Clinical trial NCT04564846
Conditions: Diabetes Mellitus, Type 2
Sponsor: Oramed, Ltd.
Start date: 2020-11-23; Completion date: 2022-06-07
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to explore the efficacy of ORMD-0801 compared to placebo on endogenous glucose production in subjects with type 2 diabetes (T2DM). Subjects will undergo an initial Screening Visit (Visit 0) to establish their eligibility to participate in the study. At Visit 1 (2 weeks after the Screening Visit), qualifying subjects will be randomized to either ORMD-0801 (8 mg) or matching placebo, study medication will be dispensed and subjects will dose, twice a day, once in the morning prior to breakfast and once at night prior to bedtime

Detailed description:
This study is designed to explore the efficacy of ORMD-0801 compared to placebo on endogenous glucose production in subjects with type 2 diabetes (T2DM). Subjects will undergo an initial Screening Visit (Visit 0) to establish their eligibility to participate in the study. At Visit 1 (2 weeks after the Screening Visit), qualifying subjects will be randomized to either ORMD-0801 (8 mg) or matching placebo, study medication will be dispensed and subjects will dose, twice a day, once in the morning prior to breakfast and once at night prior to bedtime. Doses will occur at 45 minutes (± 15 minutes) before breakfast and no later than 10 AM each morning, and at 8 PM (± 120 minutes) each night, and no sooner than 1 hour after dinner. Subjects will return to the clinic, 2 weeks later, for Visit 2. At this visit, subject compliance will be assessed, medication will be dispensed, a blood sample will be collected to measure HbA1c and subjects will be questioned for any adverse events. Subjects will be scheduled to return to the clinic in 2 weeks for morning admission (8 AM ± 120 minutes) to the PK unit (Visit 3). Subjects will be provided with standardized meals and the morning dose in-clinic. A light standardized dinner meal will be provided at 6 PM ± 30 minutes. At approximately 8 PM (± 60 minutes, and no sooner than 1 hour after dinner), subjects will be dosed with their study medication and will be started on a 16-hour infusion of \[6,6-2H2\]-glucose tracer.

Arms: arm 1: Subjects will be administered a single capsule of placebo( fish oil); placebo will be dispensed and subjects will dose twice a day, once in the morning prior to breakfast and once at night prior to bedtime. arm 2: Subjects will be administered a single 8mg capsule of ORMD-0801; study medication will be dispensed and subjects will dose twice a day, once in the morning prior to breakfast and once at night prior to bedtime.
Interventions: intervention 1: ORMD-0801 intervention 2: Placebo
Intervention descriptions: intervention 1: 8 mg capsules of ORMD-0801 (Oral Insulin) intervention 2: Placebo capsule (Fish Oil)

Protocol documents:
Prot_SAP_000.pdf: 
Oramed Ltd. 
 
Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 1 
CONFIDENTIAL 
 
 
Clinical Study Protocol: ORA-D-018 
Study Title: 
A Randomized, Double Blind, Phase 2b Study to Evaluate the Effect 
of ORMD-0801 Compared to Placebo on Endogenous Glucose 
Production in Patients with Type 2 Diabetes Mellitus 
Protocol Number: 
ORA-D-018 
Study Phase:  
Phase 2b 
Principal 
Investigators: 
Joel M. Neutel, M.D. 
Orange County Research Center (OCRC) 
14351 Myford Rd., Suite B, Tustin, CA 92780 
 
Ele Ferrannini, M.D. 
CNR Institute of Clinical Physiology 
Via Savi, 19 
56126 Pisa, Italy 
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: 
May 13, 2020 
CONFIDENTIALITY STATEMENT:  THIS DOCUMENT IS THE PROPERTY OF ORAMED LTD. AND MAY 
NOT—IN FULL OR IN PART—BE PASSED ON, REPRODUCED, PUBLISHED, OR DISTRIBUTED TO ANY 
PERSON, OR SUBMITTED TO ANY REGULATORY AUTHORITY, WITHOUT THE EXPRESS WRITTEN 
PERMISSION OF ORAMED LTD. OR THEIR OFFICIAL REPRESENTATIVES. 


Oramed Ltd. 
 
Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 2 
CONFIDENTIAL 
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE 
The undersigned has reviewed and approved Protocol No. ORA-D-018 for issuance: 
 
 
 
 
Miriam Kidron, PhD 
Chief Scientific Officer and Director 
Oramed Ltd. 
 
 
 
Signature 
 
Date 
 
 
 
 
 


Oramed Ltd. 
 
Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
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. 
 
Principal Investigator Name 
 
 
 
Signature 
 Date 
 
 
 


Oramed Ltd. 
 
Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 4 
CONFIDENTIAL 
SYNOPSIS 
Title 
A Randomized, Double Blind, Phase 2b Study to Evaluate the Effect 
of ORMD-0801 Compared to Placebo on Endogenous Glucose 
Production in Patients with Type 2 Diabetes Mellitus 
Indication 
Type 2 Diabetes Mellitus (T2DM) 
Clinical Phase 
Phase 2b 
Study Treatment  
ORMD-0801 (insulin) 
Dose 
ORMD-0801 8 mg Capsule 
Dosage Regimen 
BID 
Formulation 
Soft gel capsule [SBTI, disodium EDTA, fish oil, aerosol, and Tween 
80], Recombinant Human Insulin 
Mode of 
Administration 
Oral 
Primary Objective 
1. To assess the differences in endogenous glucose production in 
subjects with type 2 diabetes treated for 4 weeks either with 
ORMD-0801 or matching placebo following an intravenous 
infusion of [6,6-2H2]-glucose tracer using AUC(0-last). 
Secondary 
Objectives 
1. To compare the change from baseline in HbA1c levels measured 
at Week 4 in type 2 diabetic patients treated for 4 weeks with 
either ORMD-0801 or matching placebo. 
2. To compare the change from baseline in plasma glucose levels 
measured at Week 4 in type 2 diabetic patients treated for 4 
weeks with either ORMD-0801 or matching placebo. 
3. To compare the change from baseline in ketone levels measured 
at Week 4 in type 2 diabetics treated for 4 weeks with either 
ORMD-0801 or matching placebo. 
4. To compare the change from baseline in FFAs measured at Week 
4 in type 2 diabetics treated for 4 weeks with either ORMD-0801 
or matching placebo. 
5. To compare the change from baseline in TC, LDLC, HDLC, and 
TG measured at Week 4 in type 2 diabetics treated for 4 weeks 
with either ORMD-0801 or matching placebo. 
6. To assess the differences in endogenous glucose production in 
patients with type 2 diabetes treated for 4 weeks either with 
ORMD-0801 or matching placebo following an intravenous 
infusion of [6,6-2H2]-glucose tracer using other parameters 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 5 
CONFIDENTIAL 
including, but not limited to, Cmax, Tmax, Tlag and AUC over 
different time intervals. 
7. To assess the safety of repeat administration of ORMD-0801 in 
patients with type 2 diabetes inadequately controlled on oral 
therapy. 
Total Sample Size 
Approximately 40 adult male and female subjects, aged 18 to 70 years, 
with T2DM. 
Study Design 
This study is designed to explore the efficacy of ORMD-0801 
compared to placebo on endogenous glucose production in subjects 
with type 2 diabetes (T2DM). Subjects will undergo an initial 
Screening Visit (Visit 0) to establish their eligibility to participate in 
the study. At Visit 1 (2 weeks after the Screening Visit), qualifying 
subjects will be randomized to either ORMD-0801 (8 mg) or matching 
placebo, study medication will be dispensed and subjects will dose 
twice a day, once in the morning prior to breakfast and once at night 
prior to bedtime. Doses will occur at 45 minutes (± 15 minutes) before 
breakfast) and no later than 10 AM each morning, and at 8 PM (± 120 
minutes) each night, and no sooner than 1 hour after dinner. Subjects 
will return to the clinic, 2 weeks later, for Visit 2. At this visit, subject 
compliance will be assessed, medication will be dispensed, a blood 
sample will be collected to measure HbA1c and subjects will be 
questioned for any adverse events. Subjects will be scheduled to return 
to the clinic in 2 weeks for morning admission (8 AM ± 120 minutes) 
to the PK unit (Visit 3). Subjects will be provided with standardized 
meals and the morning dose in-clinic. A light standardized dinner meal 
will be provided at 6 PM ± 30 minutes. At approximately 8 PM (± 60 
minutes, and no sooner than 1 hour after dinner), subjects will be dosed 
with their study medication and will be started on a 16-hour infusion 
of [6,6-2H2]-glucose tracer. Blood samples will be collected to measure 
endogenous glucose (tracer attached), plasma glucose, metabolites and 
hormones for the duration of the infusion. Blood samples will be drawn 
at baseline (pre-infusion), 45, 90, 120 and 150 minutes, and 3, 4, 5, 6, 
7, 8, 9, 10, 11, 12, 13, 14, 15 and 16 hours. Subjects will be required to 
remain fasting from the evening of Day 28 until the end of the infusion. 
Water intake will be unrestricted. On Day 29, blood sample will also 
be collected to measure HbA1c. Following completion of the infusion, 
the subjects will receive a standardized lunch and will be observed for 
an additional 6 hours. Prior to discharge, a physical examination will 
be performed, and blood/urine samples will be collected for safety 
chemistry, hematology and urinalysis, following which subjects will 
be discharged from the CRU and will exit the study. 
Primary Endpoint 
1. Difference in endogenous glucose production between active and 
placebo as measured by the glucose with tracer attached using 
AUC(0-16) as the primary parameter. 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 6 
CONFIDENTIAL 
Secondary 
Endpoints 
1. Mean changes in HbA1c from baseline to Day 29 of the treatment 
period. 
2. Mean changes plasma glucose levels from baseline to Day 29 of 
the treatment period. 
3. Mean changes in ketones from baseline to Day 29 of the treatment 
period. 
4. Mean Changes in FFA from baseline to Day 29 of the treatment 
period. 
5. Mean change in TC, LDLC, HDLC and TG from baseline to Day 
29 of the treatment period. 
6a. Difference in endogenous glucose production between active and 
placebo as measured by the glucose with tracer attached using 
other parameters including, but not limited to: 
a. AUC(0-2), AUC(0-4), AUC(0-8), AUC(0-12), 
b. AUC(2-16), AUC(4-16), AUC(8-16), AUC(12-16), 
c. Cmax, 
d. Tmax, and 
e. Tlag. 
6b. Difference in metabolites (β-hydroxybutyrate, acetoacetate, 
lactate, pyruvate, FFA, glycerol) and hormones (insulin, C-
peptide, glucagon) between active and placebo using the same 
AUC intervals as endogenous glucose production.  
7. Safety assessed by adverse event reporting including adverse 
events of special significance such as hypoglycemia. 
Duration of 
Participation 
Subjects will be evaluated for participation in the study during a 1 to 
3-week Screening period. Following Screening, eligible subjects will 
enter a 4-week double blind treatment period. 
Subject Selection 
Criteria 
Inclusion criteria 
1. Male and female subjects aged, 18 - 70 years. 
2. Established diagnosis of T2DM for at least 6 months prior to 
Screening, with HbA1c ≥ 7.5%. and ≤ 11%. 
3. Stable dose of metformin (at least 1500 mg or maximal tolerated 
dose) for a period of at least 3 months prior to Screening. 
4. Taking metformin only or metformin in addition to no more than 
two of the following: DPP-4, SGLT-2, or TZD. 
5. Body mass index (BMI) of up to 35 kg/m2 at Screening and 
stable weight, with no more than 5 kg gain or loss in the 3 
months prior to Screening. 
6. Renal function – eGFR > 30 ml/min/1.73 m2. 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 7 
CONFIDENTIAL 
7. Females of childbearing potential must have a negative serum 
pregnancy test result at Screening.  
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). 
†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 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 8 
CONFIDENTIAL 
of contraception for subjects participating at sites in this 
country/region. 
Exclusion criteria 
1. Subjects with insulin-dependent diabetes:  
a. Has a history of type 1 diabetes mellitus or a history of 
ketoacidosis, or subject is assessed by the investigator as 
possibly having type 1 diabetes mellitus confirmed by a C-
peptide < 0.7 ng/mL (0.23 nmol/L).   
b. Has a history of other specific types of diabetes (e.g., genetic 
syndromes, secondary pancreatic diabetes, diabetes due to 
endocrinopathies, drug- or chemical-induced, and post-organ 
transplant). 
2. Treatment with glucosidase inhibitor, insulin secretagogues 
(other than sulfonylureas), glucagon-like peptide 1 (GLP-1) 
agonists within 3 months prior to Visit 1. 
3. History of any basal, pre-mix or prandial insulin (greater than 7 
days) within 6 months prior to Screening. 
4. History of > 2 episodes of severe hypoglycemia within 6 months 
prior to Screening.  
5. History of hypoglycemic unawareness (episodes of severe 
hypoglycemia with seizure or requiring third party intervention 
or documented low blood glucose without associated autonomic 
symptoms).    
6. Subjects with the following secondary complications of diabetes:  
a. Active proliferative retinopathy as confirmed by a dilated 
ophthalmoscopy/retinal photography examination performed 
(by a qualified person as per the country legislation) within 6 
months prior to Screening. 
b. Renal dysfunction: estimated creatinine clearance < 30 
ml/min. 
c. History of proliferative retinopathy or severe form of 
neuropathy or cardiac autonomic neuropathy (CAN).  
d. Uncontrolled or untreated severe hypertension defined as 
systolic blood pressure above or equal to 180 mmHg and/or 
diastolic blood pressure above or equal to 120 mmHg. 
e. Presence of unstable angina or myocardial infarction within 6 
months prior to Screening, Grade 3 or 4 congestive heart 
failure (CHF) according to the New York Heart Association 
(NYHA) criteria, valvular heart disease, cardiac arrhythmia 
requiring treatment, pulmonary hypertension, cardiac 
surgery, history/occurrence of coronary angioplasty and/or 
stroke or transient ischemic attack (TIA) within 6 months 
prior to Screening. 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 9 
CONFIDENTIAL 
7. Subjects with psychiatric disorders which, per investigator 
judgment, may have impact on the safety of the subject or 
interfere with subject’s participation or compliance in the study. 
8. Subjects who needed (in the last 12 months) or may require 
systemic (oral, intravenous, intramuscular) glucocorticoid 
therapy for more than 2 weeks during the study period. 
9. Laboratory abnormalities at Screening including: 
a. C-peptide < 0.7 ng/mL (0.23 nmol/L). 
b. Abnormal serum thyrotropin (TSH) levels below the lower 
limit of normal or > 1.5X the upper limit of normal. 
c. Elevated liver enzymes (alanine transaminase (ALT), alanine 
aminotransferase (AST), alkaline phosphatase) > 2X the 
upper limit of normal. 
d. Very high triglyceride levels (> 600 mg/dL); a single repeat 
test is allowable. 
e. Any relevant abnormality that would interfere with the 
efficacy or the safety assessments during study treatment 
administration. 
10. 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. 
11. Positive history of HIV. 
12. Use of the following medications: 
a. History of any basal, pre-mix or prandial insulin (greater than 
7 days) within 6 months prior to Screening. 
b. Administration of thyroid preparations or thyroxine (except 
in subjects on stable replacement therapy) within 6 weeks 
prior to Screening. 
c. 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. 
d. 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. 
13. Known allergy to soy. 
14. 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.   


