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7Self-monitoring (finger-stick) of fasting blood glucose will required 3 days weekly in the morning, before breakfast, and recorded in patient diaries. 
8HCV-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). 
9Adverse events will be collected throughout the study beginning from the time the patient signs the consent form until the EOS evaluations 
 
 
 


Oramed Ltd. 
 
Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
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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 > 6.5-11%28 or on treatment with at least one and no more 
than three of the following oral anti-diabetic medications metformin, sulfonylurea, DPP-
4 inhibitors, oral GLP-1 receptor agonists (semaglutide), SGLT-2 inhibitor or 
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 pregnancy test at study entry for females of childbearing potential. 
9. Females must have a negative urine pregnancy test result at screening, prior to the start 
of the run-in period, at initiation of active dosing and every 4 weeks following till the 
end of the study. A negative urine and serum pregnancy test must be obtained prior to 
active dosing. Males and females of childbearing potential must use two methods of 
contraception , one of which must be  a highly effective method from the time of 
screening to the last dosing study visit (22 weeks).  
Highly effective methods include:  
o combined (estrogen and progestogen containing) hormonal contraception (oral, 
intravaginal or transdermal) associated with inhibition of ovulation  
o progestogen-only hormonal contraception (oral, injectable or implantable) 
associated with inhibition of ovulation 
o intrauterine device (IUD)  
o intrauterine hormone-releasing system (IUS)  
o bilateral tubal occlusion  
Acceptable methods include: 
Double barrier methods of contraception include male condoms plus spermicide, 
diaphragm with spermicide plus male condom, cervical cap with spermicide plus male 
condom. 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>40), b) 
who are surgically menopausal (surgical sterility defined by tubal occlusion, bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy). 


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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. 
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 
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 at least one and no more than three 
of the following medications: metformin, sulfonylurea, DPP-4 inhibitors, oral GLP-1 
receptor agonists (semaglutide), SGLT-2 inhibitors, or TZDs 
15.  Fibrates and 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. 


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22. Subjects meeting criteria for contraindication for MRI – including the following: 
x History of severe claustrophobia impacting ability to perform MRI during the 
study, even despite mild sedation/treatment with as anxiolytic. 
x Subjects with metal implants, devices, paramagnetic objects contained within the 
body and excessive or metal containing tattoos. 
x 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 
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. 


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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 CRF.  
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 
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. 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 a 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 IEC/IRB and the Competent Authority 
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. 
 
 
 


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Protocol No.: ORA-D-N01B 
Phase 2 Clinical Study 
Final; Version 1.3; Dated: March 30, 2021 
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5 STUDY TREATMENT (IMP) 
5.1 Description of Investigational Drug 
ORMD-0801 
Dosage form: 2 soft gelatin capsules per dose 
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. 
 
5.1.1 Packaging and Labeling 
This study is an open-label study. All study medication will be shipped in bulk. The 
Investigational Site pharmacist will be responsible for dispensing the appropriate treatment 
period IMP.   
Study medication will be dispensed to the site with instructions for when treatment can be 
administered. Medication containers and any unused capsules will be retained at the study site 
after the treatment phase of the study is complete. 
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: For Clinical Trial Use Only.  
 Name of Sponsor  
A separate label with the identical information will be provided with the label on the package 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 in the original packaging 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 temperature, as well as the occurrence of excessive humidity, should be 
documented, and the Sponsor should be notified.  
IMP should be handled and disposed, using proper procedures as defined by Investigational Site 
standard operating procedures (SOPs) for Investigational Drugs. 


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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 IMP Administration 
5.2.1 Visit 3 to Visit 8 
The treatment regimen (Active) will consist of a soft gelatin capsule containing 8 mg insulin, and 
75 mg SBTI. Patients will take 2 capsules daily in the morning 30 to 45 minutes prior to 
breakfast and no later than 10AM. At Visit 2 (placebo) and at Visits 3, 6, 7, 8 (Active) capsules 
will be administered in the clinic. Blood samples and weights will be taken prior to dosing, after 
which the patients will take the drug, so he\she will be provided with a small snack to eat after 30 
to 45 minutes. 
5.3 Dose Modifications 
This study does not include any planned dose modifications. From Visit 3 to Visit 8, subjects 
will daily take the IMP orally at the assigned dose level unless discontinuation criteria as defined 
in Section 4.3 are met. 
5.4 Measuring Subject Compliance 
All treatments on visit days will be administered in the, Clinical Research Unit. Compliance for 
oral capsules (Visit 3 to Visit 8) will be assessed through a count of unused study medication 
during clinic. 
5.5 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 CRF. 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. 


