Clinical trial NCT04150107
Conditions: Type 1 Diabetes
Sponsor: Oramed, Ltd.
Start date: 2019-10-17; Completion date: 2020-03-12
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is a Phase 2 randomized, crossover study comparing ORMD-0801 given QD versus TID in subjects with T1D. Subjects with T1D will have a screening visit (Visit 1) during which they will be required to review and sign the informed consent form. Medical history and demographics will be collected. Vital signs will be measured, physical exam will be performed, and blood and urine samples will be collected for hematology/chemistry/urinalysis

Placebo capsules will be given QD at bedtime during placebo run-in period 10 days prior to randomization.

Detailed description:
This study is a Phase 2 randomized, crossover study comparing ORMD-0801 given QD versus TID in subjects with T1D. Subjects with T1D will have a screening visit (Visit 1) during which they will be required to review and sign the informed consent form. Medical history and demographics will be collected. Vital signs will be measured, physical exam will be performed, and blood and urine samples will be collected for hematology/chemistry/urinalysis. Eligible subjects will be scheduled to return to the clinic in 1 week (Visit 2). Subjects fulfilling all inclusion/exclusion criteria will have a CGM placed, provided with a diary, dispensed Placebo capsules and asked to return to the clinic in 10 Days (Visit 3, Day 1) for randomization. At Visit 3, data from CGM will be downloaded and diaries will be collected. Blood samples will be collected in fasting for chemistry and HbA1c. Subjects will be randomized to receive either ORMD-0801 24 mg given once daily at bedtime, or ORMD-0801 8 mg given three times a day, 45-90 minutes before meals.

Subjects will be instructed to continue their normal diet, and to adjust their basal and bolus insulin in the normal fashion. Subjects will be instructed to return to the clinic 10 days before Visit 5 (Visit 4, Day 18). At Visit 4, compliance will be assessed, IMP and diary dispensed and the CGM will be placed. Subjects will be instructed to return to the clinic in 10 days for Visit 5 (Day 28). At Visit 5 a fasting blood sample for chemistry panel and HbA1C will be drawn and after the diary has been collected and the CGM monitor removed, they will be crossed over to the alternate treatment regimen. IMP will be dispensed, and the subject will be asked to return 10 days before Visit 7 for Visit 6 (Day 46). At Visit 6, compliance will be checked, IMP and diary will be dispensed and the CGM will be placed. Subjects will be instructed to return in 10 days for Visit 7 (Day 56). At Visit 7 the CGM will be removed, compliance checked, the diary will be collected, and a blood sample will be drawn for a chemistry panel and HbA1C. A physical examination will be performed, and the subject will exit the study. Subjects will be provided with diaries at Visits 2, 4 and 6, and will be asked to capture the amount of basal and bolus exogenous insulin administered each day and calculate their carbohydrate count for all meals and snacks over the 10-day CGM monitoring period. Diaries will be collected at Visits 3, 5 and 7.

Arms: arm 1: Treatment administered in the following order:

1. Period 1: Placebo (Fish Oil Capsule)
2. Period 2: Treatment A: 24 mg ORMD-0801;(16 mg + 8 mg capsules) Once Daily (QD) at Bedtime
3. Period 3:Treatment B: 8 mg ORMD-0801; one 8 mg capsule three times a day (TID) 45-90 minutes before meals arm 2: Treatment administered in the following order:

1. Period 1: Placebo (Fish Oil Capsule)
2. Period 2:Treatment B: 8 mg ORMD-0801; one 8 mg capsule three times a day (TID) 45-90 minutes before meals
3. Period 3: Treatment A: 24 mg ORMD-0801;(16 mg + 8 mg capsules) Once Daily (QD) at Bedtime

Treatment B: 8 mg ORMD-0801; one 8 mg capsule three times a day (TID) 45-90 minutes before meals
Interventions: intervention 1: ORMD-0801 Treatment A intervention 2: ORMD-0801 Treatment B intervention 3: Placebo
Intervention descriptions: intervention 1: Treatment A: 24 mg (16 mg capsule + 8 mg capsule) Once Daily (QD) at bedtime intervention 2: Treatment B: 8 mg (8 mg capsule) three times a day (TID) 45-90 minutes before meals intervention 3: Fish oil capsule

Protocol documents:
Prot_000.pdf: 
Oramed Ltd. 
 
Protocol No. ORA-D-017 
Phase 2 Clinical Study 
 
Version 1.0 (Aug 25, 2019) 
Confidential                                                                                                                                               Page 1 of 62 
 
 
Clinical Study Protocol: ORA-D-017 
Study Title: 
A Phase 2 Randomized, Open Label Crossover Study to Compare 
ORMD-0801 Given Once Daily at Bedtime to ORMD-0801 given 
Three Times Daily (45-90 minutes before Meals) in Subjects with 
Type 1 Diabetes  
Protocol Number: 
ORA-D-017 
Study Phase:  
Phase 2 
Principal 
Investigator: 
Joel M. Neutel, M.D. 
Orange County Research Center (OCRC) 
14351 Myford Rd., Suite B, Tustin, CA 92780 
Sponsor: 
Oramed Ltd. 
Hi-Tech Park 2/4 Givat Ram 
PO Box 39098 
Jerusalem, 91390, Israel 
Name of Sponsor 
Signatory: 
Miriam Kidron, PhD 
Chief Scientific Officer and Director 
Oramed Ltd. 
Protocol Version: 
1.0 
Date of Version: 
August 25, 2019 
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-017 
Phase 2 Clinical Study 
 
Version 1.0 (Aug 25, 2019) 
Confidential                                                                                                                                               Page 3 of 62 
 
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. 
 
<Name of Investigator and Site> 
 
 
Signature 
 Date 
 
 
 


Oramed Ltd. 
 
Protocol No. ORA-D-017 
Phase 2 Clinical Study 
 
Version 1.0 (Aug 25, 2019) 
Confidential                                                                                                                                               Page 4 of 62 
 
SYNOPSIS 
 
Title 
A Phase 2 Randomized Open Label Crossover Study to Compare 
ORMD-0801 Given Once Daily at Bedtime to ORMD-0801 given 
Three Times Daily (45-90 minutes before Meals) in Subjects with 
Type 1 Diabetes  
Indication 
Type 1 Diabetes  
Clinical Phase 
Phase 2 
Investigational 
Medicinal Product 
(IMP)  
Name of the IMP: ORMD-0801 
Dose and dosage regimen: 
Treatment A: 24 mg (16 mg capsule + 8 mg capsule) Once Daily (QD) 
at bedtime 
Treatment B: 8 mg (8 mg capsule) three times a day (TID) 45-90 
minutes before meals 
Placebo capsules will be administered to subjects for 10 day run-in 
period prior to Randomization (subjects will take one capsule daily at 
bedtime).   
Formulation: 
Coated soft gel capsule [SBTI], disodium EDTA, fish oil, aerosol, and 
Tween 80 
Mode of administration: 
Oral 
Primary Objectives 
1. To compare the impact of Oral Insulin dosed QD to Oral Insulin 
dosed TID on exogenous basal and bolus insulin requirements in 
subjects with Type 1 Diabetes (T1D) on their regular diet over a 
4-week period. 
2. To compare the impact of Oral Insulin dosed QD to Oral Insulin 
dosed TID and associated adjustments of basal and bolus insulin 
on mean 24-hour glucose and parameters of glycemic variability 
as measured by a Continuous Glucose Monitor over a 10-day 
period in subjects with T1D 


Oramed Ltd. 
 
Protocol No. ORA-D-017 
Phase 2 Clinical Study 
 
Version 1.0 (Aug 25, 2019) 
Confidential                                                                                                                                               Page 5 of 62 
 
Secondary 
Objectives 
1. To compare the change from baseline in number of 
hypoglycemic episodes in subjects treated with Oral Insulin 
dosed QD to Oral insulin Dosed TID in subjects with T1D 
2. To compare the change from baseline in Plasma A1C levels in 
subjects with T1D treated with Oral Insulin dosed QD or Oral 
Insulin dosed TID. 
3. To explore changes in glucodynamics between the different 
dosing regimens. 
4. To evaluate the safety of Oral Insulin 
Total Sample Size 
Approximately 26 completers 
Sites 
3 sites  
Study Design 
This study is a Phase 2 randomized, crossover study comparing 
ORMD-0801 given QD versus TID in subjects with T1D. Subjects 
with T1D will have a screening visit (Visit 1) during which they will 
be required to review and sign the informed consent form. Medical 
history and demographics will be collected. Vital signs will be 
measured, physical exam will be performed, and blood and urine 
samples will be collected for hematology/chemistry/urinalysis. 
Eligible subjects will be scheduled to return to the clinic in 1 week 
(Visit 2). Subjects fulfilling all inclusion/exclusion criteria will have 
a CGM placed, provided with a diary, dispensed Placebo capsules 
and asked to return to the clinic in 10 Days (Visit 3, Day 1) for 
randomization. At Visit 3, data from CGM will be downloaded and 
diaries will be collected. Blood samples will be collected in fasting 
for chemistry and HbA1c. Subjects will be randomized to receive 
either ORMD-0801 24 mg given once daily at bedtime, or ORMD-
0801 8 mg given three times a day, 45-90 minutes before meals. 
Subjects will be instructed to continue their normal diet, and to 
adjust their basal and bolus insulin in the normal fashion. Subjects 
will be instructed to return to the clinic 10 days before Visit 5 (Visit 
4, Day 18). At Visit 4, compliance will be assessed, IMP and diary 
dispensed and the CGM will be placed. Subjects will be instructed to 
return to the clinic in 10 days for Visit 5 (Day 28). At Visit 5 a 
fasting blood sample for chemistry panel and HbA1C will be drawn 
and after the diary has been collected and the CGM monitor 
removed, they will be crossed over to the alternate treatment 
regimen. IMP will be dispensed, and the subject will be asked to 
return 10 days before Visit 7 for Visit 6 (Day 46). At Visit 6, 
compliance will be checked, IMP and diary will be dispensed and 


Oramed Ltd. 
 
Protocol No. ORA-D-017 
Phase 2 Clinical Study 
 
Version 1.0 (Aug 25, 2019) 
Confidential                                                                                                                                               Page 6 of 62 
 
the CGM will be placed. Subjects will be instructed to return in 10 
days for Visit 7 (Day 56). At Visit 7 the CGM will be removed, 
compliance checked, the diary will be collected, and a blood sample 
will be drawn for a chemistry panel and HbA1C. A physical 
examination will be performed, and the subject will exit the study. 
Subjects will be provided with diaries at Visits 2, 4 and 6, and will 
be asked to capture the amount of basal and bolus exogenous insulin 
administered each day and calculate their carbohydrate count for all 
meals and snacks over the 10-day CGM monitoring period. Diaries 
will be collected at Visits 3, 5 and 7. 
Study Endpoints 
Primary Endpoints: 
1. To compare the amount of basal, bolus and total (basal + 
bolus) exogenous insulin utilized over the final 10 days of 
each treatment period. 
2. To compare the impact of Oral Insulin dosed QD to Oral 
Insulin dosed TID and associated adjustments of basal 
and bolus insulin on mean 24-hour CGM glucose levels 
during the final 10 days of each treatment period. 
 
