Conditions: Type 2 Diabetes Mellitus
Keywords: Oral Insulin DM T2 (Diabetes Mellitus Type 2)
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 31
Healthy volunteers: no

Brief summary:
This is a four-way crossover (non-parallel) study with each subject receiving three of the four arms. The study will enroll approximately 30 adult subjects with T2DM from age 20 to 75 inclusive.

Following a 7-10 day Screening period, eligible subjects will enter a 3-day single-blind placebo run-in. On Day 4, each subject will be randomized to a treatment sequence that will include three treatment assignments for each of three treatment Periods according to the randomization scheme.

Detailed description:
Following the screening, eligible subjects entered a 3-day, single-blind placebo run-in. On Day 4, each subject was randomized to a treatment sequence that included three treatment assignments for each of three treatment Periods according to the randomization scheme.

Pre-assignment Details The number of participants receiving each Intervention, in each Period, is reported.

Subjects received the randomized treatment from Day 4 through Day 8. There was a 24-hour single-blind placebo washout on Day 9. Each subject received placebo for one of the three treatment periods. Each subject also received 1 of the 3 active doses randomly in each of the two other treatment periods respectively. The dosing order is random.

Arms:
arm 1: Placebo (fish oil) arm 2: Dose 1 ORMD-0801 (qd) arm 3: Dose 2 ORMD-0801 (bid) arm 4: Dose 3 ORMD-0801 (tid)

Interventions: intervention 1: ORMD-0801 (qd) intervention 2: ORMD-0801 (bid) intervention 3: ORMD-0801 (tid) intervention 4: Placebo
Intervention descriptions: intervention 1: Dose 1 = ORMD-0801 (qd) intervention 2: Dose 2 = ORMD-0801 (bid) intervention 3: Dose 3 = ORMD-0801 (tid) intervention 4: fish oil placebo

Protocol document:
Prot_000.pdf: 
Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 1 
CONFIDENTIAL 
 
Clinical Study Protocol: ORA-D-012 
Study Title: 
A Phase 2a, Randomized, Double-Blind, Double-Dummy, Placebo-
Controlled, 3-Way Crossover Study to Compare Safety, Efficacy 
and Pharmacodynamics of Single and Multiple Doses of ORMD-
0801 or Placebo in Adult Subjects with Type 2 Diabetes Mellitus 
Protocol Number: 
ORA-D-012 
Study Phase:  
Phase 2a 
Principal 
Investigator: 
Joel M. Neutel, M.D. 
Orange County Research Center (OCRC) 
14351 Myford Rd., Suite B, Tustin, CA 92780 
Sponsor: 
Oramed Ltd. 
Hi-Tech Park 2/5 Givat Ram 
PO Box 39098 
Jerusalem, 91390, Israel 
Name of Sponsor 
Signatory: 
Miriam Kidron, PhD 
Chief Scientific Officer and Director 
Oramed Ltd. 
Protocol Version: 
1 
Date of Version: 
August 23, 2016 
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. 


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Protocol No. ORA-D-012 
Phase 2a Clinical Study 
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CONFIDENTIAL 
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE 
The undersigned has reviewed and approved Protocol No. ORA-D-012 for issuance: 
 
Miriam Kidron, PhD 
Chief Scientific Officer and Director 
Oramed Ltd. 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 




Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 3 
CONFIDENTIAL 
INVESTIGATOR SIGNATURE PAGE 
I have read the attached protocol and agree that it contains all the necessary details for 
performing the study. 
I will provide copies of the protocol and of the Investigator’s Brochure (IB), which was 
furnished to me by the Sponsor, to all members of the study team responsible to me who 
participate in the study.  I will discuss this material with them to assure that they are fully 
informed regarding the study treatment, including the potential risks and side effects, and the 
conduct of the study. 
Once the protocol has been approved by the Institutional Review Board (IRB), I will not modify 
this protocol without obtaining the prior approval of the Sponsor and of the IRB.  I will submit 
the protocol modifications and/or any informed consent form (ICF) modifications to the Sponsor 
and the IRB, and approval will be obtained before any modifications are implemented. 
I understand the protocol and will work according to it, the principles of Good Clinical Practice 
[GCP; current International Council for Harmonisation (ICH) guidelines], and the Declaration of 
Helsinki (1964) including all amendments up to and including the October 2013 revision. 
 
Joel M. Neutel, M.D. 
Principal Investigator 
Orange County Research Center 
 
 
 
Signature 
 Date 
 
 
 




Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 4 
CONFIDENTIAL 
SYNOPSIS 
 
Title 
A Phase 2a, Randomized, Double-Blind, Double-Dummy, Placebo-
Controlled, 3-Way Crossover Study to Compare Safety, Efficacy and 
Pharmacodynamics of Single and Multiple Doses of ORMD-0801 or 
Placebo in Adult Subjects with Type 2 Diabetes Mellitus 
Indication 
Type 2 Diabetes Mellitus (T2DM) 
Clinical Phase 
Phase 2a 
Study Treatment 
Dose 
Dosage Regimen 
Formulation 
Mode of 
Administration 
ORMD-0801 
460 IU (16 mg) total 
Once daily, twice daily, or three times daily 
Soft gel capsules, 2 capsules per dose 
Oral 
Primary Objective 
 To compare pre-treatment (Day 3) to end of treatment (Day 8) 
24-hour CGM glucose for single and multiple doses of ORMD-
0801 vs placebo. 
 To evaluate safety parameters for single and multiple doses of 
ORMD-0801 vs placebo.  
Secondary 
Objectives 
 To compare pre-treatment (Day 3) to end of treatment (Day 8) 
mean daytime CGM glucose for single and multiple doses of 
ORMD-0801 vs placebo. 
 To compare pre-treatment (Day 3) to end of treatment (Day 8) 
mean nighttime CGM glucose for single and multiple doses of 
ORMD-0801 vs placebo. 
 To compare pre-treatment (Day 3) to post-treatment washout 
(Day 9) 24-hour CGM glucose for single and multiple doses of 
ORMD-0801 vs placebo. 
 To compare post-prandial glucose measurements for single and 
multiple doses of ORMD-0801 vs placebo. 
 To compare pre-treatment (Day 3) to end of treatment (Day 8) 
insulin pharmacokinetics (PK) for single and multiple doses of 
ORMD-0801 vs placebo. 
 To compare pre-treatment (Day 3) to end of treatment (Day 8) 
C-peptide pharmacodynamics (PD) for single and multiple 
doses of ORMD-0801 vs placebo. 
 To compare defined events of hypoglycemia for single and 
multiple doses of ORMD-0801 vs placebo. 
Total Sample Size 
Approximately 30 adult male and female subjects between the ages of 
20 and 75 inclusive with T2DM. 
Study Design 
Following Screening, eligible subjects will enter a 3-day single-blind 
placebo run-in. On Day 4, each subject will be randomized to a 
treatment sequence that will include three treatment assignments for 


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each of three treatment Periods according to the randomization scheme. 
All subjects will receive placebo plus two of the following:  ORMD-
0801 460 IU qd, ORMD-0801 bid, or ORMD-0801 tid.  Subjects will 
receive the randomized treatment from Day 4 through Day 8. A 24-
hour single-blind placebo washout will be done on Day 9.  For all 
treatment Periods, pre-treatment CGM data will be collected for 
approximately 36 hours prior to treatment (Days 1-3). The cannula will 
be changed and the monitor will remain in place until the morning of 
Day 10. Blood samples for PD analysis will be taken pre-treatment 
(Day 3) and at end of treatment (Day 8) to check for concentrations of 
insulin and C-peptide in the blood.  In addition, adverse events, clinical 
laboratory values, vital signs, and ECGs will be evaluated periodically 
for safety. Subjects will be discharged on the morning of Day 10. Each 
treatment Period will be separated by a 2-week washout. A final 
follow-up visit will be performed 1 week after the end of the third 
treatment Period.  
Summary of 
Assessments 
Safety will be verified by monitoring adverse events, clinical 
laboratory values, vital signs, physical examinations, and ECG. 
CGM Monitoring will be used throughout the entire treatment period 
to compare pre-treatment, treatment, and post-treatment glucose levels, 
as well as post-prandial glucose. 
Pharmacokinetics/Pharmacodynamics will be used to compare pre-
treatment and post-treatment C-peptide and insulin levels. 
Duration of 
Participation 
Subjects will be evaluated for participation in the study during a 7-10 
day Screening period. The planned length of participation is about 65 
days (from Visit 2 through Visit 3). During each Visit 2 treatment 
Period, the subjects will be confined to the unit for 8 nights from 
check-in on the evening of Day 2 through completion of the post-
treatment procedures on the morning of Day 10. 
Subject Selection 
Criteria 
This study will enroll T2DM subjects with an HbA1c ≥7.5% and 
≤10.5%, who are taking metformin only, metformin in addition to 
sulfonylurea, metformin in addition to TZD, metformin in addition to 
an SGLT-2 inhibitor, or metformin in addition to a DPP-4 inhibitor 
with all treatment regimens stable for a minimum of 8 weeks prior to 
Visit 2/Period 1/Day 1. 
Statistical Methods Pharmacokinetics/Pharmacodynamics (PK/PD) 
The PK/PD analysis will be conducted using model-independent 
methods and will be based on plasma concentrations of insulin and C-
peptide. 
Continuous Glucose Monitoring 
The placebo adjusted change in means will be analyzed using an 
Analysis of Variance (ANOVA) with treatment as the main effect to 


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determine whether multiple doses a day has an effect on the CGM 
parameters. 
The ratios of the placebo adjusted change in means between the active 
treatments within each subject will also be derived to estimate the 
magnitude of the dose response. 
Summary statistics will be presented for both the placebo adjusted 
change in means and the ratios of the placebo adjusted change in 
means. Analysis results will be presented for the change in means. 
Safety 
All safety parameters will be summarized and listed using descriptive 
statistics. 


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Table of Contents 
TITLE PAGE .............................................................................................................................1 
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE ..................................................2 
INVESTIGATOR SIGNATURE PAGE ...................................................................................3 
SYNOPSIS .................................................................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................11 
1 
INTRODUCTION ...........................................................................................................13 
2 
STUDY OBJECTIVES ....................................................................................................15 
2.1 
Primary Objectives.................................................................................................15 
2.2 
Secondary Objectives.............................................................................................15 
3 
INVESTIGATIONAL PLAN ..........................................................................................15 
3.1 
Overall Study Design and Plan ..............................................................................15 
3.2 
Screening (7 to 10 Days prior to Visit 2) ...............................................................16 
3.2.1 
Screen Failure ..............................................................................................17 
3.3 
Visit 2 (Treatment Periods 1, 2, and 3) ..................................................................17 
3.3.1 
Period 1 ........................................................................................................17 
3.3.1.1 
Day 1 ..................................................................................................17 
3.3.1.2 
Day 2 ..................................................................................................18 
3.3.1.3 
Day 3 ..................................................................................................18 
3.3.1.4 
Day 4 ..................................................................................................19 
3.3.1.5 
Days 5-7 .............................................................................................19 
3.3.1.6 
Day 8 ..................................................................................................20 
3.3.1.7 
Day 9 ..................................................................................................20 
3.3.1.8 
Day 10 ................................................................................................21 
3.3.2 
Period 2 ........................................................................................................21 
3.3.2.1 
Day 1 ..................................................................................................21 
3.3.2.2 
Day 2 ..................................................................................................21 
3.3.2.3 
Day 3 ..................................................................................................22 
3.3.2.4 
Day 4 ..................................................................................................23 
3.3.2.5 
Days 5-7 .............................................................................................23 
3.3.2.6 
Day 8 ..................................................................................................23 
3.3.2.7 
Day 9 ..................................................................................................24 
3.3.2.8 
Day 10 ................................................................................................24 
3.3.3 
Period 3 ........................................................................................................25 
3.3.3.1 
Day 1 ..................................................................................................25 
3.3.3.2 
Day 2 ..................................................................................................25 
3.3.3.3 
Day 3 ..................................................................................................26 
3.3.3.4 
Day 4 ..................................................................................................26 


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3.3.3.5 
Days 5-7 .............................................................................................27 
3.3.3.6 
Day 8 ..................................................................................................27 
3.3.3.7 
Day 9 ..................................................................................................28 
3.3.3.8 
Day 10 ................................................................................................28 
3.4 
Follow-up Visit (Visit 3, 7 to 9 Days after the end of Visit 2, Period 3) ...............28 
3.5 
Early Withdrawal (EW) .........................................................................................29 
3.6 
Schedule of Events .................................................................................................29 
4 
STUDY SUBJECT SELECTION....................................................................................32 
4.1 
Inclusion Criteria ...................................................................................................32 
4.2 
Exclusion Criteria ..................................................................................................33 
4.3 
Subject and Trial Discontinuation .........................................................................35 
5 
STUDY TREATMENT ...................................................................................................37 
5.1 
Description of Investigational Drug.......................................................................37 
5.1.1 
Packaging and Labeling ...............................................................................37 
5.1.2 
Storage and Handling ...................................................................................38 
5.2 
Randomization .......................................................................................................38 
5.3 
Study Treatment Administration............................................................................38 
5.3.1 
Study Treatment Periods ..............................................................................38 
5.3.1.1 
Single-Blind Placebo Administration ................................................38 
5.3.1.2 
Double-Blind Treatment Administration ...........................................39 
5.4 
Dose Modifications ................................................................................................39 
5.5 
Measuring Subject Compliance .............................................................................39 
5.5.1 
Study Treatment Periods 1 and 2 .................................................................39 
5.6 
Drug Accountability...............................................................................................39 
5.7 
Concomitant Medications and Supplements ..........................................................40 
5.8 
Dietary Restrictions ...............................................................................................40 
6 
STUDY PROCEDURES AND ASSESSMENTS ...........................................................42 
6.1 
Informed Consent...................................................................................................42 
6.2 
Medical History and Prior Medications .................................................................42 
6.3 
Safety Assessments ................................................................................................42 
6.3.1 
Weight and Height .......................................................................................42 
6.3.2 
Vital Signs ....................................................................................................42 
6.3.3 
Physical Examination...................................................................................42 
6.3.4 
12-Lead ECG ...............................................................................................42 
6.3.5 
Clinical Laboratory Tests .............................................................................43 
6.3.5.1 
Clinical Safety Labs ...........................................................................43 
6.3.5.2 
Pregnancy Test ...................................................................................44 
6.3.5.3 
Additional Screening Bloodwork ......................................................44 


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6.3.5.1 
Drugs of Abuse and Breathalyzer ......................................................44 
6.4 
Efficacy Assessments.............................................................................................44 
6.4.1 
Continuous Glucose Monitors (CGM).........................................................44 
6.5 
Pharmacokinetic/Pharmacodynamic Assessments ................................................45 
6.6 
Review and Documentation of Medications and Supplements .............................45 
7 
ADVERSE EVENTS AND SAFETY REPORTING......................................................46 
7.1 
Safety and Tolerability Assessments .....................................................................46 
7.2 
Definition of Adverse Event ..................................................................................46 
7.3 
Definition of Serious Adverse Event .....................................................................46 
7.3.1 
Adverse Events of Hypoglycemia ...............................................................47 
7.4 
Eliciting and Reporting of Adverse Events ...........................................................47 
7.4.1 
Routine Reporting of Adverse Events .........................................................47 
7.4.2 
Reporting of Serious Adverse Events, Including Death ..............................48 
7.5 
Causality Assessment of Adverse Events ..............................................................50 
7.5.1 
Potential Adverse Events Associated with ORMD-0801 ............................50 
7.6 
Adverse Event Severity Assessment ......................................................................51 
7.7 
Expectedness of Adverse Event .............................................................................51 
7.8 
Assessment of Adverse Event Outcome ................................................................51 
7.9 
Clinical Findings ....................................................................................................52 
8 
STATISTICAL METHODS ............................................................................................52 
8.1 
Sample Size ............................................................................................................52 
8.2 
Pharmacokinetic/Pharmacodynamic Evaluation ...................................................52 
8.3 
Continuous Glucose Monitor Evaluation...............................................................52 
8.4 
Safety Evaluation ...................................................................................................53 
8.4.1 
Safety Population .........................................................................................53 
8.4.2 
Adverse Events ............................................................................................53 
8.4.3 
Laboratory Evaluations ................................................................................54 
8.4.4 
Vital Signs ....................................................................................................54 
8.4.5 
12-lead ECG.................................................................................................54 
8.4.6 
Physical Examination...................................................................................54 
8.4.7 
Prior and Concomitant Medications and Supplements ................................54 
8.4.8 
Handling of Missing, Unused, or Spurious Data .........................................55 
9 
DATA MANAGEMENT.................................................................................................56 
9.1 
Data Collection ......................................................................................................56 
9.2 
Electronic Data Capture .........................................................................................56 
9.3 
Quality Assurance and Database Lock ..................................................................56 
10 AMENDMENTS/MODIFICATIONS OF THIS PROTOCOL.......................................56 
11 INVESTIGATOR OBLIGATIONS ................................................................................57 