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
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CONFIDENTIAL 
15. Subject has had bariatric surgery. 
16. Subject is pregnant or breast-feeding.  
17. 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. Occasional intermittent 
use of cannabinoid products will be allowed provided that no 
cannabinoid products have been used during the 1 week prior to 
each visit. 
18. Subject is smoking more than 10 cigarettes per day.  
19. One or more contraindications to metformin as per local label. 
20. History of gastrointestinal disorders (e.g. hypochlorhydria) with 
the potential to interfere with drug absorption. 
21. At the Principal Investigator’s discretion, any condition or other 
factor that is deemed unsuitable for subject enrollment into the 
study. 
Statistical Methods This study is a parallel design in which subjects will receive one of two 
treatments (ORMD-0801 8mg BID (active) or placebo). The primary 
endpoint of the study is based on a 16-hour infusion that is done once 
after 28 days of treatment. 
The analyses performed using information from the 16-hour 
Harmonisation infusion will be analyzed using an Analysis of Variance 
model with treatment as the main effect. Change from baseline 
analyses will be analyzed using an Analysis of Covariance model with 
treatment as the main effect and baseline value as the covariate. 
 
 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
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CONFIDENTIAL 
TABLE OF CONTENTS  
TITLE PAGE .............................................................................................................................1 
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE ..................................................2 
INVESTIGATOR SIGNATURE PAGE ...................................................................................3 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................15 
1 
INTRODUCTION ...........................................................................................................17 
2 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................18 
3 
INVESTIGATIONAL PLAN ..........................................................................................19 
3.1 
Overall Study Design and Plan ..............................................................................19 
3.2 
Screening/Visit 0 (Week -3 to -1, Day -21 to -7) ..................................................19 
3.2.1 
Screen Failure ..............................................................................................20 
3.3 
Treatment Period ....................................................................................................21 
3.3.1 
Visit 1 (Week 0, Day 0) ...............................................................................21 
3.3.2 
Visit 2 (Week 2, Day 14) .............................................................................21 
3.4 
Tracer Infusion .......................................................................................................22 
3.4.1 
Visit 3 (Week 4, Day 28) .............................................................................22 
3.5 
Discharge/End of Study .........................................................................................22 
3.5.1 
Visit 3 (Week 4, Day 29) .............................................................................22 
3.6 
Early Withdrawal (EW) .........................................................................................23 
3.7 
Schedule of Events .................................................................................................23 
4 
STUDY SUBJECT SELECTION ...................................................................................27 
4.1 
Inclusion Criteria ...................................................................................................27 
4.2 
Exclusion Criteria ..................................................................................................28 
4.3 
Subject and Trial Discontinuation .........................................................................30 
5 
STUDY TREATMENT ...................................................................................................31 
5.1 
Description of Investigational Drug.......................................................................31 
5.1.1 
Packaging and Labeling ...............................................................................31 
5.1.2 
Storage and Handling ...................................................................................32 
5.2 
Randomization .......................................................................................................32 
5.3 
Study Treatment Administration............................................................................33 
5.3.1.1 
Double-Blind Treatment Administration ...........................................33 
5.4 
Measuring Subject Compliance .............................................................................33 
5.5 
Drug Accountability...............................................................................................33 
5.6 
Concomitant Medications and Supplements ..........................................................33 
5.7 
Dietary Restrictions ...............................................................................................34 


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6 
STUDY PROCEDURES AND ASSESSMENTS ...........................................................35 
6.1 
Safety Assessments ................................................................................................35 
6.1.1 
Weight, Height and BMI..............................................................................35 
6.1.2 
Vital Signs ....................................................................................................35 
6.1.3 
Physical Examination...................................................................................35 
6.1.4 
12-Lead ECG ...............................................................................................35 
6.1.5 
Clinical Laboratory Tests .............................................................................35 
6.1.5.1 
Clinical Safety Labs ...........................................................................35 
6.1.5.2 
Pregnancy Test ...................................................................................36 
6.1.5.3 
Urine Drug Test .................................................................................37 
6.2 
Efficacy Assessments.............................................................................................37 
6.2.1 
16-Hour Tracer Infusion ..............................................................................37 
6.2.2 
Hemoglobin A1c (HbA1c) ...........................................................................37 
6.2.3 
Plasma Glucose Levels ................................................................................37 
6.2.4 
Ketones and Free Fatty Acids ......................................................................37 
6.2.5 
Lipids (Total Cholesterol, LDL Cholesterol, HDL Cholesterol and 
Triglycerides) ...............................................................................................37 
7 
ADVERSE EVENTS AND SAFETY REPORTING......................................................38 
7.1 
Safety and Tolerability Assessments .....................................................................38 
7.2 
Definition of Adverse Event ..................................................................................38 
7.3 
Definition of Serious Adverse Event .....................................................................38 
7.4 
Eliciting and Reporting of Adverse Events ...........................................................39 
7.4.1 
Routine Reporting of Adverse Events .........................................................39 
7.4.2 
Reporting of Serious Adverse Events, Including Death ..............................40 
7.4.2.1 
Pregnancy Reporting ..........................................................................41 
7.4.3 
Adverse Events of Hypoglycemia ...............................................................42 
7.4.4 
Adverse Events of Hyperglycemia ..............................................................42 
7.5 
Causality Assessment of Adverse Events ..............................................................43 
7.6 
Adverse Event Severity Assessment ......................................................................43 
7.7 
Expectedness of Adverse Event .............................................................................44 
7.8 
Assessment of Adverse Event Outcome ................................................................44 
7.9 
Clinical Findings ....................................................................................................44 
8 
STATISTICAL METHODS ............................................................................................45 
8.1 
Study Design ..........................................................................................................45 
8.2 
Sample Size ............................................................................................................45 
8.3 
Primary Efficacy Evaluation ..................................................................................45 
8.4 
Secondary Efficacy Evaluation ..............................................................................45 
8.4.1 
16-Hour Tracer Infusion ..............................................................................45 