Secondary Endpoints: 
1. Glucodynamics over the final 10 days of each treatment 
period as measured by CGM: 
a. Time in range 70 - 180 mg/dL 
b. Time < 70 mg/dL 
c. Time >180 mg/dL 
d. Time >250 mg/dL 
e. Glucose Coefficient of Variation 
f. Low Blood Glucose Index (LBGI) 
g. Glucose below 70 mg/dL Area Over the Curve 
(AOC70) 
2. Total daily non-oral insulin requirements in units per 
kilogram (kg) body weight over the last 10 days of each 
treatment period.  
 
Exploratory Endpoints: 
3. HbA1c measured at the end of each treatment period 
4. Patient diary-reported carbohydrate intake over the final 10 
days of each treatment period 
5. Changes in body weight from baseline (Visit 2) to the end of 
each treatment period                                         


Oramed Ltd. 
 
Protocol No. ORA-D-017 
Phase 2 Clinical Study 
 
Version 1.0 (Aug 25, 2019) 
Confidential                                                                                                                                               Page 7 of 62 
 
6. Other measures of hypoglycemia over the last 10 days of each 
treatment period: 
a. Severe hypoglycemia (SH) events (impaired or 
loss of consciousness requiring assistance of 
another)  
b. Documented symptomatic hypoglycemia (an event 
during which typical symptoms of hypoglycemia 
are accompanied by a measured plasma glucose 
concentration <70 mg/dl (3.9 mmol/L)) 
c. Total time <70 mg/dL by CGM 
d. Nocturnal hypoglycemia, severe or documented 
symptomatic episodes (as defined above) 
occurring after the subject has retired for the 
primary sleeping period 
 
  Safety assessments evaluating: 
• 
Changes in clinical laboratory tests (hematology, chemistry, 
urinalysis); 
• 
Collection of adverse events (AEs);   
• 
Changes in Vital sign measurements 
 
Duration of 
Participation 
Including screening period, subjects will participate in this study for 
about 77 days (11 weeks). 
Subject Selection 
Criteria 
 
Inclusion Criteria 
Each subject must meet all of the following criteria to be eligible for 
study participation: 
1. Male and female subjects aged 18 and older. 
2. Body mass index (BMI) of 19-30 kg/m2 at Screening and stable 
weight, with no more than 5 kg gain or loss in the 3 months 
prior to Screening. 
3. T1D subjects must have: 
a. A documented history of type 1 diabetes for at least 6 
months 
b. Should be on an MDI regimen 
c. C peptide levels of ˂ 0.7 ng/mL 
d. HbA1C ≥ 6.5% to ≤10%  
4. Females of childbearing potential must have a negative serum 
pregnancy test result at Screening. 
5. Females who are not of childbearing potential are defined as: 
a. post-menopausal (defined as at least 12 months with no 
menses in women ≥45 years of age) or 


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Protocol No. ORA-D-017 
Phase 2 Clinical Study 
 
Version 1.0 (Aug 25, 2019) 
Confidential                                                                                                                                               Page 8 of 62 
 
b. has had a hysterectomy and/or bilateral oophorectomy, 
or had bilateral tubal ligation or occlusion at least 6 
weeks prior to Screening 
6. Subjects who are of childbearing potential must:  
a. agree to remain abstinent from heterosexual activity† or 
agree to use (or have their partner use) acceptable 
contraception to prevent pregnancy within the projected 
duration of the trial and for 14 days after the last dose of 
blinded investigational product.  Two methods of 
contraception will be used to avoid 
pregnancy.  Acceptable combinations of methods 
include: 
i. Use of one of the following double-barrier 
methods: diaphragm with spermicide and a 
condom; cervical cap and a condom; or a 
contraceptive sponge and condom 
ii. Use of hormonal contraception (any registered 
and marketed contraceptive agent that contains 
an estrogen and/or a progestational agent 
[including oral, subcutaneous, intrauterine and 
intramuscular agents, and cutaneous patch]) with 
one of the following:  diaphragm with 
spermicide; cervical cap; contraceptive sponge; 
condom; vasectomy; or IUD. 
iii. Use of an IUD with one of the following: 
condom; diaphragm with spermicide; 
contraceptive sponge; vasectomy; or hormonal 
contraception (see above). 
iv. Vasectomy with one of the 
following:  diaphragm with spermicide; cervical 
cap; contraceptive sponge; condom; IUD; or 
hormonal contraception (see above). 
†Abstinence can be used as the sole method of contraception 
if it is in line with the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and 
ethics committees.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
Exclusion Criteria 


Oramed Ltd. 
 
Protocol No. ORA-D-017 
Phase 2 Clinical Study 
 
Version 1.0 (Aug 25, 2019) 
Confidential                                                                                                                                               Page 9 of 62 
 
Subjects who meet any of the following criteria must be excluded from 
the study: 
1. Clinical diagnosis of type 2 diabetes; 
2. Evidence of unawareness of hypoglycemia unawareness, a 
documented plasma glucose ≤50 mg/dL in the absence of 
symptoms of hypoglycemia at Screening. 
3. FPG >300 mg/dL at Screening; a single repeat test is allowable. 
4. Use of the following medications: 
a. Administration of thyroid preparations or thyroxine 
(except in subjects on stable replacement therapy) 
within 6 weeks prior to Screening. 
b. 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. 
5. Laboratory abnormalities at Screening including: 
a. Abnormal serum thyrotropin (TSH) levels below the 
lower limit of normal or >1.5X the upper limit of normal 
b. Elevated liver enzymes (alanine transaminase (ALT), 
alanine aminotransferase (AST), alkaline phosphatase) 
>2X the upper limit of normal. 
c. Very high triglyceride levels (>600 mg/dL); a single 
repeat test is allowable. 
d. Any relevant abnormality that would interfere with the 
efficacy or the safety assessments during study 
treatment administration. 
6. Subject has a Screening systolic blood pressure ≥165 mmHg or 
diastolic blood pressure ≥100 mmHg. Subjects will be allowed 
to take a BP rescue medication. 
7. Any clinically significant ECG abnormality at Screening or 
cardiovascular disease. Clinically significant cardiovascular 
disease will include:  
a. History of stroke, transient ischemic attack, or 
myocardial infarction within 6 months prior to 
Screening,  
8. History of or currently have New York Heart Associate Class 
II-IV heart failure prior to Screening.  
9. Presence of any clinically significant endocrine disease 
according to the Investigator (euthyroid subjects on replacement 


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Phase 2 Clinical Study 
 
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Confidential                                                                                                                                               Page 10 of 62 
 
therapy will be included if the dosage of thyroxine is stable for 
at least six weeks prior to Screening). 
10. Presence of any clinically significant condition (in the opinion 
of the Investigator) that might interfere with the evaluation of 
study medication, such as significant renal, hepatic, 
gastrointestinal (GI), cardiovascular (CV), immune disease, 
blood dyscrasias or any disorders causing hemolysis or unstable 
red blood cells, or clinically important hematological disorders 
(i.e. aplastic anemia, myeloproliferative or myelodysplastic 
syndromes, thrombocytopenia) at Screening. 
11. History of gastrointestinal disorders (e.g. hypochlorhydria) with 
the potential to interfere with drug absorption. 
12. Presence or history of cancer within the past 5 years of 
Screening, with the exception of adequately-treated localized 
basal cell skin cancer or in situ uterine cervical cancer.  
a. A subject with a history of malignancy >5 years prior to 
Screening should have no evidence of residual or 
recurrent disease.  
b. A subject with a history of melanoma, leukemia, 
lymphoma, or renal carcinoma is excluded. 
13. 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. 
14. Positive history of HIV. 
15. Known allergy to soy. 
16. Subject is on a weight loss program and is not in the 
maintenance phase, or subject has started weight loss 
medication (e.g., orlistat or liraglutide), within 8 weeks prior to 
Screening.  Subjects who have had bariatric surgery are also 
excluded. 
17. Subject is pregnant or breast-feeding.  
18. 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. 
19. 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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Phase 2 Clinical Study 
 
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Statistical Methods Subjects will be analyzed under 3 treatment regimens: Standard of Care 
(Baseline), Once a Day Dosing (QD) and Three Times a Day Dosing 
(TID).  
Information collected in the daily diaries or via the Continuous Glucose 
Monitor (CGM) on the final 10 days of treatment will be analyzed 
using a Repeated Measures Analysis of Covariance with subject as a 
random effect with each of the 10 days being a single measure. When 
analyzing the exogenous insulin variables, CGM parameters (mean 24 
hour glucose value and 24 hour time within 70-180 mg/dL range) and 
patient reported carbohydrate intake will be included as covariates. 
When analyzing CGM parameters, exogenous insulin (basal and bolus 
insulin amounts) and patient reported carbohydrate intake will be 
included as covariates. Treatment least squares means and change from 
baseline estimates will be derived using this linear model. 
Information collected at the day 28 visits will be analyzed using an 
Analysis of Covariance model with subject as a random effect. 
Treatment least squares means and change from baseline estimates will 
be derived using this linear model. 


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Phase 2 Clinical Study 
 
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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................ 1 
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE ................................................ 2 
INVESTIGATOR SIGNATURE PAGE................................................................................ 3 
SYNOPSIS ........................................................................................................................... 4 
Inclusion Criteria ............................................................................................................. 7 
TABLE OF CONTENTS .................................................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 15 
1 
INTRODUCTION ....................................................................................................... 17 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 19 
2.1 
Objectives .......................................................................................................... 19 
2.1.1 
Primary Objective .................................................................................... 19 
2.1.2 
Secondary Objectives ............................................................................... 19 
2.2 
Endpoints........................................................................................................... 19 
3 
INVESTIGATIONAL PLAN ...................................................................................... 20 
3.1 
Overall Study Design and Plan........................................................................... 20 
3.2 
Screening (-21 Days prior to Randomization) .................................................... 21 
3.2.1 
Screen Failure .......................................................................................... 22 
3.3 
Visit 2 (Day -10 ± 2 days) .................................................................................. 22 
3.4 
Visit 3 (Day 1 ± 2 days) ..................................................................................... 23 
3.5 
Visit 4 (Day 18 ± 2 days) ................................................................................... 23 
3.6 
Visit 5 (Day 28 ± 2 days) ................................................................................... 24 
3.7 
Visit 6 (Day 46 ± 2 days) ................................................................................... 24 
3.8 
Visit 7 (Day 56 ± 2 days) ................................................................................... 25 
3.9 
Early Withdrawal (EW) ..................................................................................... 25 
3.10 
Schedule of Events ............................................................................................ 26 
4 
STUDY SUBJECT SELECTION ................................................................................ 28 
4.1 
Inclusion Criteria ............................................................................................... 28 
4.2 
Exclusion Criteria .............................................................................................. 29 
4.3 
Subject and Trial Discontinuation ...................................................................... 30 
5 
STUDY TREATMENT ............................................................................................... 33 
5.1 
Description of Investigational Drug ................................................................... 33 
5.1.1 
Packaging and Labeling ........................................................................... 33 
5.1.2 
Storage and Handling ............................................................................... 33 
5.2 
Randomization ................................................................................................... 34 
5.3 
Study Treatment Administration ........................................................................ 34 
5.4 
Dose Modifications ............................................................................................ 34 
5.5 
Measuring Subject Compliance .......................................................................... 34 