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11.1 
Regulatory Documentation ....................................................................................57 
11.1 
Protection of Human Subjects ...............................................................................57 
11.1.1 
Declaration of Helsinki ................................................................................57 
11.1.2 
Good Clinical Practice and Regulatory Compliance ...................................57 
11.1.3 
Institutional Review Board ..........................................................................57 
11.1.4 
Subject Informed Consent............................................................................58 
11.2 
Subject Confidentiality ..........................................................................................59 
11.3 
Case Report Forms .................................................................................................59 
11.4 
Source Documentation ...........................................................................................59 
11.5 
Retention of Records..............................................................................................59 
11.6 
Clinical Study Report .............................................................................................60 
12 STUDY ADMINISTRATION.........................................................................................60 
12.1 
Study Monitoring ...................................................................................................60 
12.2 
On-Site Audits .......................................................................................................61 
12.3 
Data Quality Assurance .........................................................................................61 
12.4 
Publication Policy ..................................................................................................61 
12.5 
Disclosure and Confidentiality ..............................................................................62 
13 REFERENCES ................................................................................................................63 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
 
adverse event 
ALT  
alanine aminotransferase 
AST 
 
aspartate aminotransferase 
AUC  
area under the curve 
BP 
 
blood pressure 
BUN  
blood urea nitrogen 
CFR 
 
Code of Federal Regulations 
CGM  
Continuous glucose monitoring 
CRF 
 
case report form 
CRO  
contract research organization 
CRU  
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP  
diastolic blood pressure 
ECG  
electrocardiogram 
EDC  
electronic data capture 
EDTA  
ethylenediaminetetraacetic acid 
EW 
 
early withdrawal 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
GGT  
gamma-glutamyltransferase 
GI 
 
gastrointestinal 
GLP-1  
glucagon-like peptide 1 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
 
Human Immunodeficiency Virus 
HR 
 
heart rate 
IB 
 
Investigator's Brochure 
ICF 
 
informed consent form 
ICH 
 
International Council for Harmonization 
IND 
 
Investigational New Drug application 
IRB 
 
Institutional Review Board 
IUD 
 
intrauterine device 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
 
Pharmacodynamic 
PI 
 
Principal Investigator 
PK 
 
Pharmacokinetic 
SAE 
 
serious adverse event 
SBP 
 
systolic blood pressure 
SBTI  
soybean trypsin inhibitor 
SOP 
 
standard operating procedure 
T2DM  
Type 2 diabetes mellitus 
TEAE  
treatment-emergent adverse event 
TSH 
 
thyroid stimulating hormone 
ULN  
upper limit of normal 
WCBP  
woman of childbearing potential 


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WHO  
World Health Organization 


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1 INTRODUCTION 
Diabetes mellitus is a chronic metabolic disorder that has reached epidemic proportions in the 
United States, affecting almost 8% of the U.S. population in 2007, and worldwide (Centers for 
Disease Control and Prevention, 2008). Diabetes mellitus is defined by hyperglycemia (increased 
concentration of glucose in the blood) caused by defective insulin secretion (type 1), resistance 
to insulin action (type 2), or a combination of both. Diabetes mellitus leads to an increased risk 
of microvascular damage (retinopathy, nephropathy and neuropathy), reduced life expectancy, 
increased risk of macrovascular complications (ischemic heart disease, stroke, and peripheral 
vascular disease), and diminished quality of life. This illness requires continuing medical care 
and patient self-management and education to prevent acute complications and to reduce the risk 
of long-term complications (American Diabetes Association, 2009). 
The World Health Organization has established diagnosis criteria for type 2 diabetes mellitus 
(T2DM) of fasting plasma glucose greater than or equal to 126 mg/dL (7.0 mmol/L), plasma 
glucose greater than or equal to 200 mg/dL (11.1 mmol/L) at 2 hours following ingestion of 75 g 
anhydrous glucose in an oral glucose tolerance test, or random plasma glucose greater than 200 
mg/dL (11.1 mmol/L) in a person with symptoms of diabetes (World Health Organization, 
2006). The treatment goal for patients with this disease is long-term glycemic control (over both 
fasting and non-fasting blood glucose levels), which has been demonstrated in both type 1 and 
type 2 patients to reduce the morbidities associated with uncontrolled glycemic levels (Diabetes 
Control and Complications Trial Research Group, 1993; Cleary et al., 2006; UK Prospective 
Diabetes Study Group, 1998a & 1998b). Typical options for glycemic control in patients with 
T2DM include lifestyle management (diet and exercise), exogenously administered insulin, 
insulin plus oral drugs such as metformin or sulfonylureas, and oral drugs alone. Glycemic 
control is measured by patient self-monitoring of blood glucose (SMBG), patient self-monitoring 
of interstitial glucose, and periodic blood tests for measurement of hemoglobin A1C (HbA1c). 
HbA1c levels reflect average glycemia over several months and therefore provide a surrogate for 
glycemic control (U.S. Food and Drug Administration, 2008). A consensus statement written by 
the American Diabetes Association and the European Association for the Study of Diabetes 
targets an HbA1c level of <7% as an objective for nonpregnant adults, who do not have 
complicating factors, for the prevention of micro- and macrovascular disease (Nathan et al., 
2009). 
In addition to lifestyle modification through diet and exercise, a number of treatments are 
available to treat hyperglycemia in diabetic patients. The choice of antihyperglycemic agents is 
made between physicians and patients based upon the agents’ effectiveness in lowering glucose, 
other effects that can reduce long-term complications, safety, tolerability, ease of use, and 
expense. For example, metformin is widely prescribed as an initial therapy to improve glycemic 
control in patients with T2DM. It decreases hepatic glucose output and lowers fasting glycemia, 
thereby reducing HbA1c levels. It is generally well-tolerated, with possible gastrointestinal 
adverse events and low incidence of hypoglycemia, but is contraindicated in patients with renal 
dysfunction. Sulfonylureas lower glycemia by enhancing insulin secretion, and are effective in 
lowering HbA1c levels. Possible adverse events associated with this class of drugs include 
hypoglycemia (more frequent in elderly patients) and weight gain. Other drugs such as 
thiazolidinediones (TZDs), Glucagon-Like Peptide 1(GLP-1) analogue, α-glucosidase inhibitors, 
glinides, and pramlintide are commercially available in the U.S., but are considered less well-


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validated with respect to established use, efficacy, and cost-effectiveness for achieving target 
glycemic goals than lifestyle management, metformin, and sulfonylureas (Nathan et al., 2009). 
Subcutaneously administered insulin is highly effective at lowering glycemia and helping 
patients achieve target HbA1c levels. Insulin has no overall dose limit with respect to safety and 
provides an improved lipid profile. However, subcutaneously administered insulin requires daily 
injections and blood glucose monitoring, and is associated with weight gain and an increased risk 
of hypoglycemia. Insulin is available as formulations with different pharmacokinetic (PK) and 
pharmacodynamic (PD) profiles (e.g, rapid, regular, intermediate, or long acting, or mixtures of 
these). These different formulations are used (Nathan et al., 2006) to tailor appropriate insulin 
regimens on a per patient basis. 
Oramed Ltd. is developing a proprietary oral formulation of recombinant human insulin 
(ORMD-0801). Oramed, located in Jerusalem, Israel, was established in 2006 and the company’s 
proprietary platform technology is based on over 25 years of medical research at the Hadassah 
University Medical Center in Jerusalem, Israel. In addition to ORMD-0801, which is the most 
advanced product in Oramed’s pipeline, the pipeline also includes an insulin suppository, and a 
GLP-1 analogue.  
ORMD-0801 is based on Oramed’s platform technology for the oral delivery of polypeptides, 
which includes a proprietary formulation of excipients to facilitate oral uptake by hindering 
proteolysis in the small intestine and facilitating translocation of peptides across the gut 
epithelial lining, and into the systemic circulation. The formulation for ORMD-0801 includes 
aprotinin and soybean trypsin inhibitor (SBTI) to hinder proteolysis, and disodium 
ethylenediaminetetraacetic acid (EDTA) to facilitate translocation. The fish oil provides omega-3 
fatty acids. The gelucire is used for its emulsifying properties. The enteric-coated capsules are 
designed to disintegrate in a pH-dependent manner in the small intestine. The initial indication 
for ORMD-0801 is to reduce fasting blood glucose in adult subjects with type 2 diabetes mellitus 
with the objective of controlling the overall average glycemic level.  
The potential advantage of oral insulin in the treatment of elevated fasting blood glucose as 
compared to subcutaneously-administered insulin lies in its delivery to the hepatic portal vein. 
Orally-administered insulin, once transported across the gut wall, is ferried to the hepatic portal 
vein, mimicking the natural route of endogenous pancreatic insulin and delivering the insulin 
directly to the intended site of action. In contrast, subcutaneously-administered insulin reaches 
the liver through the systemic circulation thereby requiring higher systemic levels of insulin in 
order to achieve the same effect. Thus, oral insulin administration is expected to avoid systemic 
hyperinsulinemia and provide a markedly reduced risk of hypoglycemia. he PK/PD profile of 
ORMD-0801 is well-suited to the control of both fasting blood glucose and subsequent pre-meal 
blood glucose levels due to the delayed onset of glucose lowering activity. Therefore, Oramed is 
pursuing the oral administration of ORMD-0801 at bed time and one or two other times during 
the day for the improvement of glycemic control in adult subjects with type 2 diabetes mellitus.  
Oramed has completed five Phase 1 safety studies of various formulations of ORMD-0801 in 
healthy human volunteers. Four Phase 2 studies have been completed, two in patients with type 2 
diabetes, and two in patients with type 1 diabetes. These Phase 2 studies investigated different 
formulations, the effect of meals at different times following ORMD-0801 administration, and 
the effect of ORMD-0801 on glucose as measured by continuous glucose monitoring over a ten 
day treatment period with three doses per day prior to meals. Notably, one Phase 2 study 


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assessed the safety and effectiveness on fasting blood glucose of repeat bed time administration 
of ORMD-0801 in patients with type 2 diabetes over a period of 6 weeks. A Phase 1/2 dose-
response study was also conducted. These studies demonstrated that the drug product is well-
tolerated and can effectively reduce plasma glucose and C-peptide levels. There were no 
significant safety observations and no serious adverse reactions were reported for the completed 
studies, although there were two self-reported events of hypoglycemia in the six-week, Phase 2 
study.  
Oramed intends to continue with clinical development of ORMD-0801 under a U.S. IND 
application.  
 
2 STUDY OBJECTIVES 
2.1 Primary Objectives 
 To compare pre-treatment (Day 3) to end of treatment (Day 8) 24-hour CGM glucose for 
single and multiple doses of ORMD-0801 vs placebo. 
 To evaluate safety parameters for single and multiple doses of ORMD-0801 vs placebo. 
2.2 Secondary Objectives 
 To compare pre-treatment (Day 3) to end of treatment (Day 8) mean daytime CGM 
glucose for single and multiple doses of ORMD-0801 vs placebo. 
 To compare pre-treatment (Day 3) to end of treatment (Day 8) mean nighttime CGM 
glucose for single and multiple doses of ORMD-0801 vs placebo. 
 To compare pre-treatment (Day 3) to post-treatment washout (Day 9) 24-hour CGM 
glucose for single and multiple doses of ORMD-0801 vs placebo. 
 To compare post-prandial glucose measurements for single and multiple doses of 
ORMD-0801 vs placebo. 
 To compare pre-treatment (Day 3) to end of treatment (Day 8) insulin pharmacokinetics 
(PK) for single and multiple doses of ORMD-0801 vs placebo. 
 To compare pre-treatment (Day 3) to end of treatment (Day 8) C-peptide 
pharmacodynamics (PD) for single and multiple doses of ORMD-0801 vs placebo. 
 To compare defined events of hypoglycemia for single and multiple doses of ORMD-
0801 vs placebo. 
 
3 INVESTIGATIONAL PLAN  
3.1 Overall Study Design and Plan 
This study will enroll approximately 30 adult subjects with T2DM from age 20 to 75 inclusive. 
Following a 7-10 day Screening period, eligible subjects will enter a 3-day single-blind placebo 
run-in. On Day 4, each subject will be randomized to a treatment sequence that will include three 
treatment assignments for each of three treatment Periods according to the randomization 
scheme. All subjects will receive placebo plus two of the following:  ORMD-0801 460 IU qd, 
OMRD-0801 bid, or ORMD-0801 tid.  Subjects will receive the randomized treatment from Day 


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4 through Day 8. A 24-hour single-blind placebo washout will be done on Day 9.  For all 
treatment Periods, pre-treatment CGM data will be collected for approximately 36 hours prior to 
treatment (Days 1-3). The cannula will be changed and the monitor will remain in place 
throughout the 5-day treatment period (Days 4-8) and for an additional 24 hours post-treatment 
(Day 9). Blood samples for PD analysis will be taken pre-treatment (Day 3) and at end of 
treatment (Day 8) to check for concentrations of insulin and C-peptide in the blood.  In addition, 
adverse events, clinical laboratory values, vital signs, and electrocardiograms (ECGs) will be 
evaluated periodically for safety. Subjects will be discharged on the morning of Day 10. Each 
treatment Period will be separated by a 2-week washout. A final follow-up visit will be 
performed 1 week after the end of the third treatment period.  
3.2 Screening (7 to 10 Days prior to Visit 2) 
At the Screening Visit, potential subjects will be given a detailed oral presentation describing the 
nature, purpose, risks, and requirements of the study and will also receive detailed written 
information (ICF).  They will have adequate opportunity to ask the appropriate person of the 
Investigational staff (i.e., Principal Investigator or designee) presenting the study about any 
aspect of the study.   
Once the subject is satisfied that he/she is willing to participate in the study, he/she will be asked 
to sign the study ICF (refer to Section 11.1.4 for further detail regarding the ICF).  The 
Investigational Site personnel obtaining written consent from the subject will also sign the form 
to confirm consent has been obtained.  
Once signed, the Investigator will retain the original ICF for the subject’s study records and 
provide the subject with a signed copy.  The Investigator will verify that informed consent has 
been obtained from each subject prior to enrollment into the study and prior to the subject 
undergoing any study-related procedures.  
Screening activities subsequent to obtaining informed consent will be conducted and consist of 
the following: 
 Completion of medical and social history, including tobacco, alcohol, caffeine, and drug 
use; 
 Collection of demographic data (sex, age, race/ethnicity); 
 Review of prior and current medications and supplements; 
 Review inclusion and exclusion criteria; 
 Physical examination; 
 12-lead ECG; 
 Measurement of vital signs (height, weight, seated SBP/DPB, and heart rate); 
 Perform breathalyzer; 
 Collection of fasted blood and urine samples for: 
o Clinical safety labs, including hematology, serum chemistry (with HbA1c, C-peptide, 