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Phase 2b Clinical Study 
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8.4.2 
Hemoglobin A1c (HbA1c) ...........................................................................46 
8.4.3 
Plasma Glucose Levels ................................................................................46 
8.4.4 
Ketones and Free Fatty Acids ......................................................................46 
8.4.5 
Lipids (Total Cholesterol, LDL Cholesterol, HDL Cholesterol and 
Triglycerides) ...............................................................................................46 
8.5 
Safety Evaluation ...................................................................................................46 
8.5.1 
Safety Population .........................................................................................46 
8.5.2 
Adverse Events ............................................................................................46 
8.5.3 
Laboratory Evaluations ................................................................................47 
8.5.4 
Vital Signs ....................................................................................................47 
8.5.5 
12-lead ECG.................................................................................................47 
8.5.6 
Physical Examination...................................................................................47 
8.5.7 
Prior and Concomitant Medications and Supplements ................................47 
8.5.8 
Handling of Missing, Unused, or Spurious Data .........................................48 
9 
DATA MANAGEMENT.................................................................................................49 
9.1 
Data Collection ......................................................................................................49 
9.1.1 
Electronic Data Capture ...............................................................................49 
9.2 
Quality Assurance and Database Lock ..................................................................49 
10 AMENDMENTS/MODIFICATIONS OF THIS PROTOCOL.......................................49 
11 INVESTIGATOR OBLIGATIONS ................................................................................50 
11.1 
Regulatory Documentation ....................................................................................50 
11.2 
Protection of Human Subjects ...............................................................................50 
11.2.1 
Declaration of Helsinki ................................................................................50 
11.2.2 
Good Clinical Practice and Regulatory Compliance ...................................50 
11.2.3 
Institutional Review Board ..........................................................................50 
11.2.4 
Subject Informed Consent............................................................................51 
11.3 
Subject Confidentiality ..........................................................................................52 
11.4 
Electronic Data Capture .........................................................................................52 
11.5 
Source Documentation ...........................................................................................52 
11.6 
Retention of Records..............................................................................................52 
11.7 
Clinical Study Report .............................................................................................53 
12 STUDY ADMINISTRATION.........................................................................................53 
12.1 
Study Monitoring ...................................................................................................53 
12.2 
On-Site Audits .......................................................................................................54 
12.3 
Data Quality Assurance .........................................................................................54 
12.4 
Publication Policy ..................................................................................................54 
12.5 
Disclosure and Confidentiality ..............................................................................55 
13 REFERENCES ................................................................................................................56 


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Phase 2b Clinical Study 
May 13, 2020 
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14 APPENDIX A ..................................................................................................................57 
14.1 
Guidelines for TRACER Infusion .........................................................................57 
 
LIST OF IN-TEXT TABLES 
Table 1. Schedule of Events from Screening (Visit 0) to Discharge/End of Study (Visit 3, 
Day 29)............................................................ Error! Bookmark not defined.24 
Table 2. Blood Draw Schedule ......................................................................................2643 
Table 3. General Guidelines for Severity Assessment of Adverse Events ....................4343 
 
  


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May 13, 2020 
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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 
BID 
 
twice a day 
BUN  
blood urea nitrogen 
CAN  
cardiac autonomic neuropathy 
CFR 
 
Code of Federal Regulations 
CHF  
congestive heart failure 
Cmax 
 
maximum concentration 
CRO  
contract research organization 
CRU  
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP  
diastolic blood pressure 
DPP-4  
dipeptidyl peptidase 4 
ECG  
electrocardiogram 
eCRF  
electronic case report form 
eGFR  
estimated glomerular filtration rate 
EDC  
electronic data capture 
EDTA  
ethylenediaminetetraacetic acid 
ET 
 
early term  
EW 
 
early withdrawal 
FDA  
Food and Drug Administration 
FFA 
 
free fatty acid 
GCP  
Good Clinical Practice 
GGT  
gamma-glutamyltransferase 
GLP-1  
glucagon-like peptide 1 
HbA1c  
hemoglobin A1c 
HDLC  
high-density lipoprotein cholesterol 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
 
Human Immunodeficiency Virus 
IB 
 
Investigator’s Brochure 
ICF 
 
informed consent form 
ICH 
 
International Council for Harmonisation 
IND 
 
Investigational New Drug application 
IRB 
 
Institutional Review Board 
IUD 
 
intrauterine device 
LDLC   
low-density lipoprotein cholesterol 
MedDRA 
Medical Dictionary for Regulatory Activities 
NYHA  
New York Heart Association 
PK 
 
pharmacokinetic 
SAE 
 
serious adverse event 
SBP 
 
systolic blood pressure 
SBTI  
soybean trypsin inhibitor 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 16 
CONFIDENTIAL 
SGLT-2 
sodium-glucose co-transporter 2 
SOP 
 
standard operating procedure 
TC 
 
total cholesterol 
TG 
 
triglycerides 
TEAE  
treatment-emergent adverse event 
Tmax 
 
time to reach maximum concentration 
TIA 
 
transient ischemic attack 
Tlag 
 
absorption lag time 
TSH 
 
serum thyrotropin 
TZD 
 
thiazolidinedione 
T2DM  
type 2 diabetes mellitus 
WCBP  
woman of childbearing potential 
WHO  
World Health Organization 
 
 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 17 
CONFIDENTIAL 
1 INTRODUCTION 
Endogenous insulin – secreted by the ß-cells of the endocrine pancreas – flows to the liver in the 
portal blood before reaching the systemic circulation through the hepatic veins. Following oral 
administration, the insulin in ORMD-0801 is absorbed through the gastrointestinal mucosa into 
the mesenteric veins (mostly, the superior mesenteric vein that drains blood from the jejunum 
and ileum) and reaches the liver via the portal vein, thereby mimicking the route of entry of 
endogenous insulin. The main action of insulin in the liver is to suppress glucose production; for 
this action, sensitivity is higher, and onset and offset time of this action are faster than for insulin 
stimulation of glucose uptake by peripheral tissues. First-pass extraction of insulin by the liver is 
50-60%; recirculation raises this percentage to ~80%. As a consequence, portal plasma insulin 
concentrations normally are ~3-fold higher than peripheral insulin levels. 
The hypothesis behind ORMD-0801 is that sufficient oral insulin survives gastrointestinal 
degradation to arrive at the liver where it inhibits glucose production and, through this effect, 
lowers fasting plasma glucose concentrations. As the majority of this exogenous insulin dose is 
degraded in the liver, the resulting systemic insulin levels may be only marginally increased, 
thereby avoiding the risk of hypoglycemia. 
The use of glucose tracers is the standard non-invasive approach to measure endogenous glucose 
production (EGP) [1].  A tracer (in this protocol, [6,6-2H2]-glucose, a stable isotope of glucose) 
infused intravenously at a constant rate will equilibrate with endogenous glucose across its 
distribution space within ~3 hours. From this time onward, the ratio of the tracer infusion rate to 
the plasma tracer/tracee ratio (as assayed by GCMS) measures EGP. As compared to placebo, 
oral insulin is expected to reduce EGP over the ensuing 13 hours of continued fasting. In patients 
with type 2 diabetes, EGP is known to be abnormally elevated and to contribute the 
hyperglycemia [2]. Oral insulin is therefore addressing a key pathophysiological derangement of 
type 2 diabetes. 
 
 
 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 18 
CONFIDENTIAL 
2 STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary Objective: 
Primary Endpoint: 
1. To assess the differences in endogenous glucose 
production in subjects with type 2 diabetes 
treated for 4 weeks either with ORMD-0801 or 
matching placebo following an intravenous 
infusion of [6,6-2H2]-glucose tracer using 
AUC(0-last). 
1. Difference in endogenous glucose production 
between active and placebo as measured by the 
glucose with tracer attached using AUC(0-16) as 
the primary parameter. 
Secondary Objectives: 
Secondary Endpoints: 
1. To compare the change from baseline in HbA1c 
levels measured at Week 4 in type 2 diabetic 
patients treated for 4 weeks with either ORMD-
0801 or matching placebo. 
2. To compare the change from baseline in plasma 
glucose levels measured at Week 4 in type 2 
diabetic patients treated for 4 weeks with either 
ORMD-0801 or matching placebo. 
3. To compare the change from baseline in ketone 
levels measured at Week 4 in type 2 diabetics 
treated for 4 weeks with either ORMD-0801 or 
matching placebo. 
4. To compare the change from baseline in FFAs 
measured at Week 4 in type 2 diabetics treated 
for 4 weeks with either ORMD-0801 or 
matching placebo. 
5. To compare the change from baseline in TC, 
LDLC, HDLC, and TG measured at Week 4 in 
type 2 diabetics treated for 4 weeks with either 
ORMD-0801 or matching placebo. 
6. To assess the differences in endogenous 
glucose production in patients with type 2 
diabetes treated for 4 weeks either with 
ORMD-0801 or matching placebo following 
an intravenous infusion of [6,6-2H2]-glucose 
tracer using other parameters including, but 
not limited to, Cmax, Tmax, Tlag and AUC over 
different time intervals. 
7. To assess the safety of repeat administration of 
ORMD-0801 in patients with type 2 diabetes 
inadequately controlled on oral therapy. 
1. Mean changes in HbA1c from baseline to Day 
29 of the treatment period. 
2. Mean changes plasma glucose levels from 
baseline to Day 29 of the treatment period. 
3. Mean changes in ketones from baseline to Day 
29 of the treatment period. 
4. Mean Changes in FFA from baseline to Day 29 
of the treatment period. 
5. Mean change in TC, LDLC, HDLC and TG 
from baseline to Day 29 of the treatment 
period. 
6a. Difference in endogenous glucose production 
between active and placebo as measured by the 
glucose with tracer attached using other 
parameters including, but not limited to: 
a. AUC(0-2), AUC(0-4), AUC(0-8), AUC(0-12), 
b. AUC(2-16), AUC(4-16), AUC(8-16), AUC(12-16), 
c. Cmax, 
d. Tmax, and 
e. Tlag. 
6b. Difference in metabolites (β-hydroxybutyrate, 
acetoacetate, lactate, pyruvate, FFA, glycerol) 
and hormones (insulin, C-peptide, glucagon) 
between active and placebo using the same 
AUC 
intervals 
as 
endogenous 
glucose 
production.  
7. Safety assessed by adverse event reporting 
including adverse events of special significance 
such as hypoglycemia. 
 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 19 
CONFIDENTIAL 
3 INVESTIGATIONAL PLAN  
3.1 Overall Study Design and Plan 
This study is designed to explore the efficacy of ORMD-0801 compared to placebo on 
endogenous glucose production in subjects with type 2 diabetes (T2DM). Subjects will undergo 
an initial Screening Visit (Visit 0) to establish their eligibility to participate in the study. At Visit 1 
(2 weeks after the Screening Visit), qualifying subjects will be randomized to either ORMD-0801 
(8 mg) or matching placebo, study medication will be dispensed and subjects will dose, twice a 
day, once in the morning prior to breakfast and once at night prior to bedtime. Doses will occur at  
45 minutes (± 15 minutes) before breakfast and no later than 10 AM each morning, and at 8 PM 
(± 120 minutes) each night, and no sooner than 1 hour after dinner. Subjects will return to the 
clinic, 2 weeks later, for Visit 2. At this visit, subject compliance will be assessed, medication will 
be dispensed, a blood sample will be collected to measure HbA1c and subjects will be questioned 
for any adverse events. Subjects will be scheduled to return to the clinic in 2 weeks for morning 
admission (8 AM ± 120 minutes) to the PK unit (Visit 3). Subjects will be provided with 
standardized meals and the morning dose in-clinic. A light standardized dinner meal will be 
provided at 6 PM ± 30 minutes. At approximately 8 PM (± 60 minutes, and no sooner than 1 hour 
after dinner), subjects will be dosed with their study medication and will be started on a 16-hour 
infusion of [6,6-2H2]-glucose tracer. Blood samples will be collected to measure endogenous 
glucose (tracer attached), plasma glucose, metabolites and hormones for the duration of the 
infusion. Blood samples will be drawn at baseline (pre-infusion), 45, 90, 120 and 150 minutes, 
and 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16 hours (see Table 2 for blood draw schedule). 
Subjects will be required to remain fasting from the evening of Day 28 until the end of the 
infusion. Water intake will be unrestricted. On Day 29, blood sample will also be collected to 
measure HbA1c. Following completion of the infusion, the subjects will receive a standardized 
lunch and will be observed for an additional 6 hours. Prior to discharge, a physical examination 
will be performed, and blood/urine samples will be collected for safety chemistry, hematology 
and urinalysis, following which subjects will be discharged from the CRU and will exit the study. 
3.2 Screening/Visit 0 (Week -3 to -1, Day -21 to -7) 
At the Screening Visit (Visit 0), potential subjects will be given a detailed oral presentation 
describing the nature, purpose, risks, and requirements of the study and will receive detailed written 
information. Subjects will be given ample time to consider participation and ask questions which 
will be adequately addressed by site personnel. 
Once the subject is satisfied that he/she is willing to participate in the study, he/she will be asked to 
sign the study informed consent form (ICF) (refer to Section 11.2.4 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.  