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5.6 
Drug Accountability .......................................................................................... 34 
5.7 
Concomitant Medications and Supplements ....................................................... 35 
5.8 
Dietary Restrictions ........................................................................................... 35 
6 
STUDY PROCEDURES AND ASSESSMENTS ........................................................ 37 
6.1 
Informed Consent .............................................................................................. 37 
6.2 
Medical History and Prior Medications .............................................................. 37 
6.3 
Safety Assessments ............................................................................................ 37 
6.3.1 
Weight and Height ................................................................................... 37 
6.3.2 
Vital Signs ............................................................................................... 37 
6.3.3 
Physical Examination ............................................................................... 37 
6.3.4 
12-Lead ECG ........................................................................................... 37 
6.3.5 
Clinical Laboratory Tests ......................................................................... 38 
6.3.5.1 
Clinical Safety Labs........................................................................ 38 
6.3.5.2 
Follicle Stimulating Hormone Test ................................................. 39 
6.3.5.3 
Additional Screening Bloodwork .................................................... 39 
6.3.6 
Continuous Glucose Monitor (CGM) ....................................................... 39 
6.4 
Review and Documentation of Medications and Supplements ............................ 40 
7 
ADVERSE EVENTS AND SAFETY REPORTING ................................................... 40 
7.1 
Safety and Tolerability Assessments .................................................................. 40 
7.2 
Definition of Adverse Event .............................................................................. 40 
7.3 
Definition of Serious Adverse Event .................................................................. 41 
7.3.1 
Adverse Events of Hypoglycemia............................................................. 41 
7.3.2 
Adverse Events of Hyperglycemia ........................................................... 42 
7.4 
Eliciting and Reporting of Adverse Events ......................................................... 42 
7.4.1 
Routine Reporting of Adverse Events ....................................................... 43 
7.4.2 
Reporting of Serious Adverse Events, Including Death............................. 44 
7.5 
Causality Assessment of Adverse Events ........................................................... 45 
7.5.1 
Potential Adverse Events Associated with ORMD-0801........................... 46 
7.6 
Adverse Event Severity Assessment................................................................... 46 
7.7 
Expectedness of Adverse Event ......................................................................... 47 
7.8 
Assessment of Adverse Event Outcome ............................................................. 47 
7.9 
Clinical Findings................................................................................................ 48 
8 
STATISTICAL METHODS  ....................................................................................... 49 
8.1 
Sample Size ....................................................................................................... 49 
8.2 
Statistical Considerations ................................................................................... 49 
8.3 
Basal, Bolus and Total Exogenous Insulin ......................................................... 49 
8.4 
Continuous Glucose Monitor Evaluation ............................................................ 50 
8.5 
Other Endpoints of Interest ................................................................................ 50 


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8.6 
Safety Evaluation ............................................................................................... 50 
8.6.1 
Safety Population ..................................................................................... 50 
8.6.2 
Adverse Events ........................................................................................ 50 
8.6.3 
Laboratory Evaluations ............................................................................ 51 
8.6.4 
Vital Signs ............................................................................................... 51 
8.6.5 
12-lead ECG ............................................................................................ 51 
8.6.6 
Physical Examination ............................................................................... 51 
8.6.7 
Prior and Concomitant Medications and Supplements .............................. 51 
8.6.8 
Handling of Missing, Unused, or Spurious Data ....................................... 52 
9 
DATA MANAGEMENT ............................................................................................ 53 
9.1 
Data Collection .................................................................................................. 53 
9.2 
Electronic Data Capture ..................................................................................... 53 
9.3 
Quality Assurance and Database Lock ............................................................... 53 
10 AMENDMENTS/MODIFICATIONS OF THIS PROTOCOL ..................................... 54 
11 INVESTIGATOR OBLIGATIONS ............................................................................. 55 
11.1 
Regulatory Documentation ................................................................................ 55 
11.2 
Protection of Human Subjects ............................................................................ 55 
11.2.1 
Declaration of Helsinki ............................................................................ 55 
11.2.2 
Good Clinical Practice and Regulatory Compliance ................................. 55 
11.2.3 
Institutional Review Board ....................................................................... 55 
11.2.4 
Subject Informed Consent ........................................................................ 56 
11.3 
Subject Confidentiality ...................................................................................... 57 
11.4 
Entering Data Into EDC ..................................................................................... 57 
11.5 
Source Documentation ....................................................................................... 57 
11.6 
Retention of Records ......................................................................................... 58 
11.7 
Clinical Study Report ......................................................................................... 58 
12 STUDY ADMINISTRATION ..................................................................................... 59 
12.1 
Study Monitoring ............................................................................................... 59 
12.2 
On-Site Audits ................................................................................................... 59 
12.3 
Data Quality Assurance ..................................................................................... 60 
12.4 
Publication Policy .............................................................................................. 60 
12.5 
Disclosure and Confidentiality ........................................................................... 60 
13 REFERENCES ............................................................................................................ 61 
 
 
 


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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 
BUN  
blood urea nitrogen 
CFR 
 
Code of Federal Regulations 
CGM  
Continuous glucose monitoring 
CRO  
contract research organization 
CRU  
clinical research unit 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
 
diastolic blood pressure 
ECG  
electrocardiogram 
eCRF  
electronic case report form 
EDC  
electronic data capture 
EDTA  
ethylenediaminetetraacetic acid 
EW 
 
early withdrawal 
FDA  
Food and Drug Administration 
FPG 
 
fasting plasma glucose 
FSH 
 
follicle-stimulating hormone 
GCP 
 
Good Clinical Practice 
GGT  
gamma-glutamyltransferase 
GI 
 
gastrointestinal 
GLP-1  
glucagon-like peptide 1 
HbA1c             hemoglobin A1c 
HBV  
hepatitis B virus 
HCV  
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
 
Human Immunodeficiency Virus 
HR 
 
heart rate 
IB 
 
Investigator's Brochure 


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ICF 
 
informed consent form 
ICH 
 
International Council for Harmonization 
IND 
 
Investigational New Drug application 
IRB 
 
Institutional Review Board 
IUD 
 
intrauterine device 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
 
Pharmacodynamic 
PI 
 
Principal Investigator 
PK 
 
Pharmacokinetic 
SAE 
 
serious adverse event 
SBP 
 
systolic blood pressure 
SBTI  
soybean trypsin inhibitor 
SOP 
 
standard operating procedure 
T1D 
 
Type 1 diabetes 
TEAE  
treatment-emergent adverse event 
TSH 
 
thyroid stimulating hormone 
ULN  
upper limit of normal 
WCBP  
woman of childbearing potential 
WHO  
World Health Organization 


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1 INTRODUCTION 
Diabetes mellitus is a chronic metabolic disorder that has reached epidemic proportions in the 
United States, affecting almost 8% of the U.S. population in 2007 (Centers for Disease Control 
and Prevention, 2008). Diabetes mellitus is defined by hyperglycemia (increased concentration 
of glucose in the blood) caused by defective insulin secretion (Type 1, T1D), resistance to 
insulin action (Type 2, T2DM), or a combination of both. Diabetes mellitus leads to an 
increased risk of microvascular damage (retinopathy, nephropathy and neuropathy), reduced 
life expectancy, increased risk of macrovascular complications (ischemic heart disease, stroke, 
and peripheral vascular disease), and diminished quality of life. This illness requires 
continuing medical care, subject self-management, and education to prevent acute 
complications and reduce the risk of long-term complications (American Diabetes Association, 
2009). 
The treatment goal for subjects with this disease is long-term glycemic control (over both fasting 
and non-fasting blood glucose levels), which has been demonstrated in both T1D and T2DM 
subjects to reduce the morbidities associated with uncontrolled glycemic levels (Diabetes Control 
and Complications Trial Research Group, 1993; Cleary et al., 2006; UK Prospective Diabetes 
Study Group, 1998a & 1998b). Typical options for glycemic control in subjects with T1D 
include two or more injections of insulin daily, with doses adjusted on the basis of self-
monitoring of blood glucose levels. Insulin replacement is accomplished by giving a basal insulin 
and pre-prandial insulin. The basal insulin is either long acting (glargine or detemir) or 
intermediate-acting (NPH). The pre-prandial insulin is either rapid-acting (lispro, aspart, or 
glulisine) or short-acting (regular). 
 
Glycemic control is measured by subject self-monitoring of blood glucose (SMBG), subject self-
monitoring of interstitial glucose, and periodic blood tests for measurement of hemoglobin A1C 
(HbA1c or A1C). HbA1c levels reflect average glycemia over several months and therefore 
provide a surrogate for glycemic control (U.S. Food and Drug Administration, 2008). A 
consensus statement written by the American Diabetes Association and the European Association 
for the Study of Diabetes targets an HbA1c level of <7% as an objective for nonpregnant adults, 
who do not have complicating factors, for the prevention of micro- and macrovascular disease 
(Nathan et al., 2009). 
 
Subcutaneously administered insulin is highly effective at lowering glycemia and helping 
subjects achieve target HbA1c levels. Insulin has no overall dose limit with respect to safety 
(except for hypoglycemia) and provides an improved lipid profile. However, subcutaneously 
administered insulin requires daily injections and blood glucose monitoring, and is associated 
with weight gain and an increased risk of hypoglycemia. Insulin is available as formulations 
with different pharmacokinetic (PK) and pharmacodynamic (PD) profiles (e.g, rapid, regular, 


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intermediate, or long acting, or mixtures of these). These different formulations are used to tailor 
appropriate insulin regimens on a per subject basis (Nathan et al., 2006). 
ORMD-0801 is based on Oramed’s platform technology for the oral delivery of polypeptides, 
which includes a proprietary formulation of excipients to facilitate oral uptake by hindering 
proteolysis in the small intestine and facilitating translocation of peptides across the gut epithelial 
lining, and into the systemic circulation. The formulation for ORMD-0801 includes soybean 
trypsin inhibitor (SBTI) to hinder proteolysis, and disodium ethylenediaminetetraacetic acid 
(EDTA) to facilitate translocation. The fish oil provides omega-3 fatty acids. The enteric-coated 
capsules are designed to disintegrate in a pH- dependent manner in the small intestine. The initial 
indication for ORMD-0801 is to reduce fasting blood glucose in adult subjects with Type 2 
diabetes mellitus with the objective of controlling the overall average glycemic level. 
 
The potential advantage of oral insulin in the treatment of elevated fasting blood glucose as 
compared to subcutaneously-administered insulin lies in the more physiological mechanism of 
delivery. Orally-administered insulin, once transported across the gut wall, is ferried to the 
hepatic portal vein, mimicking the natural route of endogenous pancreatic insulin and delivering 
the insulin directly to the intended site of action. In contrast, subcutaneously-administered insulin 
reaches the liver through the systemic circulation thereby requiring higher systemic levels of 
insulin in order to achieve the same effect. Thus, oral insulin administration (in combination with 
subcutaneously administered insulin) is expected to provide more physiological and improved 
control of blood glucose in Type 1 diabetes patients. This will reduce their risk of hypoglycemia 
and may prevent weight gain. The PK/PD profile of ORMD-0801 is well-suited to the control of 
fasting blood glucose due to the delayed onset.  
 