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and TSH), and urinalysis (see Section 6.3.5 for list of tests); 
o Urine drug screen; 
o Serum pregnancy test (WCBP only); 
o Serum FSH (to test for women in early menopause); 
For subjects who meet eligibility criteria based on the Screening assessments, instruct as follows: 
 Use adequate contraceptive methods (see Section 4.1) for the duration of the study 
(Screening through Follow-Up Visit 3); 
 Keep the use of concomitant medications at a minimum during the study, if possible, and 
avoid prohibited medications as defined in Section 5.7; 
 Maintain their usual dietary habits for the periods of the study where they will not be 
housed in the CRU and avoid drastic changes, such as a conversion to a vegetarian diet; 
 Refrain from any unusual or unaccustomed vigorous exercise during the course of the 
study; 
 Refrain from excessive alcohol use or binge drinking during the study, and not to drink 
alcohol from 72 hours prior to admission to the CRU (Visit 2/Day 1) thru discharge from 
the CRU; 
 Refrain from excessive caffeine use (i.e., more than five cups of caffeinated beverages 
per day) during the course of 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 
2/Day 1), and was not randomized to receive study treatment (active or placebo). 
The Investigator is responsible for keeping a record of all subjects screened for entry into the 
study and subsequently excluded.  The reason(s) for exclusion will be recorded in the source 
documents and on the Screening log. 
3.3 Visit 2 (Treatment Periods 1, 2, and 3) 
3.3.1 Period 1 
Subjects will report to the CRU on the morning of Day 1. 
3.3.1.1 
Day 1 
 Review of medical history; 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 


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 Provide the first dose of single-blind placebo at least 45 minutes prior to breakfast; 
 Provide breakfast; 
 Subjects will be fitted with the continuous glucose monitoring (CGM) device and data 
recording will begin; 
 Provide 4 doses (8 capsules) of single-blind placebo and instruct subjects to take one dose 
at least 45 minutes before lunch, one dose at bedtime, one dose at least 45 minutes before 
breakfast on Day 2, and one dose at least 45 minutes before lunch on Day 2.  
 Adverse events will be monitored and recorded. 
 Subjects will be instructed to return to the CRU at approximately 5pm (±30 minutes) on 
Day 2. 
3.3.1.2 
Day 2 
 Admission to the CRU at approximately 5pm (±30 minutes); 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, heart rate, and temperature); 
 Perform breathalyzer; 
 Collect a urine sample for: 
o Drug screen; 
o Pregnancy testing (WCBP only) 
 Provide a standardized diabetic meal at approximately 7pm (± 60 minutes).  Standardized 
meals will continue throughout the remainder of the study Period. 
 Provide a dose of single-blind placebo at approximately 10pm (± 60 minutes). 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.1.3 
Day 3 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, heart and rate); 
 Provide a dose of single-blind placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of single-blind placebo at approximately 1pm (± 60 minutes), at least 45 
minutes prior to lunch; 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 


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 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of single-blind placebo at approximately 10pm (± 60 minutes); 
 Collect a blood sample according to schedule (per randomization scheme, either morning, 
afternoon, or evening) prior to the specified dose of placebo for: 
o Pre-dose PD analysis 
o Serum chemistry 
 Collect scheduled (per randomization scheme) postdose PD blood draws every 30 
minutes (± 5 minutes) until 5 hours has elapsed; 
 Replace the CGM cannula at approximately 7pm (± 60 minutes), such that it does not 
interfere with any post-dose PD blood draws; 
 Adverse events will be monitored and recorded. 
3.3.1.4 
Day 4 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Randomization 
 Provide a dose of study treatment or placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of study treatment or placebo at approximately 1pm (± 60 minutes), at 
least 45 minutes prior to lunch; 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of study treatment or placebo at approximately 10pm (± 60 minutes); 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.1.5 
Days 5-7 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide a dose of study treatment or placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of study treatment or placebo at approximately 1pm (± 60 minutes); 


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 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of study treatment or placebo at approximately 10pm (± 60 minutes); 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.1.6 
Day 8 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide a dose of study treatment or placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of study treatment or placebo at approximately 1pm (± 60 minutes); 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of study treatment or placebo at approximately 10pm (± 60 minutes); 
 Collect a blood sample according to schedule (per randomization scheme, either morning, 
afternoon, or evening) prior to the specified dose of placebo for: 
o Pre-dose PD analysis 
o Serum chemistry 
 Collect scheduled (per randomization scheme) postdose PD blood draws every 30 
minutes (± 5 minutes) until 5 hours has elapsed; 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.1.7 
Day 9 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide a dose of single-blind placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of single-blind placebo at approximately 1pm (± 60 minutes); 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 


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 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of single-blind placebo at approximately 10pm (± 60 minutes); 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.1.8 
Day 10 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Remove the CGM monitor; download CGM data;  
 Provide breakfast; 
 Adverse events will be monitored and recorded. 
 Subjects will be discharged for a minimum 2-week washout period. 
3.3.2 Period 2 
Subjects will report to the CRU on the morning of Day 1. 
3.3.2.1 
Day 1 
 Review of medical history; 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide the first dose of single-blind placebo at least 45 minutes prior to breakfast; 
 Provide breakfast; 
 Subjects will be fitted with the continuous glucose monitoring (CGM) device and data 
recording will begin; 
 Provide 4 doses of single-blind placebo and instruct subjects to take one dose at least 45 
minutes before lunch, one dose at bedtime, one dose at least 45 minutes before breakfast 
on Day 2, and one dose at least 45 minutes before lunch on Day 2.  
 Adverse events will be monitored and recorded. 
 Subjects will be instructed to return to the CRU at approximately 5pm (±30 minutes) on 
Day 2. 
3.3.2.2 
Day 2 
 Admission to the CRU at approximately 5pm (±30 minutes); 
 Review of medications and supplements; 


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 Measurement of vital signs (weight, seated SBP/DPB, heart rate, and temperature); 
 Perform breathalyzer; 
 Collect a urine sample for: 
o Drug screen; 
o Pregnancy testing (WCBP only) 
 Provide a standardized diabetic meal at approximately 7pm (± 60 minutes).  Standardized 
meals will continue throughout the remainder of the study Period. 
 Provide a dose of single-blind placebo at approximately 10pm (± 60 minutes). 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.2.3 
Day 3 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, heart and rate); 
 Provide a dose of single-blind placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of single-blind placebo at approximately 1pm (± 60 minutes), at least 45 
minutes prior to lunch; 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of single-blind placebo at approximately 10pm (± 60 minutes); 
 Collect a blood sample according to schedule (per randomization scheme, either morning, 
afternoon, or evening) prior to the specified dose of placebo for: 
o Pre-dose PD analysis 
o Serum chemistry 
 Collect scheduled (per randomization scheme) postdose PD blood draws every 30 
minutes (± 5 minutes) until 5 hours has elapsed; 
 Replace the CGM cannula at approximately 7pm (± 60 minutes), such that it does not 
interfere with any post-dose PD blood draws; 
 Adverse events will be monitored and recorded. 


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3.3.2.4 
Day 4 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Randomization 
 Provide a dose of study treatment or placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of study treatment or placebo at approximately 1pm (± 60 minutes), at 
least 45 minutes prior to lunch; 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of study treatment or placebo at approximately 10pm (± 60 minutes); 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.2.5 
Days 5-7 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide a dose of study treatment or placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of study treatment or placebo at approximately 1pm (± 60 minutes); 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of study treatment or placebo at approximately 10pm (± 60 minutes); 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.2.6 
Day 8 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide a dose of study treatment or placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 


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 Provide a dose of study treatment or placebo at approximately 1pm (± 60 minutes); 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of study treatment or placebo at approximately 10pm (± 60 minutes); 
 Collect a blood sample according to schedule (per randomization scheme, either morning, 
afternoon, or evening) prior to the specified dose of placebo for: 
o Pre-dose PD analysis 
o Serum chemistry 
 Collect scheduled (per randomization scheme) postdose PD blood draws every 30 
minutes (± 5 minutes) until 5 hours has elapsed; 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.2.7 
Day 9 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide a dose of single-blind placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of single-blind placebo at approximately 1pm (± 60 minutes); 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of single-blind placebo at approximately 10pm (± 60 minutes); 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.2.8 
Day 10 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Remove the CGM monitor; download CGM data;  
 Provide breakfast; 
 Adverse events will be monitored and recorded. 


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 Subjects will be discharged for a minimum 2-week washout period. 
3.3.3 Period 3 
Subjects will report to the CRU on the morning of Day 1. 
3.3.3.1 
Day 1 
 Review of medical history; 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide the first dose of single-blind placebo at least 45 minutes prior to breakfast; 
 Provide breakfast; 
 Subjects will be fitted with the continuous glucose monitoring (CGM) device and data 
recording will begin; 
 Provide 4 doses of single-blind placebo and instruct subjects to take one dose at least 45 
minutes before lunch, one dose at bedtime, one dose at least 45 minutes before breakfast 
on Day 2, and one dose at least 45 minutes before lunch on Day 2.  
 Adverse events will be monitored and recorded. 
 Subjects will be instructed to return to the CRU at approximately 5pm (±30 minutes) on 
Day 2. 
3.3.3.2 
Day 2 
 Admission to the CRU at approximately 5pm (±30 minutes); 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, heart rate, and temperature); 
 Perform breathalyzer; 
 Collect a urine sample for: 
o Drug screen; 
o Pregnancy testing (WCBP only) 
 Provide a standardized diabetic meal at approximately 7pm (± 60 minutes).  Standardized 
meals will continue throughout the remainder of the study Period. 
 Provide a dose of single-blind placebo at approximately 10pm (± 60 minutes). 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 


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3.3.3.3 
Day 3 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, heart and rate); 
 Provide a dose of single-blind placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of single-blind placebo at approximately 1pm (± 60 minutes), at least 45 
minutes prior to lunch; 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of single-blind placebo at approximately 10pm (± 60 minutes); 
 Collect a blood sample according to schedule (per randomization scheme, either morning, 
afternoon, or evening) prior to the specified dose of placebo for: 
o Pre-dose PD analysis 
o Serum chemistry 
 Collect scheduled (per randomization scheme) postdose PD blood draws every 30 
minutes (± 5 minutes) until 5 hours has elapsed; 
 Replace the CGM cannula at approximately 7pm (± 60 minutes), such that it does not 
interfere with any post-dose PD blood draws; 
 Adverse events will be monitored and recorded. 
3.3.3.4 
Day 4 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Randomization 
 Provide a dose of study treatment or placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of study treatment or placebo at approximately 1pm (± 60 minutes), at 
least 45 minutes prior to lunch; 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of study treatment or placebo at approximately 10pm (± 60 minutes); 


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 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.3.5 
Days 5-7 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide a dose of study treatment or placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of study treatment or placebo at approximately 1pm (± 60 minutes); 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of study treatment or placebo at approximately 10pm (± 60 minutes); 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.3.6 
Day 8 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide a dose of study treatment or placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of study treatment or placebo at approximately 1pm (± 60 minutes); 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of study treatment or placebo at approximately 10pm (± 60 minutes); 
 Collect a blood sample according to schedule (per randomization scheme, either morning, 
afternoon, or evening) prior to the specified dose of placebo for: 
o Pre-dose PD analysis 
o Serum chemistry 
 Collect scheduled (per randomization scheme) postdose PD blood draws every 30 
minutes (± 5 minutes) until 5 hours has elapsed; 
 Continue CGM monitoring; 


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 Adverse events will be monitored and recorded. 
3.3.3.7 
Day 9 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Provide a dose of single-blind placebo at approximately 7am (± 60 minutes); 
 Provide breakfast no sooner than 45 minutes after the morning dose; 
 Provide a dose of single-blind placebo at approximately 1pm (± 60 minutes); 
 Provide lunch no sooner than 45 minutes after the afternoon dose; 
 Provide dinner at approximately 7pm (± 60 minutes); 
 Provide a dose of single-blind placebo at approximately 10pm (± 60 minutes); 
 Continue CGM monitoring; 
 Adverse events will be monitored and recorded. 
3.3.3.8 
Day 10 
 Review of medications and supplements; 
 Measurement of vital signs (weight, seated SBP/DPB, and heart rate); 
 Remove the CGM monitor; download CGM data;  
 Provide breakfast; 
 Adverse events will be monitored and recorded. 
 Subjects will be discharged until the 1-week follow-up visit. 
 
3.4 Follow-up Visit (Visit 3, 7 to 9 Days after the end of Visit 2, Period 3) 
Subjects will return to the clinic 7 to 9 days after Visit 2/Day 10 (approximately 65 days since 
the beginning of the study) and the following procedures will be performed: 
 Review of medications and supplements; 
 Vital signs (including weight, seated SBP/DPB, and heart rate); 
 Physical examination; 
 Collection of blood and urine samples for: 
o Clinical safety labs, including hematology, serum chemistry, and urinalysis (see 
Section 6.3.5 for list of tests); 


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 Record adverse events; 
 Discharge from the study. 
Any subject with a possible study treatment related AE at the Follow-Up Visit will be followed 
until resolution or stabilization of the event.  Further, any SAE, whether or not related to study 
treatment, that occurs within 30 days following the last dose of study treatment will be followed 
until resolution or stabilization of the event.  This may require additional clinical assessments 
and laboratory tests.  The follow-up results will be recorded in the subject's source 
documentation and in the CRF. 
3.5 Early Withdrawal (EW) 
If a randomized subject is withdrawn from the study prior to completing study treatment, the 
subject will be discharged from the CRU and instructed to return to the clinic the next day and 
the following procedures will be performed:  
 Review of medications and supplements; 
 Vital signs (including weight, seated SBP/DPB, and heart rate); 
 Physical examination; 
 Collection of blood and urine samples for: 
o Clinical safety labs, including hematology, serum chemistry, and urinalysis (see 
Section 6.3.5 for list of tests); 
 Record adverse events; 
 Discharge from the study. 
If a randomized subject is withdrawn from the study prior to completing all three treatment 
periods, the subject will be discharged from the CRU and instructed to return to the clinic the 
next day for Follow-Up evaluations as performed for Visit 3.  
Any subject with a possible study treatment related AE at the time of EW will be followed until 
resolution or stabilization of the event. 
3.6 Schedule of Events 
Table 1 below describes the daily schedule of events from Screening Visit 1 through Follow-Up 
Visit 3.   
 
 
 


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Table 1: Daily Schedule of Events from Screening Through Follow-Up Visit 
Visit 
Screening 
Visit 1 
Treatment Visit 2 
Periods 1, 2, and 3 
Follow-Up 
Visit 3 
EW 
Study Day 
Day -7 to -10 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
~65 
N/A 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/Chemistry/Urinalysis2 
X2 
 
 
X2 
 
 
 
 
X2 
 
 
X2 
X2 
Urine Drug Screen 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Breathalyzer 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test3 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Placebo Administration4 
 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
CGM Monitoring5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
CRU Admission 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Standardized Diabetic Meals6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pharmacodynamic Samples7 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Remove CGM and Download Data 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Randomization/Crossover8 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Treatment Administration9 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
CRU Discharge 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Disposition 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 31 
CONFIDENTIAL 
1Vital signs include height, weight, heart rate, systolic BP, and diastolic BP.  Height will be measured at Screening 
only. Temperature will be measured at Visit 2/Day 2 only, prior to admission. 
2Screening labs will include standard hematology/chemistry/urinalysis, plus HbA1c, C-peptide, and TSH.  FSH will 
also be performed for women who are pre-menopausal. On Visit 2 Days 3 and 8, chemistry analysis will be 
performed without hematology or urinalysis. Visit 3 and EW labs will include standard 
hematology/chemistry/urinalysis. 
3Pregnancy tests will be performed for women of childbearing potential only. 
4A single dose of placebo will be administered on the morning of Day 1. Subjects will be dispensed the next 4 doses 
(8 capsules) with dosing instructions. On Day 3 and Day 9, doses will be administered at approximately 7am 
(±60 minutes), 1pm (±60 minutes), and 10pm (±60 minutes). 
5The CGM monitor will be fitted on Day 1, the cannula will be changed on Day 3 at approximately 7pm (±60 
minutes), and the monitor will continue recording measurements until the morning of Day 10. 
6A standardized breakfast will be provided on Day 1. Beginning with dinner on Day 2 and ending with breakfast on 
Day 10, breakfast and lunch will be provided no sooner than 45 minutes after corresponding treatment doses.  
Dinner will be provided at approximately 7pm (±60 minutes).  Standardized snacks will be provided between 
breakfast and lunch, between lunch and dinner, and between dinner and bedtime. 
7Blood samples (scheduled per randomization scheme) for insulin and C-peptide will be drawn pre-dose and every 
30 minutes (± 5 minutes) postdose until 5 hours has elapsed. 
8Randomization will occur on the morning of Period 1/Day 4.  Crossover will occur on the morning of Period 2/Day 
4 and then again on the morning of Period 3/Day 4.  
9Subjects will receive their assigned randomized treatment from the morning of Day 4 through the evening of Day 8. 
Doses will be administered at approximately 7am (±60 minutes), 1pm (±60 minutes), and 10pm (±60 minutes). 
 