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5.6 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 CRF. 
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.   
5.7 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. Subjects 
must refrain from tobacco or nicotine use throughout the study. 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. 
 
 
 


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Protocol No.: ORA-D-N01B 
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6 STUDY PROCEDURES AND ASSESSMENTS 
6.1 Informed Consent 
According to the ICH guideline for GCP (E6) and all institutional local and state 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 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 as liver function tests. 
6.4 Efficacy Assessments 
Fat content in the liver will be assessed by measuring the final and baseline differences in the 
MRI and Fibroscan results.  
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). Height will be measured at Screening only with the subject 
wearing no shoes, coats, jewelry and other accessories. 
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 


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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. At the 
Investigator’s discretion, an additional physical exam may be performed during the end of the 
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. At the Investigator’s discretion, an additional 
ECG may be performed at the end of the 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 (Federicia’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. 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: 
x Hematology 
o Complete blood count (CBC)  
x Serum Chemistry 
o Electrolytes  
o BUN 
o INR 
o Creatinine 
o Glucose level  
o Liver function tests (LFT) including transaminases (ALT, AST), albumin, and alkaline 
phosphatases, creatine phosphokinase (CPK), Bilirubin 
o Urine/serum pregnancy tests 
o TSH 
o FSH test if necessary 


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6.5.5.2 Additional Bloodwork 
In addition to the blood tests listed above, viral serology (HCV-Ab, HBsAg, HBcore-total, HBs 
Ab, anti-HIV Ab), HbA1C, adiponectin and TSH will be measured according to Table 1.  
6.5.6 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. 
6.5.7 Pregnancy Test 
A urine pregnancy test will be performed for women in child bearing years at Screening (Visit 
1), Visit 2, Visit 3 and at Visits 6, 7, 8 and 9. A serum pregnancy test will be performed at Visit 
3. 
FSH testing 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. 
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 CRF.  
All medications and supplements (other than IMP) taken by the subject after Visit 2 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 CRF. 


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7 ADVERSE EVENTS AND SAFETY REPORTING 
Information about all adverse events, whether volunteered by the patient, recorded in the 
patient’s diary, 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 CRF 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 CRF. 
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: 
x Results in death. 
x Is life-threatening.  


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x Requires or prolongs existing hospitalization.  
x Results in persistent or significant disability or incapacity. 
x Is a congenital anomaly or birth defect. 
x 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:  
x Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition. 
x 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. 
x 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 CRF 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 
CRF. Adverse event documentation should include the following information: 
x Standard medical terminology for the AE  
x Description of adverse event 
x Date and time of onset 
x Date and time of resolution of the adverse event  
x Whether or not the event is ongoing 
x Severity of the event  
x Relationship between the adverse event and the investigational product 
x Description of any actions taken (e.g., medications, treatments) 
x Outcome of the AE 
x 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 CRF 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 CRF. Copies of the SAE CRF pages or an SAE 
listing generated based on the CRF 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 CRF: 
x 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); 
x 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; 
x 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; 
x Whether the event is serious (per definition in Section 7.4), and if so, the reason it is 
considered serious; 
x Severity of AE (per definition in Section 7.7); 
x Assessment of the attributability of the AE to the IMP [per definition in Section 7.5];  
x Whether the event is expected (per definition in Section 7.8); 
x 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); 
x 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 or delegate 
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. The Sponsor contact information is as follows: 
Oramed Ltd. 
Mamila 20 
 
Jerusalem, 9414908, Israel  
Contact person at Oramed:  
Sharon Perles 
Email: sharon@oramed.com  
Phone: +972-50-8312511 
 
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. 
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 CRF. 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. 