Oramed has completed five Phase 1 safety studies of various formulations of ORMD-0801 in 
healthy human volunteers. Four Phase 2 studies have been completed, two in patients with 
T2DM, and two in patients with T1D. These Phase 2 studies investigated different formulations, 
the effect of meals at different times following ORMD-0801 administration, and the effect of 
ORMD-0801 on glucose as measured by continuous glucose monitoring (CGM) over a ten-day 
treatment period with three doses per day prior to meals. Notably, one Phase 2 study assessed the 
safety and effectiveness on fasting blood glucose of repeat bed time administration of ORMD-
0801 in patients with T2DM over a period of 6 weeks. A Phase 1/2 dose-response study was also 
conducted. These studies demonstrated that the drug product is well-tolerated and can effectively 
reduce plasma glucose and C-peptide levels. There were no significant safety observations and 
no serious adverse reactions were reported for the completed studies, although there were two 
self-reported events of hypoglycemia in the six-week, Phase 2 study.  
Oramed intends to continue the clinical development of ORMD-0801.  
 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 Primary Objective 
1. To compare the impact of Oral Insulin dosed QD to Oral Insulin dosed TID on exogenous 
basal and bolus insulin requirements in subjects with Type 1 Diabetes (T1D) during the 
last 10 days of each treatment period. 
2. To compare the impact of Oral Insulin dosed QD to Oral Insulin dosed TID and associated 
adjustments of basal and bolus insulin on mean 24-hour glucose and parameters of 
glycemic variability as measured by a Continuous Glucose Monitor over the last 10 days 
of each treatment period. 
2.1.2 Secondary Objectives 
1. To compare the change from baseline in number of hypoglycemic episodes in subjects 
treated with Oral Insulin dosed QD to Oral insulin Dosed TID in subjects with T1D over 
the last 10 days of each treatment period 
2. To compare the change from baseline in HbA1C levels in subjects with T1D treated 
with Oral Insulin dosed QD or Oral Insulin dosed TID as measured at the end of each 
treatment period. 
3. To explore differences in glucodynamics between the different dosing regimens during 
the last 10 days of each treatment period. 
4. To evaluate the safety of Oral Insulin through the recording of adverse events, clinical 
laboratory test results (hematology, chemistry and urinalysis) and vital signs. 
2.2 
Endpoints 
Primary Endpoints 
1. To compare the amount of basal, bolus and total (basal + bolus) exogenous insulin 
utilized over the final 10 days of each treatment period. 
2. To compare the impact of Oral Insulin dosed QD to Oral Insulin dosed TID and 
associated adjustments of basal and bolus insulin on mean 24-hour CGM glucose 
levels during the final 10 days of each treatment period. 
 
Secondary Endpoints 
3. Glucodynamics over the final 10 days of each treatment period as measured by 
CGM: 
a. Time in range 70 - 180 mg/dL 
b. Time <70 mg/dL 
c. Time >180 mg/dL 
d. Time >250 mg/dL 
e. Glucose Coefficient of Variation 
f. Low Blood Glucose Index (LBGI) 


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g. Glucose below 70 mg/dL Area Over the Curve (AOC70) 
4. Total daily non-oral insulin requirements in units per kilogram (kg) body weight 
over the last 10 days of each treatment period.  
 
Exploratory Endpoints: 
5. HbA1c measured at the end of each treatment period 
6. Patient dairy-reported carbohydrate intake over the final 10 days of each treatment 
period 
7. Changes in body weight from baseline (Visit 2) to the end of each treatment period                               
8. Other measures of hypoglycemia: 
a. Severe hypoglycemia (SH) events (impaired or loss of consciousness 
requiring assistance of another)  
b. Documented symptomatic hypoglycemia (an event during which typical 
symptoms of hypoglycemia are accompanied by a measured plasma glucose 
concentration <70 mg/dl (3.9 mmol/L)) 
c. Total time <70 mg/dL by CGM 
d. Nocturnal hypoglycemia, severe or documented symptomatic episodes (as 
defined above) occurring after the subject has retired for the primary 
sleeping period 
 
Safety assessments evaluating: 
• 
Changes in clinical laboratory tests (hematology, chemistry, urinalysis); 
• 
Collection of adverse events (AEs);   
• 
Changes in Vital signs measurements 
 
3 
INVESTIGATIONAL PLAN  
3.1 Overall Study Design and Plan 
This study is designed to compare ORMD-0801 given QD versus TID in subjects with T1D. The 
study will consist of seven visits (including Screening Visit).   
 
During Screening, subjects will be required to sign the informed consent form.  Medical and 
medication history and demographic information will be collected. Eligibility for participation 
will be evaluated. Vital signs (height, weight, seated SBP/DBP, and heart rate) will be measured, 
physical examination will be performed, and a blood and urine sample will be collected for 
hematology/chemistry/urinalysis.  
Eligible subjects will be scheduled to return to the clinic in 1 week (Visit 2). Subjects fulfilling 
all inclusion/exclusion criteria will have a CGM placed, provided with a diary, dispensed 
placebo capsules and asked to return to the clinic in 10 days (Visit 3, Day 1) for randomization. 
At Visit 3, data from CGM will be downloaded and diaries will be collected. Blood samples 


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will be collected in fasting for chemistry and HbA1C. Subjects will be randomized to receive 
either ORMD-0801 24 mg given once daily at bedtime, or ORMD-0801 8 mg given three times 
a day, 45-90 minutes before meals. Subjects will be instructed to continue their normal diet, 
and to adjust their basal and bolus insulin in the normal fashion. Subjects will be instructed to 
return to the clinic in 10 days before Visit 5 (Visit 4, Day 18). At Visit 4, compliance will be 
assessed, IMP and diary dispensed and the CGM will be placed. Subjects will be instructed to 
return to the clinic in 10 days for Visit 5 (Day 28). At Visit 5 a blood sample for chemistry 
panel and HbA1C will be drawn, the diary collected, the CGM removed and the patient will be 
crossed over to the alternate treatment regimen. IMP will be dispensed, and the subject will be 
asked to return in 10 days before Visit 7 for Visit 6 (Day 46). At Visit 6, compliance will be 
checked, IMP and a diary will be dispensed and the CGM will be placed. Subjects will be 
instructed to return in 10 days for Visit 7 (Day 56). At Visit 7 the CGM will be removed, the 
diary will be collected, compliance checked, blood sample will be drawn for a chemistry panel 
and HbA1C. A physical examination will be performed, and the subject will exit the study. 
Subjects will be provided with diaries at Visits 2, 4 and 6, and will be asked to capture the 
amount of basal and bolus exogenous insulin administered each day and calculate their 
carbohydrate count for all meals and snacks over the 10-day CGM monitoring period of each 
treatment period. 
3.2 
Screening (-21 Days prior to Randomization) 
At the Screening Visit, potential subjects will be given a detailed oral presentation describing the 
nature, purpose, risks, and requirements of the study and will receive detailed written 
information.  Subjects will be given ample time to consider participation and ask questions 
which will be adequately addressed by site personnel. 
Once the subject is satisfied that he/she is willing to participate in the study, he/she will be asked 
to sign the study ICF (refer to Section 11.2.4 for further details regarding the ICF).  The 
investigational site personnel obtaining written consent from the subject will also sign the 
consent form.  
Once signed, the Investigator will retain the original ICF for the subject’s study records and 
provide the subject with a signed copy.  The investigator will verify that informed consent has 
been obtained from each subject prior to enrollment into the study and prior to the subject 
undergoing any study-related procedures.  
Screening activities after obtaining informed consent will be conducted and consist of the 
following: 
• Completion of medical history (including start date for T1DM),  
• Collection of demographic data (sex, age, race/ethnicity); 


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• Review of prior and current medications and supplements; 
• Review inclusion and exclusion criteria. 
• Physical examination. 
• Measurement of height and weight. 
• Measurement of vital signs (SBP/DBP and heart rate). 
• 12-lead electrocardiogram (ECG). 
• Collection of fasted blood and urine samples for: 
o Clinical safety labs, including hematology, serum chemistry (with fasting plasma 
glucose/FPG, HbA1c, C-peptide, and serum thyrotropin/TSH, FSH to confirm 
postmenopausal status in women, and urinalysis (see Section 6.3.5 for list of 
tests); 
o Infectious serology (HIV, HBV, HCV); 
o Serum pregnancy Test for women of childbearing potential 
For subjects who meet eligibility criteria based on the Screening assessments, instruction will be 
provided on the following: 
• Use of adequate contraceptive methods (see Section 4.1) for the duration of the study 
(Screening through Visit 7); 
• Minimal use of concomitant medications during the study, if possible, and avoid prohibited 
medications as defined in Section 5.7; 
• Maintenance of usual dietary habits and avoidance of drastic changes, such as a conversion 
to a vegetarian diet; 
• Restraint from excessive caffeine use (i.e., more than five cups of caffeinated beverages 
per day) during the study. 
 
3.2.1 Screen Failure 
A screen failure is defined as a subject who has signed the ICF, does not meet all the entry 
criteria outlined in Section 4 of this protocol (note that this includes assessments through 
Visit 1), and was not randomized to receive study treatment . 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 failure 
(including, where applicable, the unmet inclusion or exclusion criteria) data entered into the 
electronic data capture (EDC) system, unless an adverse event was responsible for 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 
Visit 2 (Day -10 ± 2 days) 
Subjects will report to the CRU in the morning. The following procedures will be performed: 


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• Review of medical history; 
• Review of medications and supplements; 
• Review inclusion and exclusion criteria; 
• Measurement of vital signs (weight, seated SBP/DBP, and heart rate); 
• Subjects will be fitted with the CGM device and data recording will begin; 
• Dispensing of Run-in Placebo capsules 
• Dispensing of diaries; 
• Subjects will be reminded to fast for a minimum of 10 hours prior to arrival on Visit 3 
(Day 1 ± 2 days).  
3.4 
Visit 3 (Day 1 ± 2 days) 
Subjects will report to the CRU in the morning in fasting state. The following procedures will be 
performed: 
• Collect data from CGM monitor; 
• Review of medications and supplements; 
• Collect and review diary; 
• Measurement of vital signs (weight, seated SBP/DBP, and heart rate); 
• Urine pregnancy Test for women of childbearing potential 
• Collect fasting blood samples for serum chemistry (with fasting plasma glucose/FPG) 
and HbA1c; 
• Review inclusion and exclusion criteria. 
• Randomization of subjects to their individual study treatment sequence; 
• Dispensing of IMP and instructions on use of IMP. 
• Adverse events will be monitored and recorded. 
3.5 
Visit 4 (Day 18 ± 2 days) 
Subjects will report to the CRU in the morning. The following procedures will be performed: 
• Adverse events will be monitored and recorded; 
• Review of medications and supplements; 
• Measurement of vital signs (weight, seated SBP/DBP, and heart rate); 
• Subjects will be fitted with the CGM device and data recording will begin; 