 
 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 32 
CONFIDENTIAL 
4 STUDY SUBJECT SELECTION 
4.1 Inclusion Criteria 
Each subject must meet all of the following criteria to be eligible for the study: 
1. Male or female subjects, age 20 to 75 years, inclusive with type 2 diabetes mellitus. 
2. At Visit 2/Period 1/Day 1, subjects will have been treated for their diabetes by metformin 
(≥1000 mg/day; any type and regimen), metformin and a DPP-4 inhibitor, metformin and 
an SGLT-2 inhibitor, metformin and TDZ, or metformin and sufonylurea. Subjects will 
have been on a stable regimen of metformin (defined as the same metformin dose and 
type) and other treatments for at least 8 weeks prior to Visit 2/Period 1/Day 1.  
3. Body Mass Index (BMI) between 25 and 40 kg/m2, inclusive, at Screening. 
4. Hemoglobin A1c (HbA1c) between ≥7.5 and ≤10.5% at Screening. 
5. Fasting serum glucose greater than or equal to 126 mg/dL at Screening. 
6. Females of childbearing potential must have a negative serum pregnancy test result at 
Screening and a negative urine pregnancy test at Visit 2/Day 1 for all study Periods.  
a. Females who are not of childbearing potential are defined as:  
i. Postmenopausal (defined as at least 12 months with no menses in women 
≥45 years of age) 
ii. Has had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior 
to screening; OR 
iii. Has a congenital or acquired condition that prevents childbearing. 
b. Females of childbearing potential agree to avoid becoming pregnant while 
receiving study treatment and for 14 days after the last dose of study treatment by 
complying with one of the following: 
i. practice abstinence† from heterosexual activity OR 
ii. Use (or have her partner use) acceptable contraception during heterosexual 
activity.  Acceptable methods of contraception are‡: 
1. Single method (one of the following is acceptable): 
a. Non-hormonal intrauterine device (IUD) 
b. vasectomy of a female subject’s male partner 
2. Combination method (requires use of two of the following): 
a. diaphragm with spermicide (cannot be used in conjunction 
with cervical cap/spermicide) 
b. cervical cap with spermicide (nulliparous women only) 
c. contraceptive sponge (nulliparous women only)  
d. male condom or female condom (cannot be used together) 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 33 
CONFIDENTIAL 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
4.2 Exclusion Criteria 
Subjects who meet any of the following criteria must be excluded from the study: 
1. Usage of anti-diabetic agents other than metformin, sulfonylurea, SGLT-2 inhibitors, 
TZD, or DPP-4 inhibitors within 6 weeks prior to Visit 2/Period 1/Day 1.  
2. Presence of any clinically significant endocrine disease according to the Investigator 
(euthyroid subjects on replacement therapy will be included if the dosage of thyroxine is 
stable for at least six weeks prior to Screening). 
3. Clinical diagnosis of type 1 diabetes. 
4. Fasting serum glucose >300 mg/dL at Screening; a single repeat test is allowable. 
5. Evidence of unawareness of hypoglycemia, a documented plasma glucose ≤50 mg/dL in 
the absence of symptoms of hypoglycemia at Screening. 
6. Presence of any clinically significant condition (in the opinion of the Investigator) that 
might interfere with the evaluation of study medication, such as significant renal, hepatic, 
gastrointestinal (GI), cardiovascular (CV), immune disease, blood dyscrasias or any 
disorders causing hemolysis or unstable red blood cells, or clinically important 
hematological disorders (i.e. aplastic anemia, myeloproliferative or myelodysplastic 
syndromes, thrombocytopenia) at Screening. 
7. Presence or history of cancer within the past 5 years of Screening, with the exception of 
adequately-treated localized basal cell skin cancer or in situ uterine cervical cancer.  
a. A subject with a history of malignancy >5 years prior to Screening should have 
no evidence of residual or recurrent disease.  
b. A subject with a history of melanoma, leukemia, lymphoma, or renal carcinoma is 
excluded. 
8. Laboratory abnormalities at Screening including: 
a) C-peptide < 1.0 ng/mL 
b) Positive pregnancy test in females of childbearing potential (at Screening and 
Visit 2/Periods 1-3/Day 1) 
c) Abnormal serum thyrotropin (TSH) levels below the lower limit of normal or 
>1.5X the upper limit of normal 
d) Elevated liver enzymes (alanine transaminase (ALT), alanine aminotransferase 
(AST), alkaline phosphatase) >2X the upper limit of normal. 
e) Very high triglyceride levels (>600 mg/dL); a single repeat test is allowable. 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 34 
CONFIDENTIAL 
f) Any relevant abnormality that would interfere with the efficacy or the safety 
assessments during study treatment administration. 
9. Positive history of active liver disease (other than non-alcoholic hepatic steatosis), 
including chronic hepatitis B or C, primary biliary cirrhosis, or active symptomatic 
gallbladder disease. 
10. Positive history of HIV. 
11. Use of the following medications: 
a) History of use of insulin for more than 1 week within 6 months prior to and none 
within 6 weeks prior to Visit 2/Period 1/Day 1. 
b) History of use of aprotinin at any time prior to Screening (e.g., Trasylol, any type 
or dose). 
c) Administration of thyroid preparations or thyroxine (except in subjects on stable 
replacement therapy) within 6 weeks prior to Screening. 
d) Administration of systemic long-acting corticosteroids within two months or 
prolonged use (more than one week) of other systemic corticosteroids or inhaled 
corticosteroids (if daily dosage is > 1,000 μg equivalent beclomethasone) within 
30 days prior to Screening. Intra-articular and/or topical corticosteroids are not 
considered systemic. 
e) Use of medications known to modify glucose metabolism or to decrease the 
ability to recover from hypoglycemia such as oral, parenteral, and inhaled steroids 
(as discussed above), and immunosuppressive or immunomodulating agents. 
12. Known allergy to soy or aprotinin. 
13. Subject is on a weight loss program and is not in the maintenance phase, or subject has 
started weight loss medication (e.g., orlistat or liraglutide), within 8 weeks prior to 
Screening.  Subjects who have had bariatric surgery are also excluded. 
14. Subject is pregnant or breast-feeding.  
15. Subject has a Screening systolic blood pressure ≥165 mmHg or diastolic blood pressure 
≥100 mmHg. Subjects will be allowed to take a BP rescue medication. 
16. Subject is a user of recreational or illicit drugs or has had a recent history (within 1 year 
of Screening) of drug or alcohol abuse or dependence. (Note: Alcohol abuse includes 
heavy alcohol intake as defined by >3 drinks per day or >14 drinks per week, or binge 
drinking) at Screening. 
17. Any clinically significant ECG abnormality at Screening or cardiovascular disease. 
Clinically significant cardiovascular disease will include:  
a) History of stroke, transient ischemic attack, or myocardial infarction within 6 
months prior to Screening,  
b) History of or currently have New York Heart Associate Class II-IV heart failure 
prior to Screening, or  
18. One or more contraindications to metformin. 
19. History of gastrointestinal disorders (e.g. hypochlorhydria) with the potential to interfere 
with drug absorption. 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 35 
CONFIDENTIAL 
20. At the Principal Investigator’s discretion, any condition or other factor that is deemed 
unsuitable for subject enrollment into the study. 
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 a prohibited medication (listed in Section 5.7) 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. 
 
Reasons for study drug discontinuation may include the following: 
1. Pregnancy 
2. Adverse event 
3. Episodes of hypoglycemia as defined in Section 7.3.1. 
4. Patient meets one of the exclusion criteria during the study 
5. Any clinically significant change in the patient’s medical condition 
 
The occurrence of severe hypoglycemia (as defined in Section 7.3.1) in two patients during the 
double-blind treatment period will lead to unblinding of the treatment in those two patients.  
Patients who withdraw from the study prior to treatment may be replaced. Patients who are 
withdrawn and have received at least one treatment will not be replaced. Patients 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 
study treatment.  The Investigator should obtain approval from the Sponsor and Medical Monitor 
before restarting study treatments that were temporarily discontinued for an AE. 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 36 
CONFIDENTIAL 
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 study treatment) 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 study treatment 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 study treatment -related AE should be followed until resolution or 
stabilization of the event. 
If a subject becomes pregnant, study treatment will be discontinued immediately, and the subject 
will be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling.  The subject will be followed until delivery or other termination of 
pregnancy for outcome. 
Subjects may choose to withdraw authorization to use and disclose their PHI as defined by the 
HIPAA.  Such withdrawal of authorization must be made to the Investigator in writing.  Any PHI 
collected by the Investigator prior to the date of such withdrawal will continue to be used and 
disclosed. 
Randomized subjects who are discontinued from this study for any reason will not be replaced.   
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 will notify the IRB in writing of a premature termination of a 
study or closure of Investigational Site, 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 study treatment. 
If either of the criteria listed below is met, enrollment of new subjects and dosing of ongoing 
subjects will be temporarily stopped.  The Investigator, Sponsor, and the Medical Monitor will 
discuss whether a lower dose or any additional treatment guidelines should be implemented, or if 
the trial should be permanently stopped.  Any proposed changes to the protocol to address such 
findings will be submitted for review and approval by the IRB and FDA prior to re-starting the 
trial. 
1. A death within 30 days after study treatment 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 study treatment caused 
the events. 
 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 37 
CONFIDENTIAL 
5 STUDY TREATMENT 
5.1 Description of Investigational Drug 
Active: 
Code name: ORMD-0801 
Dosage form: 2 soft gel capsules per dose 
Strength: 230 IU insulin (8 mg insulin) per capsule 
Description: API (recombinant human insulin USP), in Oramed’s proprietary formulation 
[aprotinin, SBTI, disodium EDTA, fish oil, and TWEEN 80] in capsules. 
Placebo control: 
Fish oil in capsules, identical in appearance to ORMD-0801 
Note: 230 IU Insulin and placebo capsules are all identical in appearance. 
5.1.1 Packaging and Labeling 
This study is a double-blind, double-dummy study. The Investigational Site pharmacist will be 
responsible for dispensing the appropriate treatment period study treatment based on the 
randomization schedule.  For each treatment period dose, the pharmacist will remove the 
capsules from the bottle before providing the capsules to the Investigational Site personnel. 
Shipments of placebo capsules for the run-in period will be clearly labeled to indicate they 
should be used during this patient-blinded stage of the study.  Shipments of study medication for 
the double-blinded treatment period will be received in blinded packages so that the Investigator, 
staff, and patients will be blinded to the treatment. Study medication will be dispensed to the site 
with instructions for when treatment can be administered and with a diary for recording 
administration of study medication. Medication containers and any unused capsules will be 
retained at the study site after the treatment phase of the trial is complete. 
The treatment packages will be labeled with the following information: 
 Study number 
 Patient ID 
 Kit No./Bottle ID 
 Dosage Form/Content 
 Directions for use, including route of administration 
 Number of capsules in package 
 Storage conditions 
 Instructions to “keep out of reach of children” 
 Caution: New Drug – Limited by Federal (or United States) law to investigational use.  
 Name of Sponsor  
A separate label with the identical information will be provided with the label on the package for 
drug accountability purposes.  


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 38 
CONFIDENTIAL 
5.1.2 Storage and Handling 
All study treatment must be kept in an appropriate, secure area to prevent unauthorized access.  
The study treatment is to be shipped under ambient conditions and stored in the original 
packaging at controlled room temperature (62 to 77°F; 17 to 25°C).  Excursions between 59 to 
86ºF (15 to 30ºC) will be permitted.  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.  
Study treatment should be handled and disposed of using proper procedures as defined by 
Investigational Site standard operating procedures (SOPs) for Investigational Drugs. 
5.2 Randomization 
This is a single center, randomized, double-blind, 3-way crossover study.  Approximately 30 
eligible subjects will be randomized to placebo and 2 of the 3 possible dose groups: ORMD-
0801 460 IU qd (in the evening), ORMD-0801 460 IU bid (in the morning and evening) and 
ORMD-0801 460 IU tid (morning, afternoon, and evening).  
In order to estimate the morning, afternoon, and evening PD effect, each subject will have one 
period in which the PD blood samples are drawn in the morning, one period in which the PD 
blood samples are drawn in the afternoon and one period in which the PD blood samples are 
drawn in the evening. When the subject is on active therapy, the PD blood samples will be drawn 
after an active therapy dose (not after the placebo dummy). Thus, if the subject is taking ORMD-
0801 460 IU qd, the PD blood samples will be drawn in the evening. If the subject is taking 
ORMD-0801 460 IU bid, the PD blood samples will be drawn in the morning or evening. If the 
subject is taking ORMD-0801 460 IU tid or placebo, the PD blood samples will be drawn in the 
morning, afternoon, or evening. 
Integrium, LLC will generate and implement the randomization procedures for this trial.  A 
computer-generated randomization schedule will be used for assigning treatment (active or 
placebo).  The Investigational Site pharmacist will follow this randomization schedule to 
dispense the appropriate study treatment. 
5.3 Study Treatment Administration 
5.3.1 Study Treatment Periods  
In order to achieve the desired 460 IU, 2 capsules will be administered per dose.  Accordingly, 
subjects who are randomized to placebo will also receive 2 identical placebo capsules per dose.  
5.3.1.1 
Single-Blind Placebo Administration 
Placebo will be administered during Visit 2 on Days 1, 2, 3, and 9. On Day 1, subjects will 
receive one dose of placebo in the morning, followed by breakfast at least 45 minutes later. They 
will receive 4 additional doses of placebo to take one dose at least 45 minutes before lunch, one 
dose at bedtime, one dose at least 45 minutes before breakfast on Day 2, and one dose at least 45 
minutes before lunch on Day 2.  Subjects will be provided with an evening dose of placebo at 
approximately 10 pm (± 60 minutes) on Day 2.  On Days 3 and 9, subjects will receive a dose of 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 39 
CONFIDENTIAL 
single-blind placebo at approximately 7am (± 60 minutes), approximately 1pm (± 60 minutes), 
and before bed at approximately 10 pm (± 60 minutes). 
5.3.1.2 
Double-Blind Treatment Administration 
Study treatment (active or placebo) will be administered during Visit 2 on Days 4-8. Prior to 
administering the scheduled dose of study drug, the most recent available reading on the 
CGM monitor must indicate a blood glucose of ≥70 mg/dL. On all days, subjects will receive 
a dose of study treatment or placebo at approximately 7am (± 60 minutes), approximately 1pm 
(± 60 minutes), and a dose before bed at approximately 10 pm (± 60 minutes).   
Subjects may be randomized to receive ORMD-0801 qd, bid, or tid: 
 Subjects receiving ORMD-0801 qd will receive their dose at approximately 10pm (± 60 
minutes), while receiving identical placebo at approximately 7am (± 60 minutes) and at 
approximately 1pm (± 60 minutes).   
 Subjects receiving ORMD-0801 bid will receive their doses at approximately 7am (± 30 
minutes) and before bed at approximately 10pm (± 60 minutes), while receiving placebo 
at approximately 1pm (± 60 minutes).   
 Subjects receiving ORMD-0801 tid will receive their doses at approximately 7am (± 60 
minutes), at approximately 1pm (± 60 minutes), and before bed at approximately 10pm 
(± 60 minutes).  
5.4 Dose Modifications 
This study does not include any planned dose modifications.  Subjects will be administered study 
treatment orally at the assigned (randomized) dose level unless discontinuation criteria as defined 
in Section 4.3 are met. 
5.5 Measuring Subject Compliance 
5.5.1 Study Treatment Periods 1 and 2 
Four doses of placebo (8 capsules) will be dispensed to subjects for Day 1 and Day 2.  
Compliance will be reviewed during admission on Day 2 to protect the single-blind nature of this 
treatment.  
All doses of study treatment will be administered in the CRU.  Oral dosing compliance will be 
ascertained by inspection of the oral cavity (mouth check) following dosing.   
5.6 Drug Accountability 
In accordance with current GCP, the Investigational Site will account for all study treatment 
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. 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 40 
CONFIDENTIAL 
Study treatment will only be dispensed to subjects enrolled in this protocol, and only as directed 
by this protocol.  Administration of study treatment will be accurately recorded in each subject’s 
source documents and CRF. 
5.7 Concomitant Medications and Supplements 
All medications and supplements (other than study treatment) taken by the subject from Visit 
2/Day 1 through the Follow-up Visit 3 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/Day 1 will be considered “prior” medications and supplements. 
All prior medications and supplements taken within 30 days prior to the first dose of study 
treatment and concomitant medications and supplements will be recorded in the subject’s source 
documentation and in the CRF. 
The use of concomitant medications and supplements should be kept at a minimum, if possible.  
Any medications and supplements needed for the welfare of a subject and that in the judgment of 
the Investigator will not pose a significant risk to the subject for continued participation in the 
study or that will not interfere with the interpretation of the results of this study may be given to 
the subject.  If a subject requires the use of any of the prohibited medications and supplements 
listed below, 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.   
The following are prohibited medications: 
1. Any Investigational Drug other than ORMD-0801 (or placebo) within 30 days prior to Visit 
2/Day 1 through the Follow-Up Visit 3; 
2. Any anti-diabetic drugs (except for those allowable by the inclusion criteria) including 
insulin, GLP-1 analogue, α-glucosidase inhibitors, glinides, and pramlintide; 
3. Aprotinin (e.g., Trasylol); 
4. Thyroid preparations or thyroxine (except in subjects on stable replacement therapy); 
5. Systemic long-acting corticosteroids or other systemic corticosteroids or inhaled 
corticosteroids (if daily dosage is > 1,000 μg equivalent beclomethasone). Intra-articular 
and/or topical corticosteroids are not considered systemic. 
6. Medications known to modify glucose metabolism or to decrease the ability to recover 
from hypoglycemia such as oral, parenteral, and inhaled steroids, and 
immunosuppressive or immunomodulating agents.  
If the subject initiates prohibited drug therapy, or if the Investigator determines that use of a 
prohibited therapy is in the best interest of the patient’s health and well-being, the Investigator 
and sponsor will jointly decide to continue or discontinue the subject. 
5.8 Dietary Restrictions 
Subjects will fast overnight for at least 8 hours prior to the clinical safety labs at Screening. 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 41 
CONFIDENTIAL 
Subjects should not take any food for at least 45 minutes or more prior to scheduled ORMD-
0801 (or placebo) dosing as described in the study design.  All subjects will be provided with a 
standardized diabetic breakfast on Day 1, then continuing from dinner on Day 2 through 
breakfast on Day 10.  Standardized snacks will be provided between breakfast and lunch, 
between lunch and dinner, and between dinner and bedtime.  
Excessive caffeine use (i.e., more than five cups of caffeinated beverages per day) will not be 
allowed from Screening through the Follow-Up Visit 3.  Excessive alcohol use or binge drinking 
will be discouraged during the study, and alcohol will be prohibited 72 hours prior to admission 
to the CRU (Visit 2/Period 1, 2, and 3/Day 1) and throughout the domiciled period (i.e., through 
the morning assessments on Day 10). 
Subjects will also be asked to refrain from any unusual or unaccustomed vigorous exercise 
during the course of the study. 