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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 
therapeutic interventions. 
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 CRF. 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 


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with the risk information described in the general investigational plan or elsewhere in the 
current application, as amended. 
7.9 Assessment of Adverse Event Outcome 
Outcome of AEs will be defined according to ICH Topic E2B, ICH Guideline. 
x Recovered/Resolved:  The subject has recovered fully from the AE without any 
remaining effects or impairment. 
x Recovered/Resolved with Sequelae:  The subject has recovered, but with an after effect 
possibly due to disease or treatment. 
x Not Recovered/Not Resolved:  The condition is still present. 
x Fatal:  Fatal should only be used when death is possibly related to the AE. 
x 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-N01B. Additional details will be provided in the statistical 
analysis plan. 
8.1 Sample Size 
Up to 40 patients with NASH and Type 2 DM will be enrolled in this multi-center exploratory 
study. Approximately 20 patients will be enrolled at 2 sites in Israel, approximately 10 subjects 
will be enrolled at 3 or 4 sites in Belgium and 10 patients at 2 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 2 capsules daily in the morning 30 to 45 minutes prior to breakfast. 
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 (MRI-
Proton Density Fat Fraction) images and Fibroscan including CAP. 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 were received treatment were included in the Intention to 
Treat population. 
Per Protocol: All subjects who completed all study visits without any major protocol deviations 
and took between 80% and 120% of Investigational Product were included in the Per Protocol 
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 period. 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.   


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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 
treatment-emergent SAEs.  
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 3 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 
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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 
will not be excluded from the listings. Influential cases will be handled in an appropriate 
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9 DATA HANDLING AND RECORD KEEPING 
9.1 Data Quality Assurance 
Site visits will be conducted to verify the qualifications of each Investigator, inspect the study 
center facilities, and inform the Investigators of their responsibilities and the procedures for 
ensuring adequate and correct documentation. 
Investigator training will be held to introduce Investigators and their study staff to the clinical 
protocol, CRFs, study procedures, regulatory requirements, and use of the study assessments. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
participant. All information recorded on the CRFs for this study must be consistent with the 
patient's source documentation (i.e., medical records). 
9.2 Case Report Forms  
CRF’s are provided for each patient. The site will be trained in the use and completion of the 
CRFs. All forms must be filled out as instructed by appropriate personnel who have 
undergone CRF training. Data will be entered into the CRF as information becomes available 
on a visit-by-visit basis. All data recorded on the CRF’s should be supported by source 
documentation including completed patient diaries which will act as the source for this study.  
Only incidences where the data is only recorded once in the CRF will the CRF act as source 
and additional supporting source documentation is not warranted. The study completion 
information page of the CRF must be signed and dated by the Principal Investigator. 
All CRF corrections are to be made by an Investigator or other study site personnel. The 
Principal Investigator or Sub-Investigator must authorize changes to the recorded safety and 
efficacy data, and this authorization must be documented in the source documents. 
The Investigator or Sub-Investigator will sign and date the indicated places of the CRF. This 
signature will indicate that thorough inspection of the data therein has been made and will 
thereby certify the contents of the form.  Documentation of procedures and visits will also be 
maintained in source documents and signed by the Investigator or Sub-Investigator.  
CRFs will be scanned and later mailed to the sponsor in Israel.  
9.3 Source Documents 
The Investigator will permit study-related monitoring, audits by or on behalf of the Sponsor, 
IRB/Independent Ethics Committee (IEC) review and regulatory inspections providing direct 
access to source data documents. Source documents are original records in which raw data are 
first recorded. These may be office/clinic/hospital records, charts, diaries, x-rays, laboratory 
results, printouts, pharmacy records, care records, and completed scales for each study 
participant. Source documents should be kept in a secure area with limited access. All source 
documents must be accurate, clear, unambiguous, permanent and capable of being audited. 
They should be made using a permanent form of recording (ink, typing, printing, optical disc 
etc). They should not be obscured by correcting fluid or have temporary attachments (such as 
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Source documents that are computer generated and stored electronically must be printed, signed 
and dated by the Investigator. 
Source data for patients registered to the study should indicate the date the informed consent 
form (ICF) was signed, clinical protocol number and title, treatment number, and evidence that 
inclusion/exclusion criteria have been met. 
9.4 Direct Access to Source Data and Study Audits 
Site monitors will perform onsite visits to review protocol compliance, compare CRFs and 
individual patient's source records, assess drug accountability, check for CRF completeness 
and clarity, and ensure that the study is being conducted according to pertinent regulatory 
requirements. CRF entries will be verified with source documentation. The review of 
medical records will be performed in a manner to ensure that patient confidentiality is 
maintained. 
Representatives of the IRB, FDA, and/or the Sponsor may also wish to carry out such data 
checks during onsite audit inspections. Direct access to source data will be required with due 
consideration to data protection and medical confidentiality. 
9.5 Study Monitoring 
Monitoring of the study is the responsibility of the Sponsor and may be delegated to a contract 
research organization (CRO) or a contract monitor. The study monitor will advise the 
Investigator regarding the practical conduct of the study and maintaining compliance with the 
protocol, Good Clinical Practice (GCP) and all applicable regulatory requirements. 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a study monitor 
will review the protocol and CRFs with the Investigator and his staff. 
Throughout the course of the study, the study monitor will oversee the conduct and the 
progress of the study by frequent contacts with the Investigator. This will include telephone 
calls and on-site visits. During the on-site visits, the CRF will be reviewed for completeness 
with corresponding source documents. As part of the data audit, source documents will be 
made available for review by the study monitor. The study monitor will also perform drug 
accountability checks and will periodically request review of the Investigator study file to 
ensure completeness of documentation in all respects of clinical study conduct. 
Periodically, some or all of the facilities used in the study (e.g. local laboratory, pharmacy) 
may be reviewed. Monitoring visits will be arranged in advance with site personnel at a 
mutually acceptable time. Sufficient time must be allowed by the site personnel for the 
monitor to review CRFs and relevant source documents. The Investigator should be 
available to answer questions or resolve data clarifications. The Investigator or appointed 
delegate will receive the study monitor during these on-site visits; cooperate in providing the 
documents for inspection and respond to inquiries. 
The Investigator will ensure that the study participants are aware of and consent that 
personal information may be scrutinized during the data verification process as part of study-
related monitoring and auditing by properly authorized persons associated with Oramed or 
inspection by domestic and/or foreign regulatory authority(ies). However, participation and 