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 20 
CONFIDENTIAL 
Subjects will report to the clinic in morning following a 10-hour fast. Screening activities after 
obtaining informed consent will be conducted and consist of the following: 
• Demographics (sex, age, race and ethnicity); 
• Completion of medical and social history, including tobacco, alcohol, caffeine and drug use. 
• Review of prior and current medications and supplements; 
• Review of inclusion and exclusion criteria; 
• Physical examination; 
• 12-lead electrocardiogram (ECG); 
• Measurement of height, weight and BMI; 
• Measurement of vital signs (SBP/DBP and heart rate); 
• Collection of fasted blood and urine samples for clinical safety labs: 
o Hematology, serum chemistry and urinalysis (see Section 6.1.5.1 for list of tests); 
o HbA1c; 
o Urine drug screen; 
o Serum pregnancy test (women of childbearing potential/WCBP only); 
• Breathalyzer; 
• Blood plasma sample will be collected for the assessment of plasma glucose, metabolites 
and hormones listed in the footnote of Table 2; 
• Remind subjects to arrive fasting for Visit 1 in 2 weeks. 
For subjects who meet eligibility criteria based on the Screening assessments, instruction will be 
provided on the following: 
• the use of adequate contraceptive methods (see Section 4.1) for the duration of the study 
(Screening (Visit 0) through Visit 3); 
• minimal use of concomitant medications during the study, if possible, and avoid prohibited 
medications as defined in Section 5.6; 
• maintenance of usual dietary habits and avoidance of drastic changes, such as a conversion to 
a vegetarian diet; 
• restraint from excessive alcohol use or binge drinking during the study, and restraint from 
drinking alcohol from 72 hours prior to all study visits; 
• restraint from excessive caffeine use (i.e., more than five cups of caffeinated beverages per 
day) during the study. 
 
3.2.1 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 4.3 of this protocol (note that this includes assessments prior to receiving 
treatment on Visit 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. Screen failure subjects will have only their consent, demographic and reason 
for screen failing (including, where applicable, the unmet inclusionary or exclusionary criteria) data 
entered into the electronic data capture (EDC) system, unless an adverse event was responsible for 


Oramed Ltd. 
 
Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 21 
CONFIDENTIAL 
the subject’s screen failure, in which case all data collected for that subject during the screening 
process will be entered into the EDC system. 
 
3.3 Treatment Period 
The Treatment Period will last for 4 weeks from Visit 1 (Day 0) to Visit 3 (Day 28).  
 
3.3.1 Visit 1 (Week 0, Day 0) 
Subjects will report to the clinic in morning following a 10-hour fast. At Visit 1, the following 
procedures will be performed: 
• Review of inclusion and exclusion criteria; 
• Review of prior and current medications and supplements; 
• Measurement of vital signs (SBP/DBP and heart rate); 
• Measurement of weight;  
• Breathalyzer; 
• Subjects will be randomized to either ORMD-0801 (8 mg) or placebo. Subjects will be 
instructed to dose twice a day. Doses will occur at 45 minutes (± 15 minutes) before 
breakfast and no later than 10 AM each morning, and at bedtime (@ 8 PM ± 120 minutes) 
each night, and no sooner than 1 hour after dinner;  
• Study medication will be dispensed; 
• Blood sample will be collected to measure HbA1c; 
• AEs/SAEs assessment; 
• Remind subjects to arrive fasting for Visit 2 in 2 weeks. 
 
3.3.2 Visit 2 (Week 2, Day 14) 
Subjects will report to the clinic in morning following a 10-hour fast. At Visit 2, the following 
procedures will be performed: 
• Review of prior and current medications and supplements; 
• Measurement of vital signs (SBP/DBP and heart rate); 
• Measurement of weight; 
• Breathalyzer; 
• Study medication will be collected, and compliance will be reviewed; 
• Study medication will be dispensed; 
• Blood sample will be collected to measure HbA1c; 
• AEs/SAEs assessment; 
• Remind subjects to arrive fasting for Visit 3 in 2 weeks.  
 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 22 
CONFIDENTIAL 
3.4 Tracer Infusion 
3.4.1 Visit 3 (Week 4, Day 28) 
Subjects will report to the clinic in morning following a 10-hour fast. At Visit 3 (Day 28), the 
following procedures will be performed: 
• Admission to the CRU (8 AM ± 120 minutes); 
• Review of prior and current medications and supplements; 
• Measurement of vital signs (SBP/DBP and heart rate); 
• Measurement of weight; 
• Breathalyzer; 
• Urine pregnancy test (women of childbearing potential/WCBP only); 
• Fasting blood sample will be collected to measure HbA1c; 
• Study medication will be collected, and compliance will be reviewed; 
• Subjects will be provided with a standard breakfast, lunch and dinner. The morning dose 
will be administered 45 minutes (± 15 minutes) before breakfast and no later than 10 AM, 
in-clinic. A light standardized dinner meal will be provided at 6 PM ± 30 minutes.  
• Subjects will be dosed in-clinic with either ORMD-0801 (8 mg) or placebo (@ 8 PM ± 60 
minutes) and started on a 16-hour infusion of [6,6-2H2]-glucose tracer immediately 
following dosing; 
• Blood samples will be collected to measure endogenous glucose (tracer attached), plasma 
glucose, metabolites and hormones for the duration of the infusion. Blood samples will be 
drawn at baseline (pre-infusion), 45, 90, 120 and 150 minutes, and 3 and 4 hours (see blood 
draw schedule in Table 2). Subjects will be required to remain fasting from the evening of 
Day 28 (following dinner) until the end of the infusion; 
• A backup blood sample will be collected at baseline (pre-infusion);  
• AEs/SAEs assessment.  
 
3.5 Discharge/End of Study 
3.5.1 Visit 3 (Week 4, Day 29) 
At Visit 3 (Day 29), the following procedures will be performed: 
• Review of prior and current medications and supplements; 
• Physical examination; 
• Measurement of vital signs (SBP/DBP and heart rate); 
• Fasting blood sample will be collected to measure HbA1c; 
• Collection of fasted blood and urine samples for clinical safety labs for hematology, serum 
chemistry and urinalysis (see Section 6.1.5.1 for list of tests); 
• Blood samples will be collected to measure endogenous glucose (tracer attached), plasma 
glucose, metabolites and hormones for the duration of the infusion. Blood samples will be 
drawn at 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16 hours (see blood draw schedule in Table 
2). Subjects will be required to remain fasting from the evening of Day 28 (following 
dinner) until the end of the infusion; 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 23 
CONFIDENTIAL 
• A backup blood sample will be collected 16-hour after infusion; 
• After completion of the infusion, subjects will be provided with a standard lunch; 
• AEs/SAEs assessment; 
• Following the 6-hour observation and end of study procedures, subjects will be discharged 
from the CRU in the evening. 
3.6 Early Withdrawal (EW) 
If a randomized subject is withdrawn from the study prior to completion, the subject will be 
instructed to return to the clinic the next day and will have the early term (ET) visit procedures 
completed. Subjects will then be discharged from the study. Subjects will report to the clinic in 
morning following a 10-hour fast. Subjects will complete the following evaluations: 
• Review of prior and current medications and supplements; 
• Physical examination; 
• Measurement of weight; 
• Measurement of vital signs (SBP/DBP and heart rate); 
• Collection of fasted blood and urine samples for clinical safety labs for hematology, serum 
chemistry and urinalysis (see Section 6.1.5.1 for list of tests); 
• AEs/SAEs assessment; 
• Discharge from CRU, if applicable. 
Any subject with a possible study treatment related AE at the time of EW will be followed until 
resolution or stabilization of the event. 
 
3.7 Schedule of Events 
Table 1 below describes the daily schedule of events from Screening (Visit 0) to Discharge/End of 
Study (Visit 3, Day 29).  
 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 24 
CONFIDENTIAL 
Table 1: Schedule of Events from Screening (Visit 0) to Discharge/End of Study (Visit 3, Day 29).   
 
Screening 
Treatment Period 
Discharge / End 
of Study 
Early 
Withdrawal 
 
TRACER 
Infusion 
Visit 
0 
1 
2 
3 
 
Week 
-3 to -1 
0 
2 
4 
Day 
-21 to -7 
0 
14 
28 
29 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
Demographics (sex, age, race and 
ethnicity) 
X 
 
 
 
 
 
Medical and Social History 
(including tobacco, alcohol, 
caffeine and drug use) 
X 
 
 
 
 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
Height, Weight, BMI1 
X 
X 
X 
X 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Chemistry, Hematology, 
Urinalysis2  
X 
 
 
 
X2 
X 
Blood Collection for Plasma 
Glucose, Metabolites and 
Hormones3  
X 
 
 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
 
 
Serum Pregnancy Test4  
X 
 
 
 
 
 
Urine Pregnancy Test4 
 
 
 
X 
 
 
Breathalyzer 
X 
X 
X 
X 
 
 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 25 
CONFIDENTIAL 
1 Weight will be measured at each visit. Height will be measured and BMI will be calculated at Screening. 
2 Blood draw will be performed after the 16-hour infusion is complete. 
3 A blood plasma sample will be collected at Screening and during infusion for assessment of plasma glucose, metabolites and hormones according to Table 2.  
4 Serum pregnancy test and urine pregnancy test will be performed for women of childbearing potential (WCBP) only. 
5 Subjects will be started on a 16-hour infusion of TRACER immediately following dosing. Refer to Appendix A (Guidelines for TRACER Infusion).  
6 Blood samples will be collected during the duration of infusion based on the blood draw schedule in Table 2. 
7A standard breakfast, lunch, and dinner will be provided on Day 28. Subjects will fast following dinner on Day 28 until the completion of the 16-hour infusion 
on Day 29. After completion of the infusion, subjects will be provided with a standard lunch. 
8 Following the 6-hour observation and end of study procedures, subjects will be discharged from the CRU in the evening of Day 29. 
 