Oramed Ltd. 
 
Protocol No. ORA-D-012 
Phase 2a Clinical Study 
Version 1 (August 23, 2016) 
Page 42 
CONFIDENTIAL 
6 STUDY PROCEDURES AND ASSESSMENTS 
6.1 Informed Consent 
According to the ICH guideline for GCP (E6) and all institutional local, state, and federal laws, 
the Investigator will obtain and document informed consent for each subject screened for this 
study.  All subjects will be informed in writing of the nature of the protocol and Investigational 
Drug, its possible hazards, and their right to withdraw at any time, and will 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 Medical History and Prior Medications 
At Screening, 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 Safety Assessments 
6.3.1 Weight and Height 
Weight will be measured at all visits. Height will be measured at Screening only with the subject 
wearing no shoes. 
6.3.2 Vital Signs 
Vital signs (including seated SBP/DBP, and heart rate) will be recorded at all visits as described 
in Table 1. Temperature will be recorded at Visit 2/Day 2 only. 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 that occurs at the same time point.  During Treatment Periods 1, 2, and 3, vital signs 
will be measured on Day 1, at admission on Day 2, immediately prior to morning dosing on 
Days 3-9, and on the morning of Day 10 prior to discharge.  The recorded seated SBP/DBP value 
will be the mean of two measurements taken 2 minutes apart and always using the non-dominant 
arm. 
6.3.3 Physical Examination 
A physical examination will be performed at Screening and at Follow-Up Visit 3, or in case of 
Early Withdrawal.  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. 
6.3.4 12-Lead ECG 
A 12-lead ECG will be performed at Screening. 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 


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will be read for QT and QTc (Federicia’s) intervals and clinically significant abnormalities. At 
the Investigator’s discretion, an additional ECG may be performed at the end of treatment; 
however, it will be recorded in source documents as an unscheduled assessment.  
6.3.5 Clinical Laboratory Tests 
Blood and urine for clinical safety laboratory assessments will be collected and processed using 
standard procedures.  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. 
6.3.5.1 
Clinical Safety Labs 
The clinical safety labs will include the following hematology, serum chemistry, and urinalysis 
tests: 
Hematology 
 Hematocrit 
 Hemoglobin 
 Mean corpuscular hemoglobin 
 Mean corpuscular hemoglobin concentration 
 Mean corpuscular volume 
 Platelet count 
 Red blood cell distribution width 
 Red blood cell count 
 White blood cell count with differential 
Serum Chemistry 
 Sodium 
 Potassium 
 Chloride 
 Bicarbonate 
 Alanine aminotransferase (ALT) 
 Aspartate aminotransferase (AST) 
 Gamma-glutamyltransferase (GGT) 
 Total bilirubin  
 Alkaline phosphatase  
 Albumin 
 Total Protein  
 Blood urea nitrogen (BUN) 
 Creatinine 
 Uric acid 
 Glucose 
 Calcium 
 Phosphorus 
 Total cholesterol 
 Triglycerides 


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Urinalysis 
 Appearance (color and character) 
 Bilirubin  
 Urobilinogen 
 Protein 
 Glucose 
 Ketones  
 Leukocyte esterase 
 Urine blood 
 Nitrite 
 pH 
 Specific gravity 
 
6.3.5.2 
Pregnancy Test 
A serum pregnancy test will be performed for WCBP at Screening. A urine pregnancy test will 
be performed for WCBP at treatment Periods 1, 2, and 3 (Day 2). 
FSH testing to confirm menopause should be done 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. 
 
6.3.5.3 
Additional Screening Bloodwork 
In addition to the blood tests listed above, HbA1c, C-peptide, and thyroid stimulating hormone 
(TSH) will be measured at Screening.  
6.3.5.1 
Drugs of Abuse and Breathalyzer 
Drugs of abuse urine screens will be completed at Screening and at Visit 2/Day 2 (all three 
treatment Periods) according to the laboratory manual provided by the local laboratory and will 
include testing for amphetamines, barbiturates, cocaine metabolites, opiates, benzodiazepines 
and cannabinoids.  A breathalyzer test will also be performed at Screening and at Visit 2/Day 2 
(all three treatment Periods). 
6.4 Efficacy Assessments 
6.4.1 Continuous Glucose Monitors (CGM) 
A continuous glucose monitor (CGM) will be used to monitor patient glucose levels (including 
post-prandial) during Visit 2, Periods 1, 2, and 3.  Further information about the device can be 
found in the laboratory manual.  
Subjects will have the CGM implanted on Day 1 of each treatment Period. On Day 3, the 
cannula will be changed and the CGM will be re-implanted to collect data until the morning of 
Day 10. Staff will be advised regarding appropriate procedures in the event of nocturnal 
hypoglycemia. 


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6.5 Pharmacokinetic/Pharmacodynamic Assessments 
Blood samples for PK/PD analysis of absorbed insulin based on C-peptide correction of total 
insulin levels will be collected during Visit 2, Periods 1, 2, and 3, on Day 3 and Day 8. An 
indwelling venous catheter may be inserted for the collection of blood samples if deemed 
necessary. One 4.5 mL sample of total whole blood will be collected for each blood draw.  
 
On Day 3, blood samples will be collected at the following nominal time points relative to the 
scheduled (per randomization scheme) dose of placebo: predose (45 to 5 mins prior to dosing) 
and every 30 minutes (± 5 minutes) postdose until 5 hours has elapsed. On Day 8, blood samples 
will be collected at the following nominal time points relative to the scheduled (per 
randomization scheme) dose of study treatment (active or placebo): predose (45 to 5 mins prior 
to dosing) and every 30 minutes (± 5 minutes) postdose until 5 hours has elapsed.  The total 
volume collected from each subject for PK/PD samples will be approximately 99 mL per 
treatment Period, for a total of 297 mL during the entire study. Actual blood sampling times must 
be recorded in the source and eCRF. 
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 
2/Day 1 through Follow-Up Visit 3 will be recorded in the subject’s medical record and the CRF.  
All medications and supplements (other than study treatment) taken by the subject after Visit 
2/Day 1 through Follow-Up Visit 3 assessments will be considered “concomitant” medications 
and supplements.  Medications and supplements taken prior to Visit 2/Day 1 that are no longer 
being taken at Visit 2/Day 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 
7.1 Safety and Tolerability Assessments 
Safety and tolerability will be assessed on an ongoing basis by review of reported AEs, physical 
examinations, 12-lead ECGs, vital signs (including weight, seated SBP/DBP, heart rate, and 
temperature), and clinical safety labs (hematology, serum chemistry, and urinalysis). 
7.2 Definition of Adverse Event  
An AE is defined in 21 CFR 312.32(a) as follows: 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. 
An AE (also referred to as an adverse experience) can be any unfavorable and unintended sign 
(e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a drug, and does not imply any judgment about causality.  An AE can arise with any use of the 
drug (e.g., off-label use, use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose. 
AEs will be regarded as “pretreatment” if they occur during the placebo washout period or 
placebo run-in period.  TEAEs are defined as any AE that starts or increases in severity after the 
first randomized dose of study treatment (active or placebo) on Day 4.  
7.3 Definition of Serious Adverse Event  
A SAE is defined in 21 CFR 312.32(a) as follows: 
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results 
in any of the following outcomes: 
 Death; 
 Life-threatening AE; 
 Inpatient hospitalization or prolongation of existing hospitalization; 
 Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 
 Congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
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An AE is considered “life-threatening” if, in the view of either the Investigator or Sponsor, its 
occurrence places the patient or subject at immediate risk of death.  It does not include an AE 
that, had it occurred in a more severe form, might have caused death. 
7.3.1 Adverse Events of Hypoglycemia 
The CTCAE (version 4.0) definition for mild, moderate, and severe hypoglycemia based on blood 
glucose will be used, as shown below: 
Mild: from 55 to <70 mg/dL (3.0 to < 3.8 mmol/L) 
Moderate: from 40 to < 55 mg/dL (2.2 to < 3.0 mmol/L) 
Severe: from 30 to < 40 mg/dL (1.7 to < 2.2 mmol/L) 
Life Threatening: < 30 mg/dL (< 1.7 mmol/L) 
7.4 Eliciting and Reporting of Adverse Events 
AE monitoring will start immediately following the first dose of washout period placebo and will 
continue through the Follow-Up Visit.  Any subject with a possible study treatment-related AE at 
the Follow-Up Visit will be followed until resolution or stabilization of the event.  Further, any 
SAE, whether or not related to study treatment, that occurs within 30 days following the last dose 
of study treatment will be followed until resolution or stabilization of the event.  This may 
require additional clinical assessments and laboratory tests.  The follow-up results will be 
recorded in the subject's source documentation and in the CRF. 
Subjects will be instructed to report all AEs experienced during the study, and subjects will be 
assessed for the occurrence of AEs throughout the study.  In order to avoid bias in eliciting AEs, 
subjects will be asked general, non-leading questions such as "How are you feeling?"   
All AEs, including pretreatment and TEAEs, reported by the subject, observed or otherwise 
identified by the Investigator, or other Investigational Site personnel will be documented.   
Medical conditions existing at Screening should be recorded as medical history.  New or 
worsening pre-existing medical conditions or diseases are considered AEs if they arise or worsen 
after the Screening visit, and should be recorded as AEs. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery.  The condition for which the surgery is required is an AE if it occurs or is 
detected following the first dose of Study treatment through the Follow-Up Visit.  Conditions 
leading to planned surgical procedures are not AEs if the condition(s) was (were) known before 
study treatment.  In the latter case, the condition should be reported as medical history. 
7.4.1 Routine Reporting of Adverse Events 
All AEs, whether or not associated with the study treatment, 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 (see Section 7.4.2 for further detail) and regular 
regulatory reporting requirements under 21 CFR 312.33.  


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For each AE, the following information will be entered in the CRF: 
 Medical diagnosis of the event in standard medical terminology (if a medical diagnosis 
cannot be determined, a description of each sign or symptom characterizing the event); 
 Date of onset of any new AE or worsening of a previously observed AE.  For the days 
when the subject is housed in the CRU (Day 1-2), the time (based on a 24-hour clock) of 
onset should be recorded if available; 
 Date of resolution of the event (or confirmation ongoing).  For the days when the subject 
is housed in the CRU (Day 1-2), the time (based on a 24-hour clock) of resolution should 
be recorded if available; 
 Whether the event is serious (per definition in Section 7.3), and if so, the reason it is 
considered serious; 
 Severity of AE (per definition in Section 7.6); 
 Assessment of the attributability of the AE to the study treatment [per definition in 
Section 7.5];  
 Whether the event is expected (per definition in Section 7.7); 
 Action taken in treating the AE (including concomitant medications or therapies 
administered) and/or change in the study treatment administration or dose (including 
whether the study treatment was temporarily interrupted or discontinued); 
 Outcome of AE (per definition in Section 7.8).   
7.4.2 Reporting of Serious Adverse Events, Including Death 
The Sponsor will adhere to all expedited regulatory reporting requirements as per 21 CFR 
312.32.  
SAEs, including death due to any cause, which occur during this study or within 30 days 
following the last dose of the study treatment, whether or not related to the administration of 
study treatment, must be reported by the Investigator or other Investigational Site personnel to 
the Medical Monitor by telephone or fax within 24 hours of learning of the event.  The contact 
information for the Medical Monitor is provided below. 
Medical Monitor: 
 
Carmen Margaritescu, MD 
Safety Office, Integrium, LLC 
Office: 714-210-6665  
Cellular: 714-328-7083 
Email: safety@integrium.com 
 
SAE Forms will be provided by the Sponsor or Sponsor designated CRO.  If all information is 
not known at the time of initial reporting, an initial report should still be made.  In the event there 
is a question as to whether the experience is serious, the information should be forwarded to the 
Medical Monitor for review.  The Investigator is responsible for following up on completion of 
the SAE Form.  The Investigator will submit substantiating data in hard copy form, such as 


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diagnostic test reports and progress notes, to the Medical Monitor.  In the case of fatality, 
autopsy reports will be furnished to the Medical Monitor as soon as available.  If the Medical 
Monitor is informed of a SAE via a telephone call, preliminary information will be obtained, and 
the study site will be instructed to fax an SAE Form. 
In the event of a medical emergency or an SAE that is unexpected (as defined in Section 7.7) and 
possibly related to the study treatment (s) (i.e., an adverse reaction or suspected adverse reaction 
as defined in Section 7.5), the blind will be broken for the subject that experiences the event. An 
emergency code break envelope for each subject will be provided to the Investigational Site and 
also to the Medical Monitor.  In the event that the Investigational Site personnel need to unblind 
the study treatment and cannot access the relevant code break envelope at the site, they can 
contact the Medical Monitor. 
The initial SAE Form and any subsequent follow-up SAE Forms submitted to provide more 
accurate, corrected, or new information must be signed by the Investigator.  The Investigator and 
Investigational Site Personnel must make every reasonable effort to obtain, from other 
institutions if necessary, all supporting medical case records as needed to comply with expedited 
Investigational New Drug application (IND) safety reporting requirements.   
If the SAE involves expedited IND safety reporting (as determined by the Sponsor or designee), 
all supporting medical records must be submitted to the Sponsor or designee within 4 calendar 
days for death or life-threatening events, and 10 calendar days for all other events.  In cases 
where medical records and supporting documentation are unobtainable, the Investigator must 
generate a narrative of the event utilizing, when necessary, interviews with the subject, their 
family members and care givers as appropriate.  
The Investigator must also promptly inform the governing IRB of the SAE in accordance with 
the governing IRB’s requirements.  Any SAE that is determined by the Sponsor to be reportable 
to the FDA as an IND Safety Report (as defined in 21 CFR 312.32) will be reported to FDA by 
the Sponsor or designee within the specified time frame.  All IND Safety Reports will also be 
promptly provided to the Investigator for submission to his/her IRB.  Similarly, any SAE that is 
determined by the Sponsor to require expedited reporting to other regulatory authorities will be 
reported to the appropriate authorities by the Sponsor or designee within the specified time 
frames, and will be provided to the Investigator for submission to his/her IRB. 
The Investigator, Medical Monitor, and Sponsor will review each SAE report and evaluate the 
relationship of the adverse experience to study treatment and to underlying disease.  Based on 
this assessment, a decision will be made concerning the need for further action.  The primary 
consideration governing further action is whether new findings affect the safety of subjects 
participating in the clinical trial.  If the discovery of a new adverse experience related to the 
study treatment raises concern over the safety of continued administration of study treatment, the 
Sponsor will take immediate steps to notify the regulatory authorities. 
Further action that may be required includes the following: 
1. Alteration of existing research by modification of the protocol; 
2. Discontinuation or suspension of the study; 
3. Alteration of the informed consent process by modification of the existing consent form 
and informing current study participants of new findings; 


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4. Modification of previously identified expected adverse experiences to include adverse 
experiences newly identified as study treatment-related. 
 