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• Dispensing of diaries; 
• Re-dispensing of IMP; 
• Assessment of compliance to IMP; 
• Subjects will be reminded to fast for a minimum of 10 hours prior to arrival on Visit 5 
(Day 28 ± 2 days). 
3.6 
Visit 5 (Day 28 ± 2 days) 
Subjects will report to the CRU in the morning in fasting condition. The following procedures 
will be performed: 
• Collect data from CGM monitor; 
• Review of medications and supplements; 
• Collect and review diary; 
• Measurement of vital signs (weight, seated SBP/DBP, and heart rate); 
• Urine pregnancy Test for women of childbearing potential 
• Collect fasting blood samples for serum chemistry (with fasting plasma glucose/FPG) 
and HbA1c; 
• Assessment of compliance to IMP; 
• Crossover of study treatment; 
• Dispensing of IMP; 
• Adverse events will be monitored and recorded. 
3.7 
Visit 6 (Day 46 ± 2 days) 
Subjects will report to the CRU in the morning. The following procedures will be performed: 
• Review of medications and supplements; 
• Adverse events will be monitored and recorded; 
• Measurement of vital signs (weight, seated SBP/DBP, and heart rate); 
• Subjects will be fitted with the CGM device and data recording will begin; 
• Dispensing of diaries; 
• Re-dispensing of IMP; 
• Assessment of compliance with IMP; 
• Subjects will be reminded to fast for a minimum of 10 hours prior to arrival on Visit 7 


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(Day 56 ± 2 days) 
3.8 
Visit 7 (Day 56 ± 2 days) 
Subjects will report to the CRU in the morning in fasting condition. The following procedures 
will be performed: 
• Review of medications and supplements; 
• Collect data from CGM monitor; 
• Collect and review diary; 
• Measurement of vital signs (weight, seated SBP/DBP, and heart rate); 
• Physical examination; 
• Collect fasting blood samples for hematology, serum chemistry (with fasting plasma 
glucose/FPG), HbA1c and urinalysis; 
• Returning of IMP; 
• Assessment of compliance to IMP; 
• Adverse events will be monitored and recorded.  
• Discharge from the study.  
Any subject with a possible study treatment related AE at Visit 7 will be followed until 
resolution or stabilization of the event.  Further, any SAE, whether or not related to study 
treatment that occurs within 14 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 electronic case report form (eCRF). 
3.9 
Early Withdrawal (EW) 
If a randomized subject is withdrawn from the study prior to completing study treatment, the 
subject will be discharged from the study after following procedures will be performed:  
• Review of medications and supplements; 
• Vital signs (including weight, seated SBP/DBP, and heart rate); 
• Physical examination; 
• Collect data from CGM monitor (if applicable); 
• Collect and review diary (if applicable); 
• Collection of fasted blood and urine samples for: 


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o Clinical safety labs, including hematology, serum chemistry (with fasting plasma 
glucose/FPG), HbA1c and urinalysis (see Section 6.3.5 for list of tests). 
• Returning of IMP; 
• Assessment of compliance to IMP; 
• Adverse events will be monitored and recorded; 
• Discharge from the study. 
Any subject with a possible study treatment related AE at the time of EW will be followed until 
resolution or stabilization of the event. 
3.10 
Schedule of Events 
Table 1 below describes the daily schedule of events from Screening Visit 1 through Visit 7.   
 
 
 


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Table 1. Daily Schedule of Events from Screening Through Visit 7 
 
Visit 
Screening 
Visit 1 
Visit 2 
Rando
mizatio
n 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7  
EW 
Study Day 
-21  
-10 
1 
18 
28 
46 
56 
 
Window days 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion 
Criteria 
X 
X 
X 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Test 
X 
 
 
 
 
 
 
 
Urine Pregnancy Test 
 
 
X 
 
X 
 
 
 
Infectious Serology (HIV, 
HBV, HCV) 
X 
 
 
 
 
 
 
 
C-peptide, TSH, FSH 
X 
 
 
 
 
 
 
 
Hematology 
X 
 
 
 
 
 
X 
X 
Serum Chemistry (with 
FPG) 
X 
 
X 
 
X 
 
X 
X 
HbA1c 
X 
 
X 
 
X 
 
X 
X 
Urinalysis 
X 
 
 
 
 
 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
Treatment Crossover 
 
 
 
 
X 
 
 
 
Treatment Compliance 
 
 
X 
X 
X 
X 
X 
X 
Treatment 
dispensing/returning 
 
X 
X 
X 
X 
X 
X 
X 
CGM Monitoring2 
 
X 
X 
X 
X 
X 
X 
X 
Diary 
dispensing/collecting3 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
Study Disposition 
 
 
 
 
 
 
X 
X 
 
Table 1 Footnotes 
1Vital signs include height, weight, heart rate, SBP, and DBP.  Height will be measured at Screening only, without 
shoes.  
2CGM monitor applied at Visits 2, 4, and 6; removed and downloaded at visits 3, 5, and 7 (or EW if applicable).  
3Diary dispensed at Visits 2, 4, and 6; collected and reviewed at visits 3, 5, and 7 (or EW if applicable).  
 
 


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4 STUDY SUBJECT SELECTION 
4.1 Inclusion Criteria 
Each subject must meet all of the following criteria to be eligible for study participation: 
1. Male and female (non-childbearing potential) subjects aged 18 and older. 
2. Body mass index (BMI) of 19-30 kg/m2 at Screening and stable weight, with no more 
than 5 kg gain or loss in the 3 months prior to Screening. 
3. T1D subjects must have: 
a. A documented history of type 1 diabetes for at least 6 months 
b. Should be on an MDI regimen 
c. C peptide levels of ˂ 0.7 ng/mL 
d. HbA1C ≥ 6.5% to ≤10% 
4. Females of childbearing potential must have a negative serum pregnancy test result at 
Screening. 
5. Females who are not of childbearing potential are defined as: 
a. post-menopausal (defined as at least 12 months with no menses in women ≥45 
years of age) or 
b. has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal 
ligation or occlusion at least 6 weeks prior to Screening 
6. Subjects who are of childbearing potential must:  
a. agree to remain abstinent from heterosexual activity† or agree to use (or have 
their partner use) acceptable contraception to prevent pregnancy within the 
projected duration of the trial and for 14 days after the last dose of blinded 
investigational product.  Two methods of contraception will be used to avoid 
pregnancy.  Acceptable combinations of methods include: 
i. Use of one of the following double-barrier methods: diaphragm with 
spermicide and a condom; cervical cap and a condom; or a contraceptive 
sponge and condom 
ii. Use of hormonal contraception (any registered and marketed contraceptive 
agent that contains an estrogen and/or a progestational agent [including 
oral, subcutaneous, intrauterine and intramuscular agents, and cutaneous 
patch]) with one of the following:  diaphragm with spermicide; cervical 
cap; contraceptive sponge; condom; vasectomy; or IUD. 
iii. Use of an IUD with one of the following: condom; diaphragm with 
spermicide; contraceptive sponge; vasectomy; or hormonal contraception 
(see above). 
iv. Vasectomy with one of the following:  diaphragm with spermicide; 
cervical cap; contraceptive sponge; condom; IUD; or hormonal 
contraception (see above). 


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†Abstinence can be used as the sole method of contraception if it is in line with the 
subject’s preferred and usual lifestyle and if considered acceptable by local regulatory 
agencies and ethics committees.  Periodic abstinence (e.g., calendar, ovulation, 
sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception. 
4.2 Exclusion Criteria 
 Subjects who meet any of the following criteria must be excluded from the study: 
1. Clinical diagnosis of type 2 diabetes; 
2. Evidence of unawareness of hypoglycemia unawareness, a documented plasma glucose 
≤50 mg/dL in the absence of symptoms of hypoglycemia at Screening. 
3. FPG >300 mg/dL at Screening; a single repeat test is allowable. 
4. Use of the following medications: 
a. Administration of thyroid preparations or thyroxine (except in subjects on stable 
replacement therapy) within 6 weeks prior to Screening. 
b. 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. 
5. Laboratory abnormalities at Screening including: 
a. Abnormal serum thyrotropin (TSH) levels below the lower limit of normal or 
>1.5X the upper limit of normal 
b. Elevated liver enzymes (alanine transaminase (ALT), alanine aminotransferase 
(AST), alkaline phosphatase) >2X the upper limit of normal. 
c. Very high triglyceride levels (>600 mg/dL); a single repeat test is allowable. 
d. Any relevant abnormality that would interfere with the efficacy or the safety 
assessments during study treatment administration. 
6. Subject has a Screening systolic blood pressure ≥165 mmHg or diastolic blood pressure 
≥100 mmHg. Subjects will be allowed to take a BP rescue medication. 
7. Any clinically significant ECG abnormality at Screening or cardiovascular disease. 
Clinically significant cardiovascular disease will include:  
a. History of stroke, transient ischemic attack, or myocardial infarction within 6 
months prior to Screening,  
8. History of or currently have New York Heart Associate Class II-IV heart failure prior to 
Screening.  


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9. Presence of any clinically significant endocrine disease according to the Investigator 
(euthyroid subjects on replacement therapy will be included if the dosage of thyroxine is 
stable for at least six weeks prior to Screening). 
10. Presence of any clinically significant condition (in the opinion of the Investigator) that 
might interfere with the evaluation of study medication, such as significant renal, hepatic, 
gastrointestinal (GI), cardiovascular (CV), immune disease, blood dyscrasias or any 
disorders causing hemolysis or unstable red blood cells, or clinically important 
hematological disorders (i.e. aplastic anemia, myeloproliferative or myelodysplastic 
syndromes, thrombocytopenia) at Screening. 
11. History of gastrointestinal disorders (e.g. hypochlorhydria) with the potential to interfere 
with drug absorption. 
12. Presence or history of cancer within the past 5 years of Screening, with the exception of 
adequately-treated localized basal cell skin cancer or in situ uterine cervical cancer.  
a. A subject with a history of malignancy >5 years prior to Screening should have 
no evidence of residual or recurrent disease.  
b. A subject with a history of melanoma, leukemia, lymphoma, or renal 
carcinoma is excluded. 
13. 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. 
14. Positive history of HIV. 
15. Known allergy to soy. 
16. Subject is on a weight loss program and is not in the maintenance phase, or subject has 
started weight loss medication (e.g., orlistat or liraglutide), within 8 weeks prior to 
Screening.  Subjects who have had bariatric surgery are also excluded. 
17. Subject is pregnant or breast-feeding.  
18. 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. 
19. At the Principal Investigator’s discretion, any condition or other factor that is deemed 
unsuitable for subject enrollment into the study. 
4.3 
Subject and Trial Discontinuation 
Subjects may choose to withdraw from this study at any time for any reason without penalty of 
jeopardizing their health care or loss of benefits to which the subject is otherwise entitled.   