Screening 
Treatment Period 
Discharge / End 
of Study 
Early 
Withdrawal 
 
TRACER 
Infusion 
Visit 
0 
1 
2 
3 
 
Week 
-3 to -1 
0 
2 
4 
Day 
-21 to -7 
0 
14 
28 
29 
HbA1c 
X 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
Dispense study medication  
 
X 
X 
 
 
 
Collect study medication and 
review for compliance 
 
 
X 
X 
 
 
CRU Admission 
 
 
 
X 
 
 
In-Clinic Dosing 
 
 
 
X 
 
 
TRACER Infusion5 
 
 
 
X 
X 
 
Blood Collection for Tracer 
Marked Glucose, Metabolites and 
Hormones6 
 
 
 
X 
X 
 
Standard Meals7 
 
 
 
X 
X 
 
CRU Discharge8 
 
 
 
 
X6 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
End of Study 
 
 
 
 
X 
X 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 26 
CONFIDENTIAL 
Table 2: Blood Draw Schedule 
additive 
EDTA+NaF 
EDTA 
EDTA 
EDTA+30 µL 
diprotin+20 µL 
Foy° 
EDTA+30 µL 
diprotin+20 µL 
Foy° 
 
assay 
Tracer 
Glucose 
Metabolites# Hormones§ 
Backup 
total 
Time 
mL 
mL 
mL 
mL 
mL 
mL 
Baseline* 
2 
1 
3 
3 
4 
13 
45 min 
2 
1 
3 
3 
 
9 
90 min 
2 
1 
3 
3 
 
9 
120 min 
2 
1 
3 
3 
 
9 
150 min 
2 
1 
3 
3 
 
9 
3 hours 
2 
1 
3 
3 
 
9 
4 hours 
2 
1 
3 
3 
 
9 
5 hours 
2 
1 
3 
3 
 
9 
6 hours 
2 
1 
3 
3 
 
9 
7 hours 
2 
1 
3 
3 
 
9 
8 hours 
2 
1 
3 
3 
 
9 
9 hours 
2 
1 
3 
3 
 
9 
10 hours 
2 
1 
3 
3 
 
9 
11 hours 
2 
1 
3 
3 
 
9 
12 hours 
2 
1 
3 
3 
 
9 
13 hours 
2 
1 
3 
3 
 
9 
14 hours 
2 
1 
3 
3 
 
9 
15 hours 
2 
1 
3 
3 
 
9 
16 hours 
2 
1 
3 
3 
4 
13 
 
 
 
 
 
 
 
Total 
38 
19 
57 
57 
8 
179 
* before starting tracer infusion 
° Foy master solution = 0.035 mg in 10 mL of saline 
#  ß-hydroxybutyrate, acetoacetate, lactate, pyruvate, FFA, glycerol 
§ insulin, C-peptide, glucagon 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
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4 STUDY SUBJECT SELECTION 
4.1 Inclusion Criteria 
1. Male and female subjects aged, 18 - 70 years. 
2. Established diagnosis of T2DM for at least 6 months prior to Screening, with HbA1c ≥ 7.5%. 
and ≤ 11%. 
3. Stable dose of metformin (at least 1500 mg or maximal tolerated dose) for a period of at least 
3 months prior to Screening. 
4. Taking metformin only or metformin in addition to no more than two of the following: DPP-
4, SGLT-2, or TZD. 
5. Body mass index (BMI) of up to 35 kg/m2 at Screening and stable weight, with no more than 
5 kg gain or loss in the 3 months prior to Screening. 
6. Renal function – eGFR > 30 ml/min/1.73 m2. 
7. Females of childbearing potential must have a negative serum pregnancy test result at 
Screening.  
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). 
†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 


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Protocol No. ORA-D-018 
Phase 2b Clinical Study 
May 13, 2020 
Page 28 
CONFIDENTIAL 
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 
1. Subjects with insulin-dependent diabetes:  
a. Has a history of type 1 diabetes mellitus or a history of ketoacidosis, or subject is 
assessed by the investigator as possibly having type 1 diabetes mellitus confirmed by a C-
peptide < 0.7 ng/mL (0.23 nmol/L).   
b. Has a history of other specific types of diabetes (e.g., genetic syndromes, secondary 
pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and 
post-organ transplant). 
2. Treatment with glucosidase inhibitor, insulin secretagogues (other than sulfonylureas), 
glucagon-like peptide 1 (GLP-1) agonists within 3 months prior to Visit 1. 
3. History of any basal, pre-mix or prandial insulin (greater than 7 days) within 6 months prior 
to Screening. 
4. History of > 2 episodes of severe hypoglycemia within 6 months prior to Screening.  
5. History of hypoglycemic unawareness (episodes of severe hypoglycemia with seizure or 
requiring third party intervention or documented low blood glucose without associated 
autonomic symptoms).    
6. Subjects with the following secondary complications of diabetes:  
a. Active proliferative retinopathy as confirmed by a dilated ophthalmoscopy/retinal 
photography examination performed (by a qualified person as per the country legislation) 
within 6 months prior to Screening. 
b. Renal dysfunction: estimated creatinine clearance < 30 ml/min. 
c. History of proliferative retinopathy or severe form of neuropathy or cardiac autonomic 
neuropathy (CAN).  
d. Uncontrolled or untreated severe hypertension defined as systolic blood pressure above or 
equal to 180 mmHg and/or diastolic blood pressure above or equal to 120 mmHg. 
e. Presence of unstable angina or myocardial infarction within 6 months prior to Screening, 
Grade 3 or 4 congestive heart failure (CHF) according to the New York Heart 
Association (NYHA) criteria, valvular heart disease, cardiac arrhythmia requiring 
treatment, pulmonary hypertension, cardiac surgery, history/occurrence of coronary 
angioplasty and/or stroke or transient ischemic attack (TIA) within 6 months prior to 
Screening. 
7. Subjects with psychiatric disorders which, per investigator judgment, may have impact on the 
safety of the subject or interfere with subject’s participation or compliance in the study. 
8. Subjects who needed (in the last 12 months) or may require systemic (oral, intravenous, 
intramuscular) glucocorticoid therapy for more than 2 weeks during the study period. 
9. Laboratory abnormalities at Screening including: 


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a. C-peptide < 0.7 ng/mL (0.23 nmol/L). 
b. Abnormal serum thyrotropin (TSH) levels below the lower limit of normal or > 1.5X the 
upper limit of normal. 
c. Elevated liver enzymes (alanine transaminase (ALT), alanine aminotransferase (AST), 
alkaline phosphatase) > 2X the upper limit of normal. 
d. Very high triglyceride levels (> 600 mg/dL); a single repeat test is allowable. 
e. Any relevant abnormality that would interfere with the efficacy or the safety assessments 
during study treatment administration. 
10. 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. 
11. Positive history of HIV. 
12. Use of the following medications: 
a. History of any basal, pre-mix or prandial insulin (greater than 7 days) within 6 months 
prior to Screening. 
b. Administration of thyroid preparations or thyroxine (except in subjects on stable 
replacement therapy) within 6 weeks prior to Screening. 
c. 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. 
d. 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. 
13. Known allergy to soy. 
14. 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.   
15. Subject has had bariatric surgery. 
16. Subject is pregnant or breast-feeding.  
17. 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. Occasional intermittent use of cannabinoid products will be allowed provided that 
no cannabinoid products have been used during the 1 week prior to each visit. 
18. Subjects is smoking more than 10 cigarettes per day. 
19. One or more contraindications to metformin as per local label. 
20. History of gastrointestinal disorders (e.g. hypochlorhydria) with the potential to interfere with 
drug absorption. 
21. At the Principal Investigator’s discretion, any condition or other factor that is deemed 
unsuitable for subject enrollment into the study. 
 


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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. Reasons for subject discontinuation 
include, but are not limited to the following:    
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 5.6) 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. Episodes of hypoglycemia not responsive to changes in diet or dose regimen (Section 7.4.3) 
7. Subject meets one of the exclusion criteria during the study  
8. Subject wishes to withdraw for any reason.  
9. Sponsor elects to end the study, or the Investigational Site elects to end the study at their 
site.  
10. Any other reason that in the judgment of the Investigator poses unacceptable risk to the 
subject. 
Subjects who withdraw from the study may be replaced at the discretion of the investigator and will 
be discussed on a case-by-case basis.  
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. 
In the event that a subject discontinues the study prior to completion, the date the subject is 
withdrawn and the reason for discontinuation will be recorded in the source documents and eCRF.  
Although a subject will not be obliged to give his/her reason for withdrawing prematurely, the 
investigator will make a reasonable effort to obtain the reason while fully respecting the subject’s 
rights.  
All subjects who are randomized and treated (i.e., received any amount of 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 


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early withdrawal evaluations (Section 3.6). 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. The subject will 
be followed until delivery or other termination of pregnancy for outcome. 
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. 
 
5 STUDY TREATMENT 
5.1 Description of Investigational Drug 
Active: 
Code name: ORMD-0801 
Dosage form: 1 soft gel capsule per dose to be administered twice daily 
Strength: 8 mg insulin per capsule  
Description: Soft gel capsule [SBTI, disodium EDTA, fish oil, aerosol, and Tween 80], 
Recombinant Human Insulin 
 
Placebo control: 
Fish oil in capsules, identical in appearance to ORMD-0801, administered twice daily 
 
5.1.1 Packaging and Labeling 
All study medication will be shipped in bulk. The unblinded investigational site pharmacist or 
designee will be responsible for dispensing the appropriate study treatment based on the 


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randomization schedule. Study medication will be distributed at each visit sufficient to cover the 
time between visits. Subjects will receive one bottle each at Visit 1 and Visit 2 to self-administer 
doses at home. Subjects will be dosed in-clinic from a new bottle at Visit 3.  
Study medication will be dispensed to the site with instructions for when treatment can be 
administered. Unused study medication will be returned or destroyed according to instructions 
provided by Oramed Ltd. 
The treatment packages will be labeled with the following information: 
 Study number 
 Bottle ID 
 Dosage Form/Content 
 Directions for use, including route of administration 
 Number of capsules in package 
 Storage conditions 
 Instructions to “keep out of reach of children” 
 Caution: New Drug – Limited by Federal (or United States) law to investigational use.  
 Name of Sponsor  
A label with the identical information will be made available for drug accountability purposes.  
 