If the subject or partner of a subject participating in the study becomes pregnant during the study 
or within 30 days of discontinuing study medication, the Investigator should report the 
pregnancy to Integrium within 24 hours of being notified. Safety personnel will then forward 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. 
7.5 Causality Assessment of Adverse Events 
For all AEs, the Principal Investigator will provide an assessment of causal relationship to the 
study treatment (active or placebo).  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. 
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. 
 
7.5.1 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. 


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Long-term animal studies have not been completed to assess whether ORMD-0801 impairs 
fertility.  
7.6 Adverse Event Severity Assessment 
The severity of each AE will be graded according to the NCI CTCAE, version 4.03.  The 
severity of AEs that are not specifically listed in the CTCAE will be categorized according to the 
general guidelines provided in the CTCAE, and as summarized in the table below.  
General Guidelines for Severity Assessment of Adverse Events 
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) [preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.]. 
Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL (bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden). 
Grade 4:  Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
 
Note the distinction between the severity and the seriousness of an AE.  A severe AE is not 
necessarily a SAE.  For example, a headache may be severe (interferes significantly with 
patient's usual function) but would not be classified as serious unless it met one of the criteria for 
SAEs, listed above in Section 7.3. 
7.7 Expectedness of Adverse Event 
An unexpected AE is defined in 21 CFR 312.32(a) as follows: 
An AE is considered “unexpected” if it is not listed in the IB or is not listed at the specificity 
or severity that has been observed; or, if an IB is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the 
current application, as amended. 
7.8 Assessment of Adverse Event Outcome 
Outcome of AEs will be defined according to ICH Topic E2B, ICH Guideline. 
 Recovered/Resolved:  The subject has recovered fully from the AE without any 
remaining effects or impairment. 
 Recovered/Resolved with Sequelae:  The subject has recovered, but with an after effect 
possibly due to disease or treatment. 
 Not Recovered/Not Resolved:  The condition is still present. 


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 Fatal:  Fatal should only be used when death is possibly related to the AE. 
 Unknown:  The primary outcome is not known at the time of the final assessment.  If an 
outcome for an AE is not available at the time of the initial report, follow-up will proceed 
until an outcome is known or followed up to the Final Study Visit.  Any subject with a 
possible study treatment-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 Study 
treatment (active or placebo), that occurs within 30 days following the last dose of Study 
treatment will be followed until resolution or stabilization of the event. 
7.9 Clinical Findings 
Any significant clinical findings at the Follow-Up Visit will be followed until the condition 
returns to pre-study status, stabilizes, or can be explained as not being study treatment related.  If 
the clinical finding is reported as an AE (per the criteria outlined in Section 10.2), the follow-up 
procedures for AEs defined above will apply. 
 
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-012.  Additional details will be provided in the statistical 
analysis plan. 
8.1 Sample Size 
A total of 30 subjects will be randomized to receive either placebo, ORMD-0801 460 IU qd, 
ORMD-0801 460 IU bid, or ORMD-0801 460 IU tid during each treatment period.   
Safety will be a secondary endpoint for this trial and will be assessed primarily based on AEs.  
Secondary safety assessments will include physical examination, 12-lead ECG, vital signs 
(including weight, seated SBP/DBP, heart rate, and temperature), and clinical safety labs 
(hematology, serum chemistry, and urinalysis). 
This study is not powered for statistical significance.   
8.2 Pharmacokinetic/Pharmacodynamic Evaluation 
The PK/PD analysis will be conducted using model-independent methods and will be based on 
plasma concentrations of insulin and C-peptide. 
Individual plasma concentrations of insulin and C-peptide will be listed for each subject and 
sampling time and summarized descriptively using the arithmetic mean, SD, CV (%), median, 
minimum and maximum. Individual plasma concentration-time profiles of insulin and C-peptide 
will be plotted on both a linear and a semi-logarithmic scale. Mean values will also be presented 
graphically. 
8.3 Continuous Glucose Monitor Evaluation 
For the purpose of analysis: 


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 24-hour will be considered to be from 6AM to 6AM, 
 Daytime will be considered to be from 6AM to 10PM, and 
 Nighttime will be considered to be from 10PM to 6AM. 
The last 2 days with at least 80% of expected measurements prior to dosing will be considered 
the run-in days for each of the parameters. The last 2 days with at least 80% of expected 
measurements prior to 8 hours after the last dose will be considered the on treatment days. The 
measurements more than 8 hours after the last dose will be considered the follow-up days. 
The area under the curve (AUC) will be derived for each of the time periods (24-hour, daytime 
and nighttime) using the indicated days (run-in days, treatment days and follow-up days). The 
average glucose measurement will be derived by dividing the AUC by the number of observed 
hours. The average change from run-in will be derived for each treatment regimen for both the 
treatment days and the follow-up days. 
The placebo adjusted change in means will be derived for each of the active therapy regimens by 
subtracting the placebo mean (the mean change from run-in while the subject was receiving 
placebo) from the active therapy mean (the mean change from run-in while the subject was 
receiving the active therapy).  The placebo adjusted change in means will be derived for both the 
treatment days and the follow-up days. 
The placebo adjusted change in means will be analyzed using an Analysis of Variance 
(ANOVA) with treatment as the main effect to determine whether multiple doses a day has an 
effect on the CGM parameters. 
The ratios of the placebo adjusted change in means between the active treatments within each 
subject will also be derived to estimate the magnitude of the dose response. 
Summary statistics will be presented for both the placebo adjusted change in means and the ratios 
of the placebo adjusted change in means. Analysis results will be presented for the change in 
means. 
8.4 Safety Evaluation 
8.4.1 Safety Population 
All randomized subjects who receive at least one dose of study treatment will be included in the 
safety analysis population.   
8.4.2 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 washout period or placebo run-in period.  TEAEs are defined as any 
AE that starts or increases in severity after the first randomized dose of study treatment on Visit 
2/Day 4. 
The incidence of TEAEs will be tabulated by MedDRA preferred term, system organ class, 
treatment group, severity, and assigned relationship to study treatment.  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 


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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 study treatment, action 
taken, and outcome.  A similar listing will be prepared for the pretreatment AEs.   
Pretreatment AEs and TEAEs that lead to withdrawal from the study will be separately listed and 
summarized.  Similarly, separate tabulations and listings will be prepared for pretreatment and 
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 and placebo is not planned. 
8.4.3 Laboratory Evaluations 
Individual clinical safety lab (hematology, serum chemistry, and urinalysis) 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 (Visit 2/Day 1) to postdose (Visit 3) will also be 
produced for the laboratory assessments based on the categories of Low, Normal, and High.  A 
clinically significant change from baseline (Screening) will be recorded as an AE if deemed 
appropriate by the Investigator. 
8.4.4 Vital Signs 
Individual vital sign measurements (height, weight, seated SBP/DBP, heart rate, and 
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 
(predose Day 1) in vital sign measurements will be calculated and summarized descriptively.  A 
clinically significant change from baseline (predose Day 1) will be recorded as a TEAE if 
deemed appropriate by the Investigator. 
8.4.5 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).   
8.4.6 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. 
8.4.7 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 study treatment) taken by the subject from Visit 
2/Day 1 through the Visit 3 will be considered “concomitant” medications and supplements.  


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Medications and supplements taken prior to Visit 2/Day 1 that are no longer being taken at the 
time of Visit 2/Day 1 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 study treatment.  The incidence of these prior and concomitant medications and 
supplements will be summarized. 
8.4.8 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 
statistical manner. 


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9 DATA MANAGEMENT 
9.1 Data Collection 
All data required by the study protocol will be collected in a validated database according to the 
contract research organization’s (CRO’s) SOPs. 
9.2 Electronic Data Capture 
Data from the source documents will be entered into the electronic data capture (EDC) system by 
authorized Investigational Site personnel.  Data Management staff, using both electronic and 
manual checks, will systematically check the data.  Errors or omissions will result in queries 
(which can be issued by the Study Monitor or Data Management staff), which will be presented 
to the Investigational Site within the EDC system.  The Investigational Site will resolve the 
queries within the EDC system.  The Study Monitor and Data Management staff will review the 
responses as part of the query resolution process.  The EDC system will track the queries with 
the corresponding responses. 
Medications and supplements entered into the database will be coded in the EDC system using 
the World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system.  AEs and Medical History will be coded in the EDC 
system using MedDRA terminology.  
Clinical laboratory samples will be processed by CMB and the PK/PD samples will be processed 
by New Rambam Laboratories 1997 Ltd, 16 Hillel St., Israel and the results will be sent 
electronically to Integrium. The clinical laboratory results will be imported into the database. 
9.3 Quality Assurance and Database Lock 
A 100% critical variable review of all key safety and secondary endpoint data in the database 
will be performed.  Following this review, a data quality control audit or a random sample equal 
to the square root plus 1 of the total population will be performed. 
When the database has been declared to be complete and accurate, the database will be locked.  
Any changes to the database after that time can only be made by joint written agreement between 
the Sponsor, the Investigator, Integrium, and the study biostatistician. 
 
10 AMENDMENTS/MODIFICATIONS OF THIS 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 


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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. 
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. 
11.1 
Protection of Human Subjects 
11.1.1 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. 
11.1.2 Good Clinical Practice and Regulatory Compliance 
The Investigator will conduct this study in accordance with the principles of GCP (current ICH 
guidelines) and the requirements of all local regulatory authorities regarding the conduct of 
clinical trials and the protection of human subjects. 
The study will be conducted as described in the approved protocol, with amendments and in 
accordance with the obligations of clinical Investigators set forth in the Form FDA 1572 and in 21 
CFR 50, 54, 56 and 312. 
11.1.3 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:  


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 IRB for review and approval/favorable opinion.  
 The Sponsor via appropriate designees. 
 Regulatory Authorities, if required by local regulations.  
Documentation of IRB approval signed by the chairperson or designee of the IRB will be provided 
to the Sponsor via appropriate designees.  
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).  
11.1.4 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.  


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11.2 
Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects’ state of 
health will be regarded as confidential.  This is detailed in the ICF provided to the subject.  An 
agreement for the use or disclosure of any such information (PHI) will be obtained from the 
subject in writing (HIPAA authorization) prior to performing any study-related procedures.  
Disclosure of subject medical information obtained as a result of this study to third parties other 
than those noted below is prohibited.   
Medical information resulting from a subject’s participation in this study may be given to the 
subject’s personal physician or to the appropriate medical personnel responsible for the subject’s 
welfare.  Data generated as a result of this study are to be available for inspection on request by 
FDA or other government regulatory agency auditors, the Sponsor (or designee), and the IRB.   
The information developed in this clinical study will be used by the Sponsor in the clinical 
development of the Study treatment 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. 
11.3 
Case Report Forms 
All data required by the study protocol will be recorded in the CRF provided by the EDC vendor.  
Data from the source documents will be entered into the EDC system by authorized 
Investigational Site personnel.  The CRF will be updated at the time of each subject visit.  
Results of tests performed outside the Investigational Site will be entered as soon as available to 
the Investigational Site.  The Principal Investigator must verify that all data entries in the CRF 
are accurate and correct by signing the subject’s CRF investigator signature screen. 
11.4 
Source Documentation 
All data entered in the CRF must be verifiable against source documentation.  Source documents 
may include, but are not limited to, a subject’s medical record, hospital charts, clinic charts, the 
Principal Investigator’s study files, as well as the results of diagnostic tests.   
11.5 
Retention of Records 
The Investigator has the responsibility of maintaining a comprehensive and centralized filing 
system containing all study-related documentation.  These files must be available for inspection 
by the Sponsor or designee, the IRB, and regulatory authorities (i.e., FDA or international 
regulatory authorities) at any time and should consist of the Essential Documents as defined in 
ICH E6, which include, but are not limited to, the following elements: 
 Subject files, containing the completed CRFs, supporting source documentation from the 
medical record, including laboratory data, and the signed ICF;  
 Regulatory files, containing the protocol with all amendments and Sponsor and 
Investigator signature pages, copies of all other regulatory documentation, and all 
correspondence between the site and the IRB and Sponsor; and  


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 Drug accountability files, including a complete account of the receipt and disposition of 
the Study treatment (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. 
11.6 
Clinical Study Report 
After completion or termination of the study, a clinical study report will be prepared.  The 
structure and content of the report will meet that described in Structure and Content of Clinical 
Study Reports E3 (ICH Harmonized Tripartite Guideline, dated November 30, 1995).  The 
Principal Investigator must verify that all information and data in the clinical study report is 
accurate and correct by signing the clinical study report.   
12 STUDY ADMINISTRATION 
12.1 
Study Monitoring 
This study will be monitored by the Sponsor or designee to evaluate the progress of the study, to 
verify the accuracy and completeness of the CRFs, to assure that all protocol requirements, 
applicable laws and/or regulations, and Investigator’s obligations are being fulfilled, and to 
resolve any inconsistencies in the study records.  
The Investigator will allow the Study Monitor to periodically review, at mutually convenient 
times during the study and after the study has been completed, all CRFs and office, hospital, and 
laboratory records supporting the participation of each subject in the study.   
The Study Monitor will compare the CRF data against source documentation in order to verify 
its accuracy and completeness.  The Investigator and Investigational Site staff will collaborate 
with the Study Monitor to resolve any identified data discrepancies in a timely manner.   
The Study Monitor will record any protocol deviations identified, including, but not limited to, 
subjects that were enrolled even though they did not meet all eligibility criteria, subjects who 
took concomitant medications specifically prohibited by the protocol, subjects who received the 
wrong study treatment or incorrect dose, and subjects who failed to comply with the protocol-


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CONFIDENTIAL 
defined dietary restrictions.  The Investigator and Investigational Site staff will collaborate with 
the Study Monitor to identify the reason for each protocol deviation.   
The Study Monitor will compare the Investigational Site study treatment accountability record 
against the study treatment inventory (unused and used) at the site.  The Investigator and 
Investigational Site staff will collaborate with the Study Monitor to resolve any identified 
discrepancies in a timely manner. 
Each issue identified during study monitoring visits will be documented and reported to both the 
Sponsor and the Investigator. 
12.2 
On-Site Audits 
The FDA, or other regulatory authorities, may request access to all study records for inspection 
and copying.  The Principal Investigator and Investigational Site staff will cooperate with the 
inspectors and allow access to all source documents supporting the CRFs and other study-related 
documents.  The Investigator will immediately notify the Sponsor when contacted by any 
regulatory authority for the purpose of conducting an inspection.   
The Sponsor or designee may also request to visit the Investigator’s site to conduct an audit of 
the study.  Prior to initiating this audit, the Investigator will be contacted by the Sponsor to 
arrange a convenient time for this visit.  The Principal Investigator and Investigational Site staff 
will cooperate with the auditors and allow access to all source documents supporting the CRFs 
and other study-related documents.  
12.3 
Data Quality Assurance 
All CRFs must be completed by authorized Investigational Site personnel who have undergone 
electronic CRF training.  Data will be entered into the CRF as information becomes available on 
a visit-by-visit basis.  All data recorded on the CRFs must be supported by source 
documentation.  The Principal Investigator must verify that all data entries in the CRF are 
accurate and correct by electronically signing and dating the CRF. 
All CRF corrections must be made by the Principal Investigator or authorized Investigational 
Site personnel.  The Principal Investigator must authorize changes to the recorded data, and this 
authorization must be documented in the source documents.   
Refer to Section 8 for further details regarding Data Management quality assurance, including 
query generation and resolution, final data review, and database lock. 
12.4 
Publication Policy 
All information and data obtained in the course of the study are the property of the Sponsor and 
are considered confidential.  To avoid disclosures that could jeopardize proprietary rights, the 
institution and/or the Investigator agree to certain restrictions on publications (e.g., abstracts, 
speeches, posters, manuscripts, and electronic communications), as detailed in the clinical trial 
agreement. 
The publication or presentation of any study results shall comply with all applicable privacy 
laws, including, but not limited to, HIPAA or equivalent. 