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Within the provisions of informed consent and good clinical judgment with respect to safety, 
every attempt will be made to have subjects complete the study.  The following are reasons to 
terminate a subject’s participation in the study:  
1. Subject experiences an AE that in the judgement of the Investigator poses a significant 
risk to the subject for continued participation in the study. 
a. If a subject experiences hyperglycemia, defined in Section 7.3.2, blood glucose 
will be checked 1-2 hours later. If the glucose remains elevated, the subject will 
be withdrawn from the study. 
2. Subject uses a prohibited medication (listed in Section 5.7) that in the judgment of the 
Investigator poses a significant risk to the subject for continued participation in the study 
or that will interfere with the interpretation of the results of the study. 
3. Subject becomes pregnant. 
4. Significant protocol violation or noncompliance on the part of the subject or the 
Investigator.  
5. Intercurrent illness that requires treatment that is not consistent with the protocol 
requirements, or intercurrent illness or the associated treatment that in the judgment of 
the Investigator poses a significant risk to the subject for continued participation in the 
study.  
6. Subject wishes to withdraw for any reason.  
7. Sponsor elects to end the study, or the Investigational Site elects to end the study at their 
site.  
8. Any other reason that in the judgment of the Investigator poses unacceptable risk to the 
subject. 
Reasons for study drug discontinuation may include the following: 
1. Adverse event 
2. Episodes of hypoglycemia as defined in Section 7.3.1. 
3. Subject meets one of the exclusion criteria during the study 
4. Any clinically significant change in the subject’s medical condition 
 
Subjects who withdraw from the study prior to treatment may be replaced. Subjects who are 
withdrawn and have received at least one treatment will not be replaced. Subjects who 
discontinue study drug treatment will not be replaced. 
Except in cases of emergency, the Investigator should consult with the Sponsor and the Medical 
Monitor before removing the subject from the study.  In some circumstances it may be necessary 
to temporarily interrupt treatment as a result of AEs that may have an unclear relationship to 
study treatment.  The Investigator should obtain approval from the Sponsor and Medical Monitor 
before restarting study treatments that were temporarily discontinued for an AE. 


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In the event that a subject discontinues the study prior to completion, the date the subject is 
withdrawn and the reason for discontinuation will be recorded in the source documents and CRF.  
Although a subject will not be obliged to give his/her reason for withdrawing prematurely, the 
Investigator will make a reasonable effort to obtain the reason while fully respecting the 
subject’s rights.   
All subjects who are randomized and treated (i.e., received any amount of study treatment) will 
be included in the safety analyses.  Thus, every effort will be made to contact any subject who 
fails to attend any appointments/contacts, in order to ensure that he/she is in satisfactory health.  
If a subject withdraws from the study as a result of meeting discontinuation criteria after the start 
of study treatment administration, reasonable efforts should be made to have the subject return 
for the early withdrawal evaluations (Section 3.9).  Any subject withdrawn due to a suspected 
study treatment -related AE should be followed until resolution or stabilization of the event. 
Subjects may choose to withdraw authorization to use and disclose their PHI as defined by the 
HIPAA.  Such withdrawal of authorization must be made to the Investigator in writing.  Any PHI 
collected by the Investigator prior to the date of such withdrawal will continue to be used and 
disclosed. 
Randomized subjects who are discontinued from this study for any reason will not be replaced.   
The Sponsor has the right to terminate this study, and the Investigator/Investigational Site has the 
right to close the site, at any time, although this should occur only after consultation between 
involved parties.  The Investigator will notify the IRB in writing of a premature termination of a 
study or closure of Investigational Site and will send a copy of the notification to the Sponsor.   
Events that may trigger premature termination of a study or closure of an Investigational Site 
include, but are not limited to, a new toxicity finding, a request to discontinue the trial from a 
regulatory authority, non-compliance with the protocol, GCP violations, slow recruitment/low 
enrollment, or change in development plans for the study treatment. 
If either of the criteria listed below is met, enrollment of new subjects and dosing of ongoing 
subjects will be temporarily stopped.  The Investigator, Sponsor, and the Medical Monitor will 
discuss whether a lower dose or any additional treatment guidelines should be implemented, or if 
the trial should be permanently stopped.  Any proposed changes to the protocol to address such 
findings will be submitted for review and approval by the IRB and FDA prior to re-starting the 
trial. 
1. A death within 30 days after study treatment administration where there is a reasonable 
possibility that the drug caused the event; 
2. Two Grade 4 AEs where there is a reasonable possibility that the study treatment caused 
the events. 
 


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5 STUDY TREATMENT 
5.1 
Description of Investigational Drug 
Name of the IMP: ORMD-0801 
Dose and dosage regimen: 
1. Treatment A: 24 mg (16 mg + 8 mg capsules) Once Daily (QD) at Bedtime 
2. Treatment B: 8 mg (8 mg capsule) three times a day (TID) 45-90 minutes before meals 
3. Placebo: Placebo capsules QD at bedtime during placebo run-in period 10 days prior to 
randomization. 
Formulation: Coated soft gel capsule [SBTI], disodium EDTA, fish oil, aerosol, and Tween 80 
Mode of administration: Oral 
5.1.1 Packaging and Labeling 
This study is an open label study. All study medication including Placebo will be shipped to site. 
The Investigational Site pharmacist will be responsible for dispensing the appropriate treatment 
based on the randomization schedule.   Study medication will be dispensed to the site with 
instructions for treatment administration.  
The treatment packages will be labeled with the following information: 
▪ Study number 
▪ Subject ID 
▪ Kit No./Bottle ID 
▪ Dosage Form/Content 
▪ Directions for use, including route of administration 
▪ Number of capsules in package 
▪ Storage conditions 
▪ Instructions to “keep out of reach of children” 
▪ Caution: New Drug – Limited by Federal (or United States) law to investigational use.  
▪ Name of Sponsor  
.  
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 in the original 
packaging at controlled temperature (36 to 46°F; 2 to 8°C). Excessive humidity should be 
avoided.  Storage conditions will be monitored and appropriate monitoring logs maintained as 
source data.  Deviations from the established temperature, as well as the occurrence of excessive 
humidity, should be documented, and the Sponsor should be notified.  


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5.2 
Randomization 
This is a randomized, open label, crossover study.  Approximately 26 eligible subjects with T1D 
will be randomized to all 2 treatment schedules.  
Integrium, LLC will generate and implement the randomization procedures for this trial.  A 
computer-generated randomization schedule will be used for assigning treatment schedules.  The 
Investigational Site pharmacist will follow this randomization schedule to dispense the 
appropriate study treatment. 
5.3 
Study Treatment Administration 
All subjects will receive Placebo capsules once a day at bedtime during placebo run-in period for 
10 days prior to randomization. 
Subjects receiving Treatment A should take 16 mg + 8 mg capsules once a day at bedtime. 
Subjects receiving Treatment B should take 8 mg capsule three times a day 45-90 minutes before 
meals. 
5.4 
Dose Modifications 
This study does not include any planned dose modifications.  Subjects will consume study 
treatment orally at the assigned (randomized) dose unless discontinuation criteria as defined in 
Section 4.3 are met. 
5.5 
Measuring Subject Compliance 
Treatment compliance will be ascertained by accountability of returned IMP and recording in 
diary.   
5.6 
Drug Accountability 
In accordance with current GCP, the Investigational Site will account for all study treatment 
supplies.  Details of receipt, storage, administration, and return or destruction will be recorded in 
the Investigational Drug accountability record according to the SOP of the Investigational Site.  
Copies of the Investigational Drug accountability record will be provided to the Sponsor. 
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 eCRF. 


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5.7 
Concomitant Medications and Supplements 
All medications and supplements (other than study treatment) taken by the subject from Visit 
3/Day 1 through Visit 7 will be considered “concomitant” medications and supplements.  
Medications and supplements taken prior to Visit 3/Day 1 that are no longer being taken at the 
time of Visit 3/Day 1 will be considered “prior” medications and supplements. 
All prior medications and supplements taken within 30 days prior to the first dose of study 
treatment and concomitant medications and supplements will be recorded in the subject’s source 
documentation and in the eCRF. 
The use of concomitant medications and supplements should be kept at a minimum, if possible.  
Any medications and supplements needed for the welfare of a subject and that in the judgment of 
the Investigator will not pose a significant risk to the subject for continued participation in the 
study or that will not interfere with the interpretation of the results of this study may be given to 
the subject.  If a subject requires the use of any of the prohibited medications and supplements 
listed below, the Investigator will contact the Sponsor and the Medical Monitor to discuss the 
subject’s continued participation in the study.  In the event of an emergency, subjects will be 
treated at the discretion of the Investigator according to acceptable community standards of 
medical care.   
The following are prohibited medications: 
1. Any Investigational Drug other than ORMD-0801 within 30 days prior to Visit 3/Day 1 
through Visit 7; 
2. Any anti-diabetic drugs (except for those allowable by the inclusion criteria) including 
GLP-1 analogue, α-glucosidase inhibitors, glinides, and pramlintide within 6 weeks prior 
to Screening; 
3. Thyroid preparations or thyroxine (except in subjects on stable replacement therapy); 
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 the subject. 
5.8 
Dietary Restrictions 
Subjects will be advised not to make any drastic changes in their regular diet throughout the 
study. Excessive caffeine use (i.e., more than five cups of caffeinated beverages per day) should 


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be avoided from Screening through Visit 7.  Excessive alcohol use or binge drinking will be 
discouraged during the study. 
Subjects will also be asked to refrain from any unusual or unaccustomed vigorous exercise 
during the course of the study. 


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6 STUDY PROCEDURES AND ASSESSMENTS 
6.1 
Informed Consent 
According to the ICH guideline for GCP (E6) and all institutional local, state, and federal laws, 
the Investigator will obtain and document informed consent for each subject screened for this 
study.  All subjects will be informed in writing of the nature of the protocol and Investigational 
Drug, its possible hazards, and their right to withdraw at any time, and will sign a form (ICF) 
indicating their consent to participate in the study prior to the initiation of study procedures.  The 
subject’s medical record should contain written documentation indicating that informed consent 
was obtained.  The ICF must be reviewed and approved by the Investigator’s designated IRB and 
by Oramed Ltd. designee prior to its use.  Refer to Section 11.2.4 for further details regarding 
informed consent. 
6.2 Medical History and Prior Medications 
At Screening, a complete medical history (including start date of T1DM) will be collected by 
subject interview.  Medications and supplements, recent blood donations, illnesses, and 
participation in other Investigational Drug trials or clinical trials will also be recorded. 
6.3 
Safety Assessments 
6.3.1 Weight and Height 
Weight will be measured at visits as described in Table 1. Height will be measured at Screening 
only with the subject wearing no shoes. 
6.3.2 Vital Signs 
Vital signs (including seated SBP/DBP, and heart rate) will be recorded at visits as described in 
Table 1. Blood pressure and heart rate 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. 
6.3.3 Physical Examination 
A physical examination will be performed at visits as described in Table 1, or in case of Early 
Withdrawal.  The physical examination will include the following organ or body system 
assessments:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular; abdomen 
(liver, spleen); lymph nodes; and extremities, as well as an abbreviated neurological 
examination. 
6.3.4 12-Lead ECG 
A 12-lead ECG will be performed at Screening. The 12-lead ECG will be recorded after the 
subject has been resting at least 5 minutes in the supine position in a quiet environment.  ECGs 


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will be read for QT and QTc (Federicia’s) intervals and clinically significant abnormalities. At 
the Investigator’s discretion, an additional ECG may be performed at the end of treatment; 
however, it will be recorded in source documents as an unscheduled assessment.  
6.3.5 Clinical Laboratory Tests 
Blood and urine for clinical safety laboratory assessments will be collected and processed using 
standard procedures.  A central laboratory will perform all clinical laboratory tests. 
In the event of abnormal clinical laboratory values, the Investigator will make a judgment 
whether or not the abnormality is clinically significant. 
6.3.5.1 
Clinical Safety Labs 
The clinical safety labs will include the following hematology, serum chemistry, and urinalysis 
tests: 
Hematology 
• Hematocrit 
• Hemoglobin 
• Mean corpuscular hemoglobin 
• Mean corpuscular hemoglobin concentration 
• Mean corpuscular volume 
• Platelet count 
• Red blood cell distribution width 
• Red blood cell count 
• White blood cell count with differential 
Serum Chemistry 
• Sodium 
• Potassium 
• Chloride 
• Bicarbonate 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Gamma-glutamyltransferase (GGT) 
• Total bilirubin  
• Alkaline phosphatase  
• Albumin 
• Total Protein  
• Blood urea nitrogen (BUN) 
• Creatinine 
• Uric acid 