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personal information should be treated as strictly confidential to the extent that the 
applicable law permits, and not be publicly available. 
9.6 Study Close-Out 
Upon completion of the study (defined by all patients have completed all follow-up visits, all 
CRFs are complete, and all queries have been resolved), the study monitor will notify the sites 
accordingly, and a study closeout visit will be performed. The study monitor will ensure that 
the Investigator’s regulatory files are up to date and complete, and that any outstanding issues 
from previous visits have been resolved. Other issues to be reviewed at the closeout visit 
include discussing retention of study files, possibility of site audits, publication policy, and 
notifying the IRB of study closure. 
9.7 Archiving Study Records 
Study documentation must be retained for a minimum of two years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
until at least two years have elapsed since the formal discontinuation of clinical development of 
the investigational product. However, these documents may be retained for a longer period if 
required by the applicable legal requirements. 
 
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 
or not the subject (for whom the departure from protocol was affected) is to continue in the 
study. The CRF 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 EU Clinical trials - Directive 
2001/20/EC. 
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 case report form (CRF).  
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: 
x IRB for review and approval/favorable opinion. 
x The Sponsor via appropriate designees.
x 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 prior to performing any study-related procedures.  Disclosure of subject 


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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 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: 
x Subject files, containing the completed CRFs, supporting source documentation from the 
medical record, including laboratory data, and the signed ICF;  
x 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  
x 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 
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. 


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11.5 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 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. 
12.2 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. 
12.3 Disclosure and Confidentiality 
By signing the protocol, the Investigator agrees to keep all information provided by the Sponsor 
and Julius Clinical in strict confidence and to request similar confidentiality from his/her staff 
and the IRB.  Study documents provided by the Sponsor and Julius Clinical (protocols, IBs, 
CRFs, and other material) will be stored appropriately to ensure their confidentiality. The 
information provided by the Sponsor and Julius Clinical to the Investigator may not be disclosed 
to others without direct written authorization from the Sponsor and Julius Clinical, except to the 
extent necessary to obtain informed consent from subjects who wish to participate in the study. 
 
 


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