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This trial will be registered in a publicly accessible database (clinicaltrials.gov) not later than 21 
days after enrollment of the first subject.  Results of this trial, including negative and 
inconclusive, as well as positive results, will be made publicly available. 
12.5 
Disclosure and Confidentiality 
By signing the protocol, the Investigator agrees to keep all information provided by the Sponsor 
and Integrium in strict confidence and to request similar confidentiality from his/her staff and the 
IRB.  Study documents provided by the Sponsor and Integrium (protocols, IBs, CRFs, and other 
material) will be stored appropriately to ensure their confidentiality.  The information provided 
by the Sponsor and Integrium to the Investigator may not be disclosed to others without direct 
written authorization from the Sponsor and Integrium, except to the extent necessary to obtain 
informed consent from subjects who wish to participate in the study. 
 
 


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13 REFERENCES 
American Diabetes Association (2009): “Standards of medical care in diabetes – 2009.” Diabetes 
Care 32(S1):S13-S61. 
Centers for Disease Control and Prevention (2008): “National diabetes fact sheet: general 
information and national estimates on diabetes in the United States, 2007.” U.S. Department of 
Health and Human Services, Centers for Disease Control and Prevention, Atlanta, GA. 
Cleary PA, Orchard TJ, Genuth S, Wong ND, Detrano R, Backlund JY, Zinman B, Jacobson A, 
Sun W, Lachin JM, Nathan DM; DCCT/EDIC Research Group (2006): “The effect of intensive 
glycemic treatment on coronary artery calcification in type 1 diabetic participants of the Diabetes 
Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications 
(DCCT/EDIC) Study.” Diabetes 55(12):3556-3565. 
Diabetes Control and Complications Trial Research Group (1993): “The effect of intensive 
diabetes treatment on the development and progression of long-term complications in insulin-
dependent diabetes mellitus.” N Engl J Med 329(14):977-986. 
Holm S (1979): “A simple sequentially rejective multiple test procedure.” Scandinavian Journal 
of Statistics 6:65–70. 
Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B (2006): 
“Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and 
adjustment of therapy: a consensus statement from the American Diabetes Association and the 
European A1ssociation for the Study of Diabetes.” Diabetes Care 29(8):1963-1972. 
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B (2009): 
“Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation 
and adjustment of therapy: a consensus statement of the American Diabetes Association and the 
European Association for the Study of Diabetes.” Diabetes Care 32(1):193-203. 
U.K. Prospective Diabetes Study (UKPDS) Group (1998a): “Intensive blood glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complication in 
patients with type 2 diabetes (UKPDS 33).” Lancet 352(9131):837-853. 
U.K. Prospective Diabetes Study (UKPDS) Group (1998b): “Effect of intensive blood glucose 
control with metformin on complication in overweight patients with type 2 diabetes (UKPDS 34).” 
Lancet 352(9131):854-865. 
U.S. Food and Drug Administration (2008): “Draft Guidance for Industry: Diabetes Mellitus: 
Developing Drugs and Therapeutic Biologics for Treatment and Prevention.” U.S. Department of 
Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research, Silver Spring, MD. 
World Health Organization (2006): “Definition and Diagnosis of Diabetes Mellitus and 
Intermediate Hyperglycaemia: Report of a WHO/IDF Consultation.” World Health Organization, 
Geneva, Switzerland. 
 

SAP_001.pdf: 
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Oramed Ltd. 
Version: 0.1 
 
 
Protocol No.: ORA-D-012  
Statistical Analysis Plan 
 
  
Page 1 of 17 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION.   
IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
 
 
 
INTEGRIUM, LLC 
BIOSTATISTICS AND STATISTICAL PROGRAMMING 
DEPARTMENT 
 
 
Clinical Study Protocol: ORA-D-012 
 
A Phase 2a, Randomized, Double-Blind, Double-Dummy, Placebo- 
Controlled, 3-Way Crossover Study to Compare Safety, Efficacy 
and Pharmacodynamics of Single and Multiple Doses of ORMD- 
0801 or Placebo in Adult Subjects with Type 2 Diabetes Mellitus 
  
 
Statistical Analysis Plan (SAP) Documentation 
 
Author(s): 
Kenneth E. Homer, Oliver Lopez  
Sponsor: 
Oramed Pharmaceuticals, Inc. 
Document status: 
Version 0.1 
Dates: 
 
Number of pages: 
18 


Integrium, LLC 
 
Oramed Ltd. 
Version: 0.1 
 
 
Protocol No.: ORA-D-012  
Statistical Analysis Plan 
 
  
Page 2 of 17 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION.   
IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
Signature Page 
 
Statistical Analysis Plan for Clinical Study Protocol: 
ORA-D-012 
 
 
A Phase 2a, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, 3-Way 
Crossover Study to Compare Safety, Efficacy and Pharmacodynamics of Single and Multiple 
Doses of ORMD-0801 or Placebo in Adult Subjects with Type 2 Diabetes Mellitus 
 
Approved by: 
 
 
 
 
Miriam Kidron, PhD 
Chief Scientific Officer & Director, 
Oramed Ltd. 
 
Date 
 
 
 
 
 
Author(s): 
 
 
 
 
Kenneth E. Homer, M.S. 
Director of Biometrics 
Integrium, LLC  
 
Date 
 
 
 
Oliver Lopez, PhD 
Biostatistician 
Integrium, LLC 
 
Date 


Integrium, LLC 
 
Oramed Ltd. 
Version: 0.1 
 
 
Protocol No.: ORA-D-012  
Statistical Analysis Plan 
 
  
Page 3 of 17 
 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION.   
IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
Document History 
 
Version 
Number 
Author 
Date  
Change 
0.1 
O. Lopez 
21DEC2016 Initial draft 
0.2 
O. Lopez 
05JAN2017 
Made changes from interval review 
 
 
 
 
 


Integrium, LLC 
 
Oramed Ltd. 
Version: 0.1 
 
 
Protocol No.: ORA-D-012  
Statistical Analysis Plan 
 
  
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THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION.   
IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
Glossary of Abbreviations 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUC 
Area Under the Time-Concentration Curve 
bid 
Twice Daily 
CGM 
Continuous Glucose Monitoring  
CRF 
Case Report Form 
CRU 
Clinical Research unit 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology for Adverse Events 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HR 
Hour 
ICH 
International Conference on Harmonization 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Sample Size 
NCI 
National Cancer Institute 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
qd 
Once Daily 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
T2DM 
Type 2 Diabetes Mellitus  
TEAE 
Tretment-Emergent Adverse Events 
tid 
Three Times Daily 
WHO 
World Health Organization  
 


Integrium, LLC 
 
Oramed Ltd. 
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Statistical Analysis Plan 
 
  
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THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION.   
IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
Table of Contents 
Signature Page ............................................................................................................................ 2 
Document History....................................................................................................................... 3 
Glossary of Abbreviations .......................................................................................................... 4 
1. 
Introduction ......................................................................................................................... 7 
1.1. 
Scope ........................................................................................................................ 7 
1.2. 
Study Overview ....................................................................................................... 7 
1.3. 
Study Objectives ...................................................................................................... 7 
1.3.1 Primary Objectives .................................................................................................. 7 
1.3.2 Secondary Objectives .............................................................................................. 7 
1.3.3 Exploratory Objectives ............................................................................................ 8 
2. 
Detailed Statistical Methods ................................................................................................ 8 
2.1. 
General Statistical Methods ..................................................................................... 8 
2.2. 
Study Populations .................................................................................................... 8 
2.3. 
Patient Disposition and Characteristics ................................................................... 8 
2.4. 
Demographics and Patient Baseline Characteristics ................................................ 8 
2.5. 
Study Drug Duration and Compliance .................................................................... 9 
2.6. 
Prior and Concomitant Medications ........................................................................ 9 
2.7. 
Safety Evaluations ................................................................................................... 9 
2.7.1. Adverse Events ........................................................................................................ 9 
2.7.2. Hypoglycemic Events .............................................................................................. 9 
2.7.3. Safety Laboratory Evaluations .............................................................................. 10 
2.7.4. Vital Signs ............................................................................................................. 10 
2.7.5. Electrocardiogram .................................................................................................. 10 
2.7.6. Physical Examination ............................................................................................ 10 
2.7.7. Continuous Glucose Monitoring............................................................................ 10 
2.8. 
Efficacy Evaluations .............................................................................................. 10 
2.8.1. Continuous Glucose Monitoring............................................................................ 10 
2.8.2. Pharmacokinetic / Pharmacodynamic Evaluations ................................................ 11 
2.9. 
Interim Analyses .................................................................................................... 12 
2.10. Other Analyses ....................................................................................................... 12 
2.11. Sample Size and Power Considerations ................................................................ 12 
2.12. Randomization Scheme and Codes ....................................................................... 12 
2.13. Handling Missing Data .......................................................................................... 13 
2.14. Protocol Deviations ............................................................................................... 13 
2.15. Computer Systems and Packages Used for Statistical Analyses ........................... 14 


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Statistical Analysis Plan 
 
  
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IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
3. 
Data Listing Shells ............................................................................................................ 14 
3.1. 
Data Listings Table of Contents ............................................................................ 14 
3.2. 
Data Listings .......................................................................................................... 15 
4. 
Summary Table and Figure Shells .................................................................................... 15 
4.1. 
Post-text Table of Contents ................................................................................... 15 
4.2. 
Post-text Figures Tables of Contents ..................................................................... 17 
4.3. 
Table Shells ........................................................................................................... 17 
 


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1. 
Introduction 
1.1. 
Scope 
This document contains detailed information to aid the production of the Clinical Study 
Report (CSR) including summary tables and listings for trial ORA-D-012.  The contents of 
this document were reviewed by the sponsor, Oramed, Ltd., and the trial biostatistician at 
Integrium. 
1.2. 
Study Overview 
This a phase 2a, randomized, double-blind, double-dummy, placebo-controlled, 3-way 
crossover study enrolling approximately 30 adult subjects with T2DM from age 20 to 75 
inclusive.  Following a 7-10 day Screening period, eligible subjects will be housed in the CRU 
for the duration of each treatment cycle beginning with a 3-day single-blind placebo run-in. 
On Day 4, each subject will be randomized to a treatment sequence that will include three 
treatment assignments for each of three treatment periods according to the randomization 
scheme.  
All eligible subjects will receive placebo plus two of the following: ORMD-0801 460 IU qd, 
OMRD-0801 bid, or ORMD-0801 tid. Subjects will receive the randomized treatment from 
Day 4 through Day 8. A 24-hour single-blind placebo washout will be done on Day 9.  
Subjects will be discharged on the morning of day 10. Each treatment Period will be separated 
by a 2-week washout. A final follow-up visit will be performed 1 week after the end of the 
third treatment period. 
In addition, adverse events, clinical laboratory values, vital signs, and electrocardiograms 
(ECGs) will be evaluated periodically for safety. 
1.3. Study Objectives 
1.3.1 
Primary Objectives 
The primary objectives of this study are to compare pre-treatment (Day 3) to end of treatment 
(Day 8) 24-hour CGM glucose for single and multiple doses of ORMD-0801 vs placebo and to 
evaluate safety parameters for single and multiple dose of ORMD-0801 vs placebo.  
1.3.2 
Secondary Objectives 
Secondary objectives are: 
• To compare pre-treatment (Day 3) to end of treatment (Day 8) mean daytime CGM 
glucose for single and multiple doses of ORMD-0801 vs placebo. 
• To compare pre-treatment (Day 3) to end of treatment (Day 8) mean nighttime CGM 
glucose for single and multiple doses of ORMD-0801 vs placebo. 
• To compare pre-treatment (Day 3) to post-treatment washout (Day 9) 24-hour CGM 
glucose for single and multiple doses of ORMD-0801 vs placebo. 
• To compare post-prandial glucose measurements for single and multiple doses of 
ORMD-0801 vs placebo. 


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• To compare pre-treatment (Day 3) to end of treatment (Day 8) insulin 
pharmacokinetics (PK) for single and multiple doses of ORMD-0801 vs placebo. 
• To compare pre-treatment (Day 3) to end of treatment (Day 8) C-peptide 
pharmacodynamics (PD) for single and multiple doses of ORMD-0801 vs placebo. 
• To compare defined events of hypoglycemia for single and multiple doses of ORMD-
0801 vs placebo. 
1.3.3 
Exploratory Objectives 
There are no exploratory objectives.  
2. 
Detailed Statistical Methods 
2.1. 
General Statistical Methods 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics. For descriptive statistics summary tables will include by 
study group summaries of sample size, arithmetic mean, standard deviation, coefficient of 
variation (if appropriate), median (and other percentiles, if appropriate), minimum and 
maximum values, and 95% Confidence Intervals (if appropriate). For categorical variables 
summary tables will include by study group summaries of frequency counts 
2.2. 
Study Populations 
 
Safety population: All patients who receive at least one dose of the study drug will be included 
in the safety population 
Efficacy population: Intent-to-treat (ITT) population with last observation carried forward 
(LOCF) in patients who receive at least one treatment with study drug and in whom CGM 
data was collected at least once during treatment. 
2.3. 
Patient Disposition and Characteristics 
An account of the patients by disposition will be tabulated overall.  The number of patients 
included in each analysis population will be summarized. Patients not completing the study will 
be summarized and listed with the reason for their premature discontinuation.  There will be an 
analysis of withdrawal rates by treatment group using both descriptive statistics and Fisher’s 
exact test (2-sided and alpha=0.05).  A list of screening failures will also be provided. 
2.4. 
Demographics and Patient Baseline Characteristics 
Patient demography will be presented using summary statistics (N, mean, standard deviation, 
median, minimum and maximum) for continuous measurements, or frequency tables 
(numbers and percentages) for categorical measurements. 