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• Glucose 
• Calcium 
• Phosphorus 
• Total cholesterol 
• Triglycerides 
Urinalysis 
• Appearance (color and character) 
• Bilirubin  
• Urobilinogen 
• Protein 
• Glucose 
• Ketones  
• Leukocyte esterase 
• Urine blood 
• Nitrite 
• pH 
• Specific gravity 
Pregnancy Test 
 
6.3.5.2 
Follicle Stimulating Hormone Test 
A serum FSH test will be performed in postmenopausal women.  
 
6.3.5.3 
Additional Screening Bloodwork 
In addition to the blood tests listed above, infectious serology (HIV, HCV, and HBV), FPG, 
HbA1c, C-peptide, and TSH will be measured at Screening. FPG and HbA1c will be performed at 
visits as described in Table 1 and in case of Early Withdrawal.  
6.3.6 Continuous Glucose Monitor (CGM) 
CGM will be used to monitor subject glucose levels (including post-prandial) throughout the 
study.  Further information about the device can be found in the laboratory manual.  
Subjects will have the CGM implanted at visits as described in Table 1. The device will be 
removed and the data will be downloaded at each subsequent visit. Staff will be advised 
regarding appropriate procedures in the event of nocturnal hypoglycemia. 


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6.4 
Review and Documentation of Medications and Supplements 
All medications or supplements subjects are taking or have taken within 30 days prior to Visit 
3/Day 1 through Visit 7 will be recorded in the subject’s medical record and the medical history 
CRF.  
All medications and supplements (other than study treatment) taken by the subject after Visit 
3/Day 1 through Visit 7 assessments will be considered “concomitant” medications and 
supplements.  Medications and supplements taken prior to Visit 3/Day 1 that are no longer being 
taken at Visit 3/Day 1 will be considered “prior” medications and supplements. 
Medications and supplements should be recorded according to the generic name when possible.  
The use of concomitant medications and supplements should be limited to those that are 
medically necessary.  Any medication or supplement used should have an indication recorded, 
and for concomitant medications and supplements, this indication must be represented as either 
for the treatment of an AE, for the management of a pre-existing condition, or for prophylaxis.  
Dosage increases for any concomitant medication or supplement should be noted and the reason 
for the dosage increase recorded as an AE (assumes worsening condition).  The side effects of 
concomitant medications will be recorded as AEs.  
Any subject whose condition becomes disqualifying during the course of the study may be 
treated for that condition.  If the condition is suspected during Screening, the subject should not 
be enrolled.  Treatment of the condition should be instituted according to the 
Investigator’s/attending physician's judgment.  
Medications that have no treatment intent but rather are part of supportive routine care such as 
local anesthetics, intravenous solutions to maintain fluid balance and keep access open, 
medications used for prophylaxis, and narcotics for postsurgical pain must also be recorded in 
the subject’s medical record and CRF. 
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, vital signs (including weight, seated SBP/DBP, and heart rate), and clinical safety 
labs (hematology, serum chemistry, and urinalysis). 
7.2 
Definition of Adverse Event  
An AE is defined in 21 CFR 312.32(a) as follows: 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. 


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An AE (also referred to as an adverse experience) can be any unfavorable and unintended sign 
(e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a drug, and does not imply any judgment about causality.  An AE can arise with any use of the 
drug (e.g., off-label use, use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose. 
AEs with be collected starting with Visit 2/Day -10. However, AEs occurring between Visit 2/ 
Day -10 and Visit 3/Day 1 will be regarded as “pretreatment” if they occur before IP administration 
at Visit 3/Day 1. TEAEs are defined as any AE that starts or increases in severity after the first 
randomized dose of study IP on Visit 3/Day 1.  
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 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 at immediate risk of death.  It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
7.3.1 Adverse Events of Hypoglycemia 
The CTCAE (version 4.0) definition for mild, moderate, and severe hypoglycemia based on blood 
glucose will be used, as shown below: 
Mild: from 55 to <70 mg/dL (3.0 to < 3.8 mmol/L) 
Moderate: from 40 to < 55 mg/dL (2.2 to < 3.0 mmol/L) 


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Severe: from 30 to < 40 mg/dL (1.7 to < 2.2 mmol/L) 
Life Threatening: < 30 mg/dL (< 1.7 mmol/L) 
Subjects with hypoglycemia will be provided with 2-4 glucose tablets as necessary until 
symptoms subside or blood glucose increases to greater than 70 mg/dL. If a patient has greater 
than 2 episodes of symptomatic hypoglycemia at any particular study visit, they will be 
terminated from the study. 
 
7.3.2 Adverse Events of Hyperglycemia 
Hyperglycemia will be defined as a blood glucose reading > 300 mg/dL. 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, the subject will be withdrawn from the study and treated 
according to the following criteria: 
1. Subjects who are asymptomatic with a glucose reading >300 mg/dL and <500 mg/dL will 
be provided with dietary counseling and either adjustment of their current medication or 
addition of an alternative hypoglycemic agent. 
2. Subjects who are symptomatic with a glucose reading >300 mg/dL and <500 mg/dL will 
be provided with dietary counseling, subcutaneous insulin on a sliding scale, and 
adjustment of their current medication or addition of an alternative hypoglycemic agent. 
3. Subjects with a glucose reading ≥500 mg/dL will be provided with dietary counseling, 
subcutaneous insulin on a sliding scale, and adjustment of their current medication or 
addition of an alternative hypoglycemic agent. 
7.4 
Eliciting and Reporting of Adverse Events 
AE monitoring will start immediately following the first dose study treatment and will continue 
through Visit 7.  Any subject with a possible study treatment-related AE at Visit 6/Day 2 will be 
followed until resolution or stabilization of the event.  Further, any SAE, whether or not related 
to study treatment, that occurs within 14 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 for the occurrence of AEs throughout the study.  In order to avoid bias in eliciting AEs, 
subjects will be asked general, non-leading questions such as "How are you feeling?"   
All AEs, including pretreatment and TEAEs, reported by the subject, observed or otherwise 
identified by the Investigator, or other Investigational Site personnel will be documented.   


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Medical conditions existing at Screening should be recorded as medical history.  New or 
worsening pre-existing medical conditions or diseases are considered AEs if they arise or worsen 
after the Screening visit, and should be recorded as AEs. 
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery.  The condition for which the surgery is required is an AE if it occurs or is 
detected following the first dose of study treatment through Visit 7.  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 CRF 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 7.5);  
• Whether the event is expected (per definition in Section 7.7); 
• Action taken in treating the AE (including concomitant medications or therapies 
administered) and/or change in the study treatment administration or dose (including 
whether the study treatment was temporarily interrupted or discontinued); 
• Outcome of AE (per definition in Section 7.8).   


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7.4.2 Reporting of Serious Adverse Events, Including Death 
The Sponsor will adhere to all expedited regulatory reporting requirements as per 21 CFR 
312.32.  
SAEs, including death due to any cause, which occur during this study or within 30 days 
following the last dose of the study treatment, whether or not related to the administration of 
study treatment, must be reported by the Investigator or other Investigational Site personnel to 
the Medical Monitor by telephone or fax within 24 hours of learning of the event.  The contact 
information for the Medical Monitor is provided below. 
Medical Monitor: 
 
Carmen Margaritescu, MD 
Safety Office, Integrium, LLC 
Office: 714-210-6665  
Cellular: 714-328-7083 
Email: safety@integrium.com 
 
SAE Forms will be provided by the Sponsor or Sponsor designated CRO.  If all information is 
not known at the time of initial reporting, an initial report should still be made.  In the event there 
is a question as to whether the experience is serious, the information should be forwarded to the 
Medical Monitor for review.  The Investigator is responsible for following up on completion of 
the SAE Form.  The Investigator will submit substantiating data in hard copy form, such as 
diagnostic test reports and progress notes, to the Medical Monitor.  In the case of fatality, 
autopsy reports will be furnished to the Medical Monitor as soon as available.  If the Medical 
Monitor is informed of a SAE via a telephone call, preliminary information will be obtained, and 
the study site will be instructed to fax an SAE Form. 
The initial SAE Form and any subsequent follow-up SAE Forms submitted to provide more 
accurate, corrected, or new information must be signed by the Investigator.  The Investigator and 
Investigational Site Personnel must make every reasonable effort to obtain, from other 
institutions if necessary, all supporting medical case records as needed to comply with expedited 
Investigational New Drug application (IND) safety reporting requirements.   
If the SAE involves expedited IND safety reporting (as determined by the Sponsor or designee), 
all supporting medical records must be submitted to the Sponsor or designee within 4 calendar 
days for death or life-threatening events, and 10 calendar days for all other events.  In cases 
where medical records and supporting documentation are unobtainable, the Investigator must 
generate a narrative of the event utilizing, when necessary, interviews with the subject, their 
family members and care givers as appropriate.  
The Investigator must also promptly inform the governing IRB of the SAE in accordance with 
the governing IRB’s requirements.  Any SAE that is determined by the Sponsor to be reportable 
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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. 
 
If the 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 partner should be followed by the Investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the Investigator should notify the 
Sponsor. At the completion of the pregnancy, the Investigator will document the outcome of the 
pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification as an 
SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
7.5 
Causality Assessment of Adverse Events 
For all AEs, the Principal Investigator will provide an assessment of causal relationship to the 
study treatment (active or placebo).  The causality assessment must be recorded in the subject’s 
source documents and on the AE CRF.  Causal relationship will be classified according to the 
following criteria: 
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2. Unlikely: The event is doubtfully related to active study drug.  The event was most likely 
related to other factors such as the 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. 
 
7.5.1 Potential Adverse Events Associated with ORMD-0801 
Hypoglycemia and associated symptoms (e.g., weakness, dizziness, shakiness, increased 
sweating, palpitations, or confusion), have been associated with insulin administration, including 
ORMD-0801. Animal reproductive studies have not been conducted with ORMD-0801. It is not 
known whether ORMD-0801 can cause fetal harm when administered to a pregnant woman. It is 
also not known whether this product is excreted in human milk. Pregnant or breastfeeding 
women are excluded from this study. 
Long-term animal studies have not been completed to assess whether ORMD-0801 impairs 
fertility.  
7.6 
Adverse Event Severity Assessment 
The severity of each AE will be graded according to the NCI CTCAE, version 4.03.  The 
severity of AEs that are not specifically listed in the CTCAE will be categorized according to the 
general guidelines provided in the CTCAE, and as summarized in the table below.  
General Guidelines for Severity Assessment of Adverse Events 
Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2:  Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) [preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.]. 