5.1.2 Storage and Handling 
All study treatment must be kept in an appropriate, secure area to prevent unauthorized access. The 
study treatment is to be shipped under refrigerated conditions and stored at controlled temperature 
(36 to 46°F; 2 to 8°C). Excessive humidity should be avoided. Storage conditions will be monitored 
and appropriate monitoring logs maintained as source data. Deviations from the established 
temperature, as well as the occurrence of excessive humidity, should be documented, and the 
Sponsor should be notified. Study treatment should be handled using proper procedures as defined 
by investigational site standard operating procedures (SOPs) for Investigational Drugs. IMP will be 
returned or destroyed according to instructions provided by Oramed Ltd. Drug destruction 
procedures and documentation must be retained at the site. 
5.2 Randomization 
This is a randomized, double blind, parallel study. Approximately 40 subjects with T2D will be 
randomized to one of two treatment groups. 
Integrium, LLC will generate and implement the randomization procedures for this trial. A 
computer-generated randomization schedule will be used for assigning the treatment groups. The 
Investigational Site pharmacist will follow this randomization schedule to dispense the appropriate 
study treatment. 


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5.3 Study Treatment Administration 
5.3.1.1 
Double-Blind Treatment Administration 
All subjects will receive double-blind placebo or ORMD-0801 (8 mg insulin) twice a day, once in 
the morning and once in the evening, according to their randomization schedule from Visit 1 (Day 
0) to Visit 3 (Day 28). Subjects will take one capsule (active or placebo), 45 minutes (± 15 minutes) 
before breakfast and no later than 10 AM each morning, and one capsule at 8 PM (± 120 minutes at 
Visits 1-2 and ± 60 minutes at Visit 3) each night, and no sooner than 1 hour after dinner.  
5.4 Measuring Subject Compliance 
Dosing compliance will be assessed through a count of unused study medication at each clinic visit.   
5.5 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. 
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 in the eCRF. 
5.6 Concomitant Medications and Supplements 
All medications and supplements (other than study treatment) taken by the subject from Visit 1 
through Visit 3 will be considered “concomitant” medications and supplements. Medications and 
supplements taken prior to Visit 1 that are no longer being taken at the time of Visit 1 will be 
considered “prior” medications and supplements. 
All medications and supplements taken within 30 days prior to the first dose of study treatment and 
concomitant medications and supplements taken during the course of the study will be recorded in 
the subject’s source documentation and in the eCRF. 
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 1 
through 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 unless required 
for rescue; 
3. Thyroid preparations or thyroxine (except in subjects on stable replacement therapy); 


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4. 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. 
5. 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 subject’s health and well-being, the investigator and 
sponsor will jointly decide to continue or discontinue study treatment for the subject. 
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 (Visit 0), the subject should not be 
enrolled. Treatment of the condition should be instituted according to the Investigator’s/attending 
physician's judgment.  
Medications that have no treatment intent but rather are part of supportive routine care such as local 
anesthetics, intravenous solutions to maintain fluid balance and keep access open, medications used 
for prophylaxis, and narcotics for postsurgical pain must also be recorded in the subject’s medical 
record and eCRF.  
5.7 Dietary Restrictions 
Subjects should arrive following a minimum 10-hour fast to the clinic as described in the study 
design. All subjects will continue with their regular diet. Subjects will fast from the evening of Visit 
3, Day 28, until the end of infusion. Water intake will be unrestricted.  
Excessive caffeine use (i.e., more than five cups of caffeinated beverages per day) will not be 
allowed from Screening (Visit 0) through Visit 3. Excessive alcohol use or binge drinking will be 
discouraged during the study, and alcohol will be prohibited 72 hours prior to each visit). Subjects 
must refrain from smoking more than 10 cigarettes per day. Subject should not use any recreational 
or illicit drugs within one year prior to Screening through Visit 3.  
Subjects will also be asked to refrain from any unusual or unaccustomed vigorous exercise during 
the course of the study.


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6 STUDY PROCEDURES AND ASSESSMENTS 
6.1 Safety Assessments 
6.1.1 Weight, Height and BMI 
Weight, height and BMI will be measured at every visit (Table 1). The subject will be clothed while 
being weighed, but should remove shoes, coats, jewelry and other accessories. Height will be 
measured with the subject wearing no shoes. 
6.1.2 Vital Signs 
Vital signs (including seated SBP/DBP and heart rate) will be recorded at all visits as described in 
Table 1. Vital signs will be measured after the subject has been sitting for at least 5 minutes in a 
quiet environment and prior to any blood draw that occurs at the same time point. The recorded 
seated SBP/DBP value will be the mean of two measurements taken 2 minutes apart and always 
using the non-dominant arm. 
6.1.3 Physical Examination 
A physical examination will be performed as described in Table 1 or 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. 
6.1.4 12-Lead ECG 
A 12-lead ECG will be performed at Screening (Table 1). The 12-lead ECG will be recorded after 
the subject has been resting at least 5 minutes in the supine position in a quiet environment. ECGs 
will be read for QT and QTc (Federicia’s) intervals and clinically significant abnormalities.  
6.1.5 Clinical Laboratory Tests 
Fasted blood and urine samples for clinical safety laboratory assessments will be collected and 
processed using standard procedures as indicated in Table 1. Laboratory samples will be processed 
by appropriate laboratories. 
In the event of abnormal clinical laboratory values, the Investigator will make a judgment whether 
or not the abnormality is clinically significant. 
6.1.5.1 
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 


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• Red blood cell distribution width 
• Red blood cell count 
• White blood cell count with differential 
Serum Chemistry 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• ALT 
• AST 
• Gamma-glutamyltransferase (GGT) 
• Total bilirubin  
• Alkaline phosphatase  
• Albumin 
• Total Protein  
• Blood urea nitrogen (BUN) 
• Creatinine 
• Uric acid 
• Glucose 
• Calcium 
• Phosphorus 
• Total cholesterol 
• Triglycerides 
• High-density lipoprotein cholesterol (HDLC) 
• Low-density lipoprotein cholesterol (LDLC) 
Urinalysis 
• Appearance (color and character) 
• Bilirubin  
• Urobilinogen 
• Protein 
• Glucose 
• Ketones  
• Leukocyte esterase 
• Urine blood 
• Nitrite 
• pH 
• Specific gravity 
  
6.1.5.2 
Pregnancy Test 
A serum pregnancy test will be performed for women of child-bearing potential (WCBP) at 
Screening. A urine pregnancy test will be performed for WCBP at Visit 3 (Day 28) (Table 1).   


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6.1.5.3 
Urine Drug Test 
A urine drug test will be performed for drugs of abuse at Screening as indicated in Table 1. These 
will include testing for amphetamines, barbiturates, cocaine metabolites, opiates, and 
benzodiazepines. 
 
6.2 Efficacy Assessments 
6.2.1 16-Hour Tracer Infusion 
A 16-hour tracer infusion will be performed after 28 days of treatment. The blood draw schedule 
during the tracer infusion is documented in Table 2 in Section 3.7 of the protocol. Based on the 
blood draws the values for the following lab tests will be obtained: 
• Endogenous Glucose Production (glucose that is produced by the liver which has the tracer 
attached), 
• Key metabolites (β-hydroxybutyrate, acetoacetate, lactate, pyruvate, FFA, glycerol), and 
• Key hormones (insulin, C-peptide, glucagon). 
 
For each of the lab tests, the following parameters will be derived (as appropriate): 
• AUC(0-16), 
• AUC(0-2), AUC(0-4), AUC(0-8), AUC(0-12), 
• AUC(2-16), AUC(4-16), AUC(8-16), AUC(12-16), 
• Cmax (endogenous glucose production only), 
• Tmax (endogenous glucose production only), and 
• Tlag (endogenous glucose production only). 
 
6.2.2 Hemoglobin A1c (HbA1c) 
Hemoglobin A1c will be collected at every visit.   
 
6.2.3 Plasma Glucose Levels 
Plasma glucose levels will be collected prior to dosing and after 28 days of dosing. The plasma 
glucose levels collected after the 16-hour infusion period is complete is the value that will be 
analyzed for this test. 
 
6.2.4 Ketones and Free Fatty Acids 
Ketones and free fatty acid levels will be collected prior to dosing and after 28 days of dosing. The 
values collected after the 16-hour infusion period is complete are the values that will be analyzed 
for these tests. 
6.2.5 Lipids (Total Cholesterol, LDL Cholesterol, HDL Cholesterol and Triglycerides) 
Lipids will be collected prior to dosing and after 28 days of dosing. The values collected after the 
16-hour infusion period is complete are the values that will be analyzed for these tests.


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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, weight, vital signs (SBP/DBP and heart rate) and clinical safety 
labs (hematology, serum chemistry and urinalysis). 
7.2 Definition of Adverse Event  
An adverse event (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 can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease during the course of the study, and does not imply any judgment about 
causality. 
Treatment-emergent adverse events (TEAEs) are defined as any AE that starts or increases in 
severity after the first randomized dose of study treatment (active or placebo).  
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 subject 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 dependency or drug abuse. 
An AE is considered “life-threatening” if, in the view of either the investigator or Sponsor, its 
occurrence places the subject 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. 


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7.4 Eliciting and Reporting of Adverse Events 
AE monitoring will start immediately following the first dose of active treatment or placebo (Visit 
1) and will continue through Visit 3. Any subject with a possible study treatment-related AE at the 
end of the study 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 eCRF. 
Subjects will be instructed to report all AEs experienced during the study, and subjects will be 
assessed in clinic 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 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 Visit 1. 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 eCRF. Copies of the SAE eCRF pages or 
an SAE listing generated based on the eCRF pages will be submitted to the Sponsor at regularly 
scheduled intervals to allow the Sponsor to meet expedited regulatory reporting requirements under 
21 CFR 312.32 (see Section 7.4.2 for further detail) and regular regulatory reporting requirements 
under 21 CFR 312.33.  
For each AE, the following information will be entered in the eCRF: 
• Medical diagnosis of the event in standard medical terminology (if a medical diagnosis 
cannot be determined, a description of each sign or symptom characterizing the event); 
• Date of onset of any new AE or worsening of a previously observed AE. 
• Date of resolution of the event (or confirmation ongoing).; 
• 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 7.4];  
• Whether the event is expected (per definition in Section 7.7); 


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• 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.  
 