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2.5. 
Study Drug Duration and Compliance  
During the run-in period four doses of placebo (8 capsules) will be dispensed to subjects for 
Day 1 and Day 2.  Compliance will be reviewed during admission on Day 2 to protect the 
single-blind nature of this treatment.   
All doses of study treatment will be administered in the CRU. Oral dosing compliance will be 
ascertained by inspection of the oral cavity (mouth check) following dosing. 
This study does not include dose modifications. 
2.6. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization (WHO) 
Drug dictionary March 1, 2013 version.  
Prior medications will be defined as any medication that stops prior to the day of first dose.  
Concomitant medications will be defined as any medication that stops on or after the day of 
first dose.  
Section 2.13 describes the imputation rules for partial dates. All medications will be presented 
in a data listing. 
2.7. 
Safety Evaluations 
2.7.1. Adverse Events 
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Affairs 
(MedDRA) version 16.0 and tabulated, including categorical information of interest such as 
onset and resolution times, time of onset relative to dose, severity at onset, maximum severity, 
causal relationship to study medication, and action taken. The severity of AEs will be graded 
according to NCI CTCAE version 4.03. 
Treatment-emergent adverse events (TEAEs) are defined as any AE that starts or increases in 
severity after the first randomized dose of study treatment on visit 2/Day 4.   The incidence of 
TEAEs will be tabulated by MedDRA preferred term, system organ class, treatment group, 
severity, and assigned relationship to study treatment.  Adverse events will also be 
summarized by severity and relationship to the investigational product (IP).  
The incidence of serious AEs, drug-related AEs, serious and drug-related AEs, and any AEs 
resulting in discontinuation from the study will be listed.  
2.7.2. Hypoglycemic Events 
The proportion (percentage) of patients affected by hypoglycemia and event rates for each of 
the classifications of hypoglycemic events will be reported by treatment received. The time-
distribution of hypoglycemic episodes per patient will be reported for each treatment group. 


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2.7.3. Safety Laboratory Evaluations 
Screening and end of study results, together with changes from screening at end of study, will 
be described using summary statistics for each parameter. Changes from screening will be 
compared between treatments using an Analysis of Variance (ANOVA) model. 
 
A clinically significant abnormal value or clinically significant change from baseline 
(Screening), may be recorded as an AE, if deemed appropriate by the PI or sponsor. 
2.7.4. Vital Signs 
Results, together with changes from baseline, will be described using summary statistics for 
each parameter for each day in which vital signs are collected. Changes from baseline will be 
compared between treatments using an ANOVA model. 
A clinically significant change from baseline may be recorded as an AE, if deemed 
appropriate by the PI or sponsor.  
2.7.5. Electrocardiogram 
Individual 12-lead ECG assessments will be listed by visit.   
2.7.6. Physical Examination 
The Screening and end of treatment results will be described using frequency counts for each 
body system.  
2.7.7. Continuous Glucose Monitoring 
The number of subjects who had at least one value < 60, had at least one value ≥ 125, had at 
least one value ≥ 150, had at least one value ≥ 175, had at least one value ≥ 200, had at least 
one value ≥ 225 and had at least one value ≥ 250 will be summarized for the run-in and end of 
treatment periods for the following time intervals: 
• 24 hour 
• Daytime 
• Nighttime 
2.8. 
Efficacy Evaluations 
2.8.1. Continuous Glucose Monitoring 
The last 2 days with at least 80% of expected measurements prior to dosing will be considered 
the run-in days for each of the parameters. The last 2 days with at least 80% of expected 
measurements prior to 8 hours after the last dose will be considered the on treatment days. The 
measurements more than 8 hours after the last dose will be considered the follow-up days.   


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The 24-hr period (6AM to 6AM), nighttime (from 10pm to 6am), daytime (6AM to 10PM), and 
post-prandial (first hour after meal start time including breakfast, lunch, and dinner) glucose 
values will be summarized. The mean, standard deviation, minimum, maximum, first quartile, 
median, third quartile and inner-quartile range will be presented.  
The area under the curve (AUC) will be derived for each of the time periods (24-hour, daytime 
and nighttime) using the indicated days (run-in days, treatment days and follow-up days). The 
average glucose measurement will be derived by dividing the AUC by the number of observed 
hours. The average change from run-in will be derived for each treatment regimen for both the 
treatment days and the follow-up days.   
The placebo adjusted change in means will be derived for each of the active therapy regimens 
by subtracting the placebo mean (the mean change from run-in while the subject was receiving 
placebo) from the active therapy mean (the mean change from run-in while the subject was 
receiving the active therapy).  
The placebo adjusted change in means will be derived for both the treatment days and the 
follow-up days.  The placebo adjusted change in means will be analyzed using an Analysis of 
Variance (ANOVA) with treatment as the main effect to determine whether multiple doses a 
day has an effect on the CGM parameters.  If the residuals are not normally distributed, then a 
Kruskal-Wallis test (one-way analysis of variance on the ranks) will be performed. 
The ratios of the placebo adjusted change in means between the active treatments within each 
subject will also be derived to estimate the magnitude of the dose response.   
Summary statistics will be presented for both the placebo adjusted change in means and the 
ratios of the placebo adjusted change in means. Analysis results will be presented for the change 
in means. 
2.8.2. Pharmacokinetic / Pharmacodynamic Evaluations 
Since Insulin is present in the subjects regardless of treatment, standard PK derivations do not 
apply. 
 
The PK/PD measurements are taken pre-treatment (Day 3) and at end of treatment (Day 8). 
On Day 3, all subjects received Placebo, so these measurements will be used as the within 
subject control. 
 
Time matched changes between Day 8 and Day 3 will be derived for the PK and PD 
parameters for each subject. 
 
The following time intervals will be summarized: 0 to 60 minutes, 60 to 120 minutes, 120 to 
180 minutes, 180 to 240 minutes, 240 to 300 minutes, 120 to 300 minutes and 180 to 300 
minutes. Please note that the 0 to 60 minute interval will not be summarized, since it is 
believed that the study drug takes 60 minutes to metabolize. 
 


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The following parameters will be derived for Insulin C-Peptide for each subject: 
• Positive Area (Area above 0), 
• Negative Area (Area below 0), 
• Absolute Area (Positive Area + the absolute value of the Negative Area), 
• Maximum Difference, 
• Time of Maximum Difference,  
• Positive Area / hr (for the 120 to 300 minutes and 180 to 300 minutes intervals 
only), 
• Negative Area / hr (for the 120 to 300 minutes and 180 to 300 minutes 
intervals only), and 
• Absolute Area / hr (for the 120 to 300 minutes and 180 to 300 minutes 
intervals only). 
 
The Positive Areas, Negative Areas and Absolute Areas will be compared using a one-way 
analysis of variance (ANOVA) with Fisher’s LSD being used for pairwise treatment group 
comparisons. 
 
The maximum difference and time of maximum difference will be compared in a pairwise 
fashion using the Wilcoxon Rank Sum test. 
 
The PK/PD analysis will be conducted using model-independent methods and will be based on 
plasma concentrations of insulin and C-peptide.  Individual plasma concentrations of insulin 
and C-peptide will be listed for each subject and sampling time and summarized descriptively 
using the arithmetic mean, SD, CV (%), median, minimum and maximum. Individual plasma 
concentration-time profiles of insulin and C-peptide will be plotted on both a linear and a semi-
logarithmic scale. Mean values will also be presented graphically. 
2.9. 
Interim Analyses 
No interim analyses are planned.   
2.10. Other Analyses 
No other analyses are planned at this time. 
2.11. Sample Size and Power Considerations 
A total of 30 subjects will be randomized to receive either placebo, ORMD-0801 460 IU qd, 
ORMD-0801 460 IU bid, or ORMD-0801 460 IU tid during each treatment period.   
This study is not powered for statistical significance.    
2.12. Randomization Scheme and Codes 
The randomization details are documented in a separate randomization plan. 
 
 


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2.13. Handling Missing Data 
Listings will be provided for all data. Descriptive statistics will be provided for all planned 
visits as provided on the Case Report Forms (CRFs).  
Study days will be analyzed using the study days as reported in the Case Report Form. 
Likewise, unscheduled visits will not be reassigned a visit number based on the visit date. 
Dates related to the adverse events and medications will be imputed using the rules below in 
an effort to categorize them properly into the summary tables.  
Imputing partial or missing start dates: 
• If the year is unknown, then the start date will not be imputed. The date will remain 
missing. 
• If the month is unknown and the year is the same as the first dose date of the study, 
then impute the month and day of the date to be equal to the first dose month and day. 
Otherwise, impute the month as January. 
• If the day is unknown and the month and year are the same as the first dose date of the 
study, then impute the day to be equal to the day of the first dose. Otherwise, impute 
the day as ‘01’. 
Impute partial or missing stop dates: 
• If the year is unknown, then the stop date will not be imputed. The date will remain 
missing. 
• If the month is unknown, impute the month as December. 
• If the day is unknown, impute the day to be the last day of the month. 
If an imputed stop date is greater than the date of study completion/discontinuation date of the 
study, then the imputed stop date will be set equal to the date of completion/discontinuation 
date.  
The imputed dates will be stored in the analysis datasets along with the original dates as 
recorded by the sites.  
Efficacy analyses will be performed for the ITT population in which CGM data was collected 
during treatment. The weighted mean night time glucose levels will be calculated on CGM 
data as described in Section 2.8.1. No imputation will be used other than application of linear 
interpolation for calculation of the trapezoidal areas. 
2.14. Protocol Deviations 
Protocol deviations will be displayed in a data listing as provided by the clinical team.  
 
 


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2.15. Computer Systems and Packages Used for Statistical Analyses 
SAS® version 9.4 on the Microsoft Windows 7 64 bit platform will be used for all analyses.  
All computations will be performed using SAS®.  The exact form of the various algorithms 
will be the SAS® defaults.  The output from any SAS® procedure will be used in the tables 
using SAS® macros. 
3. 
Data Listing Shells 
3.1. 
Data Listings Table of Contents 
The following post-text listings will be generated. 
 
 
16.1.7 
Randomization Schedule 
16.2.1 
Subject Completion/Discontinuation 
16.2.2 
Protocol Deviations  
16.2.3 
Population Status 
16.2.4.1 
Demographics and Baseline Characteristics 
16.2.4.2.1 
Substance Use – Alcohol Potential 
16.2.4.2.2 
Substance Use – Tobacco / Nicotine Potential 
16.2.4.2.3 
Substance Use – Caffeine Potential 
16.2.4.3 
Subject Eligibility and Informed Consent 
16.2.4.4 
Medical History / Surgical History / Procedures 
16.2.4.5 
Prior and Concomitant Medications 
16.2.5 
Drug Accountability 
16.2.6.1 
Continuous Glucose Monitoring – 24-hour Mean Values 
16.2.6.2 
Continuous Glucose Monitoring – Daytime Mean Values 
16.2.6.3 
Continuous Glucose Monitoring – Nighttime Mean Values 
16.2.6.4 
Fasting Blood Glucose 
16.2.6.5 
Post-Prandial Blood Glucose – Breakfast, Lunch, and Dinner  
16.2.6.6.1 
Serum Insulin Levels 
16.2.6.6.2 
Serum Insulin Parameters 
16.2.6.7.1 
C-peptide Levels 
16.2.6.7.2 
C-peptide Parameters 
16.2.7.1 
Adverse Events 


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16.2.7.2 
Hypoglycemic Events 
16.2.8 
Safety Laboratory Test Results 
16.2.9.1 
Vital Signs 
16.2.9.2 
Electrocardiogram Results 
16.2.9.3 
Physical Examination Results 
16.2.9.4 
Continuous Glucose Monitoring – Values Outside Observed Value Reference 
Ranges 
3.2. 
Data Listings 
All subjects and all data will be presented in the listings. The listings will be sorted by treatment 
and subject number.  
4. 
Summary Table and Figure Shells 
4.1. 
Post-text Table of Contents 
The following post-text tables will be generated. 
 
Table 
Number 
Table title 
14.1.1.1 
Summary of Subject Screening Disposition (All Subjects) 
14.1.1.2 
Summary of Subject Disposition (Safety Population) 
14.1.1.3 
Summary of Subject Disposition (ITT Population) 
14.1.2.1 
Summary of Demographics and Baseline Characteristics (Safety Population) 
14.1.2.2 
Summary of Demographics and Baseline Characteristics (ITT Population) 
14.1.3 
Summary of Medical History / Surgical History / Procedures (Safety 
Population) 
14.1.4.1 
Summary of Prior Medications (Safety Population) 
14.1.4.2 
Summary of Concomitant Medications (Safety Population) 
14.1.5. 
Summary of Study Medication Usage (Safety Population) 
14.2.1.1 
Summary of Pre-treatment (day 3) to end of Treatment (day 8) Continuous 
Glucose Monitoring Mean 24-hour Glucose – (ITT Population) 
14.2.2.1 
Summary of Pre-treatment (day 3) to end of Treatment (day 8) Continuous 
Glucose Monitoring Mean Daytime Glucose – (ITT Population) 
14.2.2.2 
Summary of Pre-treatment (day 3) to end of Treatment (day 8) Continuous 
Glucose Monitoring Mean Nighttime Glucose – (ITT Population) 


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Table 
Number 
Table title 
14.2.3.1 
Summary of Pre-treatment (day 3) to Post Treatment Washout (day 9) 
Continuous Glucose Monitoring Mean 24-hour Glucose – (ITT Population) 
14.2.4.1 
Summary of Post-Prandial (Breakfast, Lunch, and Dinner) Glucose 
Measurements – (ITT Population) 
14.2.5.1 
Insulin Levels by Time Point (ITT Population) 
14.2.5.2 
Insulin Parameters by Time Intervals (ITT Population) 
14.2.6.1 
C-Peptide Levels by Time Point (ITT Population) 
14.2.6.2 
C-Peptide Parameters by Time Intervals (ITT Population) 
14.3.1.1 
Adverse Events Overall Summary (Safety Population) 
14.3.1.2 
Summary of Treatment Emergent Adverse Events by System Organ Class, 
and Preferred Term (Safety Population)  
14.3.1.3 
Summary of Treatment Emergent Adverse Events Leading to Discontinuation 
of Study (Safety Population)  
14.3.1.4 
Summary of Serious Treatment Emergent Adverse Events (Safety Population) 
14.3.1.5 
Summary of Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Severity (Safety Population) 
14.3.2 
Summary of Laboratory Values (Safety Population) 
14.3.3 
Summary of Vital Signs (Safety Population) 
14.3.4 
Summary of Hypoglycemic Events (Safety Population) 
14.3.5 
Summary of Physical Examination Findings (Safety Population) 
14.3.6.1 
Continuous Glucose Monitoring – Number of Subjects Outside Observed 
Value Reference Ranges by Day (Safety Population) 
14.3.6.2 
Continuous Glucose Monitoring – Number of Subjects Outside Observed 
Value Reference Ranges by Number of Days (Safety Population) 
 
 
 
 
 
 
 
 
 
 


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4.2. 
Post-text Figures Tables of Contents 
The following post-text figures will be generated. 
 
Figure 
Number 
Figure Title 
14.2.1.1 
Mean Daytime Continuous Glucose Monitoring Values by Day (ITT Population) 
14.2.1.2 
Mean Nighttime Continuous Glucose Monitoring Values by Day (ITT 
Population) 
14.2.1.3 
Individual Continuous Glucose Monitoring Values Over Time (ITT Population) 
14.2.1.4 
Individual Continuous Glucose Monitoring Values by Subject (ITT Population) 
14.2.2.1 
Mean Insulin Levels by Time (ITT Population) 
14.2.2.2 
Individual Insulin Levels Over Time (ITT Population) 
14.2.2.3 
Individual Insulin Levels by Subject (ITT Population) 
14.2.3.1 
Mean C-Peptide Levels by Time (ITT Population) 
14.2.3.2 
Individual C-Peptide Levels Over Time (ITT Population) 
14.2.3.3 
Individual C-Peptide Levels by Subject (ITT Population) 
14.2.4 
Integrated Insulin and C-Peptide Levels by Subject (ITT Population) 
 
4.3. 
Table Shells 
The table shells can be found in a separate file. The following number of decimal places will be 
used when presenting summary statistics: 
• N to 0 decimal places 
• Minimum and maximum to the same number of decimal places as recorded in the raw data. 
• Means and medians to 1 more decimal place than is recorded in the raw data. Standard 
deviations to 2 more decimal places than is recorded in the raw data. 
• Percentages to 1 decimal place. 
 
The precision may be changed for individual endpoints as needed.