If an SAE, including death occurs during this study or within 30 days following the last dose of the 
study treatment, the Investigator must notify the Medical Monitor within 24 hours after becoming 
aware of the event.  
Initial notification via the telephone does not replace the need for the Investigator to complete 
and sign the SAE form within the time frames outlined in the protocol. This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports. 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: carmen.margaritescu@integrium.com 
 
SAE Forms will be provided by the Sponsor or Sponsor designated contract research 
organization (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. For all serious 
adverse events, the Investigator must to pursue and provide information to the Study Medical 
Monitor in accordance with the timeframes for reporting specified above. In general, this will 
include a description of the adverse event in enough detail to allow for a complete medical 
assessment of the case and independent determination of possible causality. Information on other 
possible causes of the event, such as concomitant medications and illnesses, must be provided. In 
the case of a subject death, a summary of available autopsy findings must be submitted as soon 
as possible to the Medical Monitor”. 
 
In the event of a medical emergency or an SAE that is unexpected (as defined in Section 7.8) and 
possibly related to the study treatment (s) (i.e., an adverse reaction or suspected adverse reaction as 
defined in Section 7.6), in the opinion of either the Investigator or the Medical Monitor, the blind 
will be broken for the subject that experiences the event. If the Investigational Site personnel need 
to unblind the study treatment they can contact the unblinded programmer and pharmacist. 
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 


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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; 
4. Modification of previously identified expected adverse experiences to include adverse 
experiences newly identified as study treatment-related. 
 
7.4.2.1 
Pregnancy Reporting 
If the subject or partner of a subject participating in the study becomes pregnant during the study or 
within 30 days 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 


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SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for reporting an SAE. 
7.4.3 Adverse Events of Hypoglycemia 
Hypoglycemia and associated symptoms (e.g., weakness, dizziness, shakiness, increased sweating, 
palpitations, or confusion), have been associated with insulin administration, including ORMD-
0801. Animal reproductive studies have not been conducted with ORMD-0801. It is not known 
whether ORMD-0801 can cause fetal harm when administered to a pregnant woman. It is also not 
known whether this product is excreted in human milk. Pregnant or breastfeeding women are 
excluded from this study. 
Long-term animal studies have not been completed to assess whether ORMD-0801 impairs fertility.  
Due to the specific relevance of hypoglycemia as a limiting factor in insulin therapy, AEs of 
hypoglycemia will be reviewed at every visit. All hypoglycemic events will be reported on a special 
hypoglycemia AE eCRF page. This will include the following information: 
• 
Subject symptoms; 
• 
Type of symptoms; 
• 
BG value during the hypoglycemic event and the event severity based on CTCAE 
criteria; 
• 
Whether treatment was required; 
• 
Whether assistance was required for treatment; 
• 
What specific treatment, if any, was used. 
 
Instructions will be given to sites to additionally report episodes consistent with hypoglycemia 
requiring third party assistance as Serious Adverse Events (SAE). 
 
Collection of data from the hypoglycemia AE eCRF including episodes consistent with 
hypoglycemia will allow analysis and characterization of hypoglycemia according to accepted ADA 
definitions (Seaquist et al, 2013) and according to common cut-off values, such as BG < 70 mg/dL 
and < 53 mg/dL for example.   
7.4.4 Adverse Events of Hyperglycemia 
Hyperglycemia is the result of inadequate treatment and a pre-condition for enrolment into the 
study, therefore in general hyperglycemia is not considered an AE. However, hyperglycemia may 
occur in participants during the study either due to worsening diabetes or lack of efficacy of study 
medication. For standardization purposes, hyperglycemia is defined as a blood glucose reading > 
300 mg/dL regardless of symptoms. Subjects who have a blood glucose reading > 300 mg/dL will 
have the reading repeated 1-2 hours later. If a subject’s glucose remains above 300 mg/dL or for 
persistent symptoms of hyperglycemia, the subject will be instructed to contact the investigative site 
for follow-up. 
 


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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 eCRF. Causal relationship will be classified according to the 
following criteria: 
1. Unrelated: The event is clearly due to causes other than the active study drug. 
2. Unlikely: The event is doubtfully related to active study drug. The event was most likely 
related to other factors such as the subject’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 subject’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 subject’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 subject’s condition, concomitant drugs or 
therapeutic interventions, AND either occurs immediately following active study drug 
administration, improves on stopping the study drug, or reappears on re-exposure. 
 
7.6 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.  
Table 3. 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. 
 


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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 subject'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 International Council for Harmonisation (ICH) 
Topic E2B, ICH Guideline. 
• Recovered/Resolved: The subject has recovered fully from the AE without any 
remaining effects or impairment. 
• Recovered/Resolved with Sequelae: The subject has recovered, but with an after effect 
possibly due to disease or treatment. 
• Not Recovered/Not Resolved: The condition is still present. 
• Fatal: Fatal should only be used when death is possibly related to the AE. 
• Unknown: The primary outcome is not known at the time of the final assessment. If an 
outcome for an AE is not available at the time of the initial report, follow-up will proceed 
until an outcome is known or followed up to the Final Study Visit. Any subject with a 
possible 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 Visit 3 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 7.4), the follow-up procedures 
for AEs defined above will apply. 
 


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8 STATISTICAL METHODS 
This section describes the statistical methods to be used for the analysis and reporting of data 
collected under Protocol No. ORA-D-018. Additional details will be provided in the statistical 
analysis plan. 
8.1 Study Design 
The primary analysis is a comparison of difference in endogenous glucose production for the 
ORMD-0801 treated group and placebo. Let pC be the endogenous glucose production for the 
control (placebo) arm and let pT be the endogenous glucose production for the treatment (ORMD-
0801) arm. The primary analysis is: 
H0 : pC=pT 
H1 : pC≠pT 
Trial success is defined as having the endogenous glucose production for the placebo group being 
greater than the endogenous glucose production for the ORMD-0801 treated group.  
8.2 Sample Size 
Sample size determination was not based on statistical considerations. 
8.3 Primary Efficacy Evaluation 
The primary endpoint for this study is the difference in endogenous glucose production between 
active and placebo as measured by the glucose with tracer attached using AUC(0-16). 
 
The primary endpoint will be analyzed using an Analysis of Variance model with treatment as the 
main effect. 
8.4 Secondary Efficacy Evaluation 
8.4.1 16-Hour Tracer Infusion 
A 16-hour tracer infusion will be performed after 28 days of treatment. The blood draw schedule 
during the tracer infusion is documented in Table 2 in Section 3.7 of the protocol. Based on the 
blood draws the values for the following lab tests will be obtained: 
• Endogenous Glucose Production (glucose that is produced by the liver which has the tracer 
attached), 
• Key metabolites (β-hydroxybutyrate, acetoacetate, lactate, pyruvate, FFA, glycerol), and 
• Key hormones (insulin, C-peptide, glucagon). 
 
For each of the lab tests, the following parameters will be derived (as appropriate): 
• AUC(0-16), 
• AUC(0-2), AUC(0-4), AUC(0-8), AUC(0-12), 
• AUC(2-16), AUC(4-16), AUC(8-16), AUC(12-16), 


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• Cmax (endogenous glucose production only), 
• Tmax (endogenous glucose production only), and 
• Tlag (endogenous glucose production only). 
 
Each of these parameters for each of the tests will be analyzed using an Analysis of Variance model 
with treatment as the main effect. 
 
8.4.2 Hemoglobin A1c (HbA1c) 
Hemoglobin A1c will be collected prior to dosing and after 28 days of dosing. This parameter will 
be analyzed using an Analysis of Covariance model with treatment as the main effect and baseline 
value as the covariate. 
 
8.4.3 Plasma Glucose Levels 
Plasma glucose levels will be collected prior to dosing and after 28 days of dosing. The plasma 
glucose levels collected after the 16-hour infusion period is complete, is the value that will be 
analyzed for this test. This parameter will be analyzed using an Analysis of Covariance model with 
treatment as the main effect and baseline value as the covariate. 
 
8.4.4 Ketones and Free Fatty Acids 
Ketones and free fatty acid levels will be collected prior to dosing and after 28 days of dosing. The 
values collected after the 16-hour infusion period is complete, are the values that will be analyzed 
for these tests. These parameters will be analyzed using an Analysis of Covariance model with 
treatment as the main effect and baseline value as the covariate. 
 
8.4.5 Lipids (Total Cholesterol, LDL Cholesterol, HDL Cholesterol and Triglycerides) 
Lipids will be collected prior to dosing and after 28 days of dosing. The values collected after the 
16 hour infusion period is complete, are the values that will be analyzed for these tests. These 
parameters will be analyzed using an Analysis of Covariance model with treatment as the main 
effect and baseline value as the covariate. 
 
8.5 Safety Evaluation 
8.5.1 Safety Population 
All randomized subjects who receive at least one dose of study treatment will be included in the 
safety analysis population. 
 
8.5.2 Adverse Events 
AEs will be coded using the most current version of MedDRA.   
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 


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percentage of the population that this represents. If a TEAE is reported more than once for a given 
subject, the greatest severity and the worst-case attribution will be presented in the summary tables. 
TEAEs will be listed for individual subjects, along with information regarding onset and end dates, 
onset time where available, severity, seriousness, relationship to study treatment, action taken, and 
outcome. A similar listing will be prepared for the pretreatment AEs.   
TEAEs that lead to withdrawal from the study will be separately listed and summarized.   
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. 
 
8.5.3 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. A 
clinically significant change from baseline will be recorded as an AE if deemed appropriate by the 
Investigator. 
 
8.5.4 Vital Signs 
Individual vital sign measurements (height, weight, seated SBP/DBP, and heart rate) 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 in vital sign 
measurements will be calculated and summarized descriptively. A clinically significant change 
from baseline will be recorded as a TEAE if deemed appropriate by the Investigator. 
 
8.5.5 12-lead ECG 
Individual 12-lead ECG assessments are only collected as screening and will be listed. 
 
8.5.6 Physical Examination 
Individual physical examination findings will be listed by visit. A clinically significant change from 
baseline will be recorded as an AE if deemed appropriate by the Investigator. 
 
8.5.7 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.   
Concomitant medications and supplements will be listed for individual subjects. A similar listing 
will be prepared for prior medications and supplements stopped within 30 days prior to the first 
dose of study treatment. The incidence of these prior and concomitant medications and supplements 
will be summarized. 
 


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8.5.8 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 
CRO’s SOPs. 
9.1.1 Electronic Data Capture 
Data from the source documents will be entered into the EDC system by authorized Investigational 
Site personnel. Data Management staff, using both electronic and manual checks, will 
systematically check the data. Errors or omissions will result in queries (which can be issued by the 
Study Monitor or Data Management staff), which will be presented to the Investigational Site 
within the EDC system. The Investigational Site will resolve the queries within the EDC system.  
The Study Monitor and Data Management staff will review the responses as part of the query 
resolution process. The EDC system will track the queries with the corresponding responses. 
Medications and supplements entered into the database will be coded in the EDC system using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. AEs and Medical History will be coded in the EDC system using MedDRA terminology.  
Laboratory samples will be processed by appropriate laboratories. Results will be reported to 
Integrium and imported  into the database. 
9.2 Quality Assurance and Database Lock 
A 100% critical variable review of all key safety and secondary endpoint data in the database will 
be performed. Following this review, a data quality control audit or a random sample equal to 10% 
of subjects, with a minimum of 5 subjects will be performed. 
When the database has been declared to be complete and accurate, the database will be locked. Any 
changes to the database after that time can only be made by joint written agreement between the 
Sponsor, the Investigator, Integrium, and the study biostatistician. 
10 AMENDMENTS/MODIFICATIONS 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 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 
eCRF and source documents will completely describe the departure from the protocol and state the 


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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. 
11.2 
Protection of Human Subjects 
11.2.1 Declaration of Helsinki  
The Investigator will conduct this study in accordance with the Declaration of Helsinki (1964) 
including all amendments up to and including the October 2013 revision. 
 
11.2.2 Good Clinical Practice and Regulatory Compliance 
The Investigator will conduct this study in accordance with the principles of GCP (current ICH 
guidelines) and the requirements of all local regulatory authorities regarding the conduct of clinical 
trials and the protection of human subjects. 
The study will be conducted as described in the approved protocol, with amendments and in 
accordance with the obligations of clinical Investigators set forth in the Form FDA 1572 and in 21 
CFR 50, 54, 56 and 312. 
11.2.3 Institutional Review Board  
The Investigator is responsible for the submission of the protocol, ICF, and other written materials 
(such as advertisements and diaries), along with relevant supporting data (e.g., IB), to the 
appropriate IRB for review and approval before the study can be initiated. The Investigator is also 
responsible for submitting amendments to the protocol and ICF to the IRB for review and approval 
prior to implementation of the change. The Investigator is responsible for providing the Sponsor 
with a letter documenting the IRB approval prior to initiation of the study or implementation of the 
changes, respectively.  
The Investigator will not have authority to implement any deviation or change to the protocol 
without prior review and documented approval/favorable opinion from the IRB of an amendment, 
except where necessary to eliminate an immediate hazard to study subjects. Any significant 
deviation from the approved protocol will be documented in the source documents and eCRF.  
Any deviation or change to the protocol required to eliminate an immediate hazard prior to 
obtaining IRB approval/favorable opinion, will be submitted as soon as possible to:  
• IRB for review and approval/favorable opinion.  


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• 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).  
11.2.4 Subject Informed Consent 
The Investigator must comply with informed consent regulations (21 CFR Part 50) and relevant 
state regulations (i.e., California Bill of Rights for California patients).   
The ICF will clearly describe the nature, scope, and potential risks and benefits of the study, in a 
language that the subject understands. The ICF will conform to all the requirements for informed 
consent according to ICH GCP and US FDA guidelines (21 CFR 50) and will include any 
additional elements required by the Investigator’s institution or local regulatory authorities. The ICF 
will adhere to the ethical principles that have their origin in the Declaration of Helsinki.   
Prior to the beginning of the study, the Investigator will obtain the IRB’s written approval/favorable 
opinion of the written ICF. The IRB approved ICF will be given to each prospective participant.  
The subjects will be given adequate time to discuss the study with the Investigator or site staff and 
to decide whether or not to participate. Each subject who agrees to participate in the trial and who 
signs the ICF will be given a copy of the signed, dated, and witnessed document. The original 
signed ICF will be retained by the Investigator in the study files. 
The ICF and any other information provided to subjects will be revised whenever important new 
information becomes available that is relevant to the subject's consent, and the Investigator will 
obtain the IRB’s written approval/favorable opinion prior to the use of the revised documents. The 
Investigator, or a person designated by the Investigator, will fully inform the subject of all pertinent 
aspects of the study and of any new information relevant to the subject's willingness to continue 
participation in the study. Subjects will read and sign any and all revised ICFs.  


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11.3 
Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects’ state of health 
will be regarded as confidential. This is detailed in the ICF provided to the subject. An agreement 
for the use or disclosure of any such information (PHI) will be obtained from the subject in writing 
(HIPAA authorization) prior to performing any study-related procedures. 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. 
11.4 
Electronic Data Capture 
All data required by the study protocol will be recorded in the electronic database. Data from the 
source documents will be entered into the EDC system by authorized Investigational Site 
personnel. The data 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 are accurate and correct by 
electronically signing the subject’s Investigator signature screen. 
11.5 
Source Documentation 
All data entered in the eCRF must be verifiable against source documentation. Source documents 
may include, but are not limited to, a subject’s medical record, hospital charts, clinic charts, the 
Principal Investigator’s study files, as well as the results of diagnostic tests.   
11.6 
Retention of Records 
The Investigator has the responsibility of maintaining a comprehensive and centralized filing 
system containing all study-related documentation. These files must be available for inspection 
by the Sponsor or designee, the IRB, and regulatory authorities (i.e., FDA or international 
regulatory authorities) at any time and should consist of the Essential Documents as defined in 
ICH E6, which include, but are not limited to, the following elements: 
• Subject files, containing the completed eCRFs, supporting source documentation from 
the medical record, including laboratory data, and the signed ICF;  
• Regulatory files, containing the protocol with all amendments and Sponsor and 
Investigator signature pages, copies of all other regulatory documentation, and all 
correspondence between the site and the IRB and Sponsor; and  


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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. 
11.7 
Clinical Study Report 
After completion or termination of the study, a clinical study report will be prepared.  The 
structure and content of the report will meet that described in Structure and Content of Clinical 
Study Reports E3 (ICH Harmonized Tripartite Guideline, dated November 30, 1995). The 
Principal Investigator must verify that all information and data in the clinical study report is 
accurate and correct by signing the clinical study report. 
 
12 STUDY ADMINISTRATION 
12.1 
Study Monitoring 
This study will be monitored by the Sponsor or designee to evaluate the progress of the study, to 
verify the accuracy and completeness of the eCRFs, to assure that all protocol requirements, 
applicable laws and/or regulations, and Investigator’s obligations are being fulfilled, and to resolve 
any inconsistencies in the study records.  
 
The Investigator will allow the Study Monitor to periodically review, at mutually convenient times 
during the study and after the study has been completed, all eCRFs and office, hospital, and 
laboratory records supporting the participation of each subject in the study.   
 
The Study Monitor will compare the eCRF data against source documentation in order to verify its 
accuracy and completeness. The Investigator and Investigational Site staff will collaborate with the 
Study Monitor to resolve any identified data discrepancies in a timely manner.   
 


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The Study Monitor will record any protocol deviations identified, including, but not limited to, 
subjects that were enrolled even though they did not meet all eligibility criteria, subjects who took 
concomitant medications specifically prohibited by the protocol, subjects who received the wrong 
study treatment or incorrect dose, and subjects who failed to comply with the protocol-defined 
dietary restrictions. The Investigator and Investigational Site staff will collaborate with the Study 
Monitor to identify the reason for each protocol deviation.   
 
The Study Monitor will compare the Investigational Site study treatment accountability record 
against the study treatment inventory (unused and used) at the site. The Investigator and 
Investigational Site staff will collaborate with the Study Monitor to resolve any identified 
discrepancies in a timely manner. 
 
Each issue identified during study monitoring visits will be documented and reported to both the 
Sponsor and the Investigator. 
12.2 
On-Site Audits 
The FDA, or other regulatory authorities, may request access to all study records for inspection 
and copying. The Principal Investigator and Investigational Site staff will cooperate with the 
inspectors and allow access to all source documents supporting the eCRFs and other study-
related documents. The Investigator will immediately notify the Sponsor when contacted by any 
regulatory authority for the purpose of conducting an inspection.  
 
The Sponsor or designee may also request to visit the Investigator’s site to conduct an audit of 
the study. Prior to initiating this audit, the Investigator will be contacted by the Sponsor to 
arrange a convenient time for this visit. The Principal Investigator and Investigational Site staff 
will cooperate with the auditors and allow access to all source documents supporting the eCRFs 
and other study-related documents.  
12.3 
Data Quality Assurance 
All eCRFs must be completed by authorized Investigational Site personnel who have undergone 
eCRF training. Data will be entered into the eCRF as information becomes available on a visit-
by-visit basis. All data recorded on the eCRFs must be supported by source documentation. The 
Principal Investigator must verify that all data entries in the eCRF are accurate and correct by 
electronically signing and dating the eCRF. 
 
All eCRF corrections must be made by the Principal Investigator or authorized Investigational 
Site personnel. The Principal Investigator must authorize changes to the recorded data, and this 
authorization must be documented in the source documents.   
 
Refer to Section 9 for further details regarding Data Management quality assurance, including 
query generation and resolution, final data review, and database lock. 
12.4 
Publication Policy 
All information and data obtained in the course of the study are the property of the Sponsor and 
are considered confidential. To avoid disclosures that could jeopardize proprietary rights, the 


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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. 
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, eCRFs, and other 
material) will be stored appropriately to ensure their confidentiality. The information provided by 
the Sponsor and Integrium to the Investigator may not be disclosed to others without direct written 
authorization from the Sponsor and Integrium, except to the extent necessary to obtain informed 
consent from subjects who wish to participate in the study.


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Phase 2b Clinical Study 
May 13, 2020 
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13 REFERENCES 
1. Gastaldelli A, Baldi S, Pettiti M, Toschi E, Camastra S, Natali A, Landau BR, Ferrannini E. 
Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a 
quantitative study. Diabetes. 2000 Aug;49(8):1367-73. 
2. Ferrannini E, Gastaldelli A, Iozzo P. Pathophysiology of prediabetes. Med Clin North Am. 
2011 Mar;95(2):327-39. 
 


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Phase 2b Clinical Study 
May 13, 2020 
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14 APPENDIX A  
14.1 
Guidelines for TRACER Infusion 
 
EGP Protocol 
 
Tracer:  [6,6-2H2]-glucose (from Cambridge Isotope Laboratories 
[https://shop.isotope.com/productdetails.aspx?itemno=DLM-349-PK]) 
Constant tracer infusion rate:  0.28 µmol.min-1.kg-1 (= 51 µg.min-1.kg-1) via an indwelling 
catheter in an antecubital vein. Assuming participants have dinner at 18:00pm, the tracer 
infusion can start at 20:00pm and continue until 12 noon the following day, i.e., for 960 
min.  
Example:  In a T2D subject weighing 90 kg, the total amount of tracer would be 0.28 x 
960 x 90 = 24,192 µmol (= 4.41 g per study). Rounding this up, on dissolves 4.5 g of [6,6-
2H2]-glucose in 500 mL of saline: this is the mother solution (from which a 5 mL aliquot 
must be saved together with the plasma samples) to be given at a rate of 0.5 mL/min to the 
90-kg person for 960 min. 
Blood sampling:  through a cannula in a contralateral antecubital vein, one sample is taken 
prior to starting the tracer infusion, then blood is drawn every hour till the end.