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Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL (bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden). 
Grade 4:  Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
 
Note the distinction between the severity and the seriousness of an AE. A severe AE is not 
necessarily a SAE.  For example, a headache may be severe (interferes significantly with 
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 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. 


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7.9 Clinical Findings 
Any significant clinical findings 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 7.2), the follow-up procedures for AEs 
defined above will apply. 
 
 
 


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8 STATISTICAL METHODS  
This section describes the statistical methods to be used for the analysis and reporting of data 
collected under Protocol No. ORA-D-017. Additional details will be provided in the statistical 
analysis plan. 
8.1 
Sample Size 
An estimated total of 24 subjects are planned to be randomized to participate in the two dosing 
conditions in a randomized order. The study objectives (primary, secondary and exploratory) 
have not been previously explored, so there are no estimates of means or standard deviations to 
perform power calculations. 
Safety will be a secondary endpoint for this trial and will be assessed primarily based on AEs.  
Secondary safety assessments will include physical examination, 12-lead ECG, vital signs 
(including weight, seated SBP/DBP, and heart rate), and clinical safety labs (hematology, serum 
chemistry, and urinalysis). 
8.2 Statistical Considerations 
Subjects will be analyzed under 3 treatment regimens: Standard of Care (Baseline), Once a Day 
Dosing (QD) and Three Times a Day Dosing (TID).  
Information collected in the daily diaries or via the Continuous Glucose Monitor (CGM) on the 
final 10 days of treatment will be analyzed using a Repeated Measures Analysis of Covariance 
with subject as a random effect with each of the 10 days being a single measure. When analyzing 
the exogenous insulin variables, CGM parameters (mean 24 hour glucose value and 24 hour time 
within 70-180 mg/dL range) and patient reported carbohydrate intake will be included as 
covariates. When analyzing CGM parameters, exogenous insulin (basal and bolus insulin 
amounts) and patient reported carbohydrate intake will be included as covariates. Treatment least 
squares means and change from baseline estimates will be derived using this linear model. 
Information collected at the day 28 visits will be analyzed using an Analysis of Covariance 
model with subject as a random effect. Treatment least squares means and change from baseline 
estimates will be derived using this linear model. 
8.3 Basal, Bolus and Total Exogenous Insulin 
The amount of basal, bolus and total exogenous insulin will be analyzed using the Repeated 
Measures Analysis of Covariance model indicated in Section 8.2. Least squares means, standard 
error and 95% confidence intervals will be presented for each treatment regimen and changes 
between treatment regimens.  
Total daily non-oral insulin requirements in units per kilogram (kg) body weight will also be 
analyzed in a fashion similar to basal, bolus and total exogenous insulin. 
 


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8.4 Continuous Glucose Monitor Evaluation 
For the purpose of analysis: 
• 24-hour will be considered to be from 6AM to 6AM, 
• Daytime will be considered to be from 6AM to 10PM,  
• Nighttime will be considered to be from 10PM to 6AM, and 
The area under the curve (AUC) will be derived for each of the time periods (24-hour, daytime 
and nighttime) for each of the 10 days for each treatment regimen. The average glucose 
measurement will be derived by dividing the AUC by the number of observed hours.  
In addition to the mean values, the following CGM parameters will be derived: 
• Time in range 70-180 mg/dL 
• Time <70 mg/dL 
• Time >180 mg/dL 
• Time >250 mg/dL 
• Glucose coefficient of variation 
• Low blood glucose index (LBGI) 
• Glucose below 70 mg/dL Area Over the Curve (AOC70) 
All of the CGM parameters will be analyzed for each of the time periods (24-hour, daytime and 
nighttime) using the Repeated Measures Analysis of Covariance Model indicated in Section 8.2. 
8.5 Other Endpoints of Interest 
HbA1c, average patient reported carbohydrate intake and body weight will be summarized using 
an Analysis of Covariance Model as indicated in Section 8.2. 
8.6 Safety Evaluation 
8.6.1 Safety Population 
All randomized subjects who receive at least one dose of study treatment will be included in the 
safety analysis population.   
8.6.2 Adverse Events 
AEs will be coded using the most current version of MedDRA.  The severity of AEs will be graded 
according to NCI CTCAE version 4.03.  AEs with be collected starting with Visit 2/Day -10. 
However, AEs occurring between Visit 2/Day -10 and Visit 3/Day 1 will be regarded as 
“pretreatment” if they occur before IP administration at Visit 3/Day 1. TEAEs are defined as any 
AE that starts or increases in severity after the first randomized dose of study IP on Visit 3/Day 1. 
The incidence of TEAEs will be tabulated by MedDRA preferred term, system organ class, 
treatment group, severity, and assigned relationship to study treatment.  The incidence for each 
TEAE will be provided as the total number of subjects that experienced the TEAE, as well as the 
percentage of the population that this represents.  If a TEAE is reported more than once for a 
given subject, the greatest severity and the worst-case attribution will be presented in the 
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TEAEs will be listed for individual subjects, along with information regarding onset and end 
dates, onset time where available, severity, seriousness, relationship to study treatment, action 
taken, and outcome.  A similar listing will be prepared for the pretreatment AEs.   
Pretreatment AEs and TEAEs that lead to withdrawal from the study will be separately listed and 
summarized.  Similarly, separate tabulations and listings will be prepared for pretreatment and 
treatment-emergent SAEs.  
Descriptive statistics will be generated as appropriate (i.e., frequency for categorical data).  
Inferential statistical analysis comparing the AE data between active and placebo is not planned. 
8.6.3 Laboratory Evaluations 
Individual clinical safety lab (hematology, serum chemistry, and urinalysis) values will be listed 
by treatment 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 (Screening) will be recorded as an 
AE if deemed appropriate by the Investigator. 
8.6.4 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 (Screening) in 
vital sign measurements will be calculated and summarized descriptively.  A clinically 
significant change from baseline (Screening) will be recorded as a TEAE if deemed appropriate 
by the Investigator. 
8.6.5 12-lead ECG 
Individual 12-lead ECG assessments at screening will be listed.  
8.6.6 Physical Examination 
Individual physical examination findings will be listed for each visit in which a physical 
examination occurred.  A clinically significant change from baseline (Screening) will be 
recorded as an AE if deemed appropriate by the Investigator. 
8.6.7 Prior and Concomitant Medications and Supplements 
Medications and supplements will be coded using the most current version of the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system.   
All medications and supplements (other than study treatment) taken by the subject from Visit 
2/Day 1 through the Visit 7 will be considered “concomitant” medications and supplements.  
Medications and supplements taken prior to the first dose of ORMD-0801 that are no longer 
being taken at the time of the first dose of ORMD-0801 will be considered “prior” medications 
and supplements.   
Concomitant medications and supplements will be listed for individual subjects.  A similar 
listing will be prepared for prior medications and supplements taken within 30 days prior to the 


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first dose of study treatment.  The incidence of these prior and concomitant medications and 
supplements will be summarized. 
8.6.8 Handling of Missing, Unused, or Spurious 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 
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9 DATA MANAGEMENT 
9.1 
Data Collection 
All data required by the study protocol will be collected in a validated database according to the 
contract research organization’s (CRO’s) SOPs. 
9.2 
Electronic Data Capture 
Data from the source documents will be entered into the electronic EDC system by authorized 
Investigational Site personnel.  Data Management staff, using both electronic and manual 
checks, will systematically check the data.  Errors or omissions will result in queries (which can 
be issued by the Study Monitor or Data Management staff), which will be presented to the 
Investigational Site within the EDC system.  The Investigational Site will resolve the queries 
within the EDC system.  The Study Monitor and Data Management staff will review the 
responses as part of the query resolution process.  The EDC system will track the queries with 
the corresponding responses. 
Medications and supplements entered into the database will be coded in the EDC system using 
the World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system.  AEs and Medical History will be coded in the EDC 
system using MedDRA terminology.  
Clinical laboratory samples will be processed by Consolidated Medical Bio-Analysis, Inc. at 
10700 Walker Street, Cypress, CA 90630. All lab results will be sent electronically to Integrium. 
The clinical laboratory results will be imported into the database. 
9.3 
Quality Assurance and Database Lock 
A 100% critical variable review of all key safety and secondary endpoint data in the database 
will be performed.  Following this review, a data quality control audit or a random sample equal 
to the square root plus 1 of the total population will be performed. 
When the database has been declared to be complete and accurate, the database will be locked.  
Any changes to the database after that time can only be made by joint written agreement between 
the Sponsor, the Investigator, Integrium, and the study biostatistician. 
 
 


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


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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 


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obtain the IRB’s written approval/favorable opinion prior to the use of the revised documents. 
The Investigator, or a person designated by the Investigator, will fully inform the subject of all 
pertinent aspects of the study and of any new information relevant to the subject's willingness to 
continue participation in the study.  Subjects will read and sign any and all revised ICFs.  
11.3 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects’ state of 
health will be regarded as confidential.  This is detailed in the ICF provided to the subject.  An 
agreement for the use or disclosure of any such information (PHI) will be obtained from the 
subject in writing (HIPAA authorization) prior to performing any study-related procedures.  
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 Entering Data Into EDC 
All data required by the study protocol will be recorded in the electronic database provided by 
the EDC vendor.  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 
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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 CRFs, supporting source documentation from the 
medical record, including laboratory data, and the signed ICF;  
• Regulatory files, containing the protocol with all amendments and Sponsor and 
Investigator signature pages, copies of all other regulatory documentation, and all 
correspondence between the site and the IRB and Sponsor; and  
• 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.   


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12 STUDY ADMINISTRATION 
12.1 Study Monitoring 
This study will be monitored by the Sponsor or designee to evaluate the progress of the study, to 
verify the accuracy and completeness of the eCRFs, to assure that all protocol requirements, 
applicable laws and/or regulations, and Investigator’s obligations are being fulfilled, and to 
resolve any inconsistencies in the study records.  
The Investigator will allow the Study Monitor to periodically review, at mutually convenient 
times during the study and after the study has been completed, all eCRFs and office, hospital, 
and laboratory records supporting the participation of each subject in the study.   
The Study Monitor will compare the eCRF data against source documentation in order to verify 
its accuracy and completeness.  The Investigator and Investigational Site staff will collaborate 
with the Study Monitor to resolve any identified data discrepancies in a timely manner.   
The Study Monitor will record any protocol deviations identified, including, but not limited to, 
subjects that were enrolled even though they did not meet all eligibility criteria, subjects who 
took concomitant medications specifically prohibited by the protocol, subjects who received the 
wrong study treatment or incorrect dose, and subjects who failed to comply with the protocol-
defined dietary restrictions.  The Investigator and Investigational Site staff will collaborate with 
the Study Monitor to identify the reason for each protocol deviation.   
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.  


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Phase 2 Clinical Study 
 
Version 1.0 (Aug 25, 2019) 
Confidential                                                                                                                                               Page 60 of 62 
 
12.3 Data Quality Assurance 
All eCRFs must be completed by authorized Investigational Site personnel who have undergone 
electronic CRF 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 CRF are 
accurate and correct by electronically signing and dating the eCRF. 
All CRF corrections must be made by the Principal Investigator or authorized Investigational 
Site personnel.  The Principal Investigator must authorize changes to the recorded data, and this 
authorization must be documented in the source documents.   
Refer to Section 8 for further details regarding Data Management quality assurance, including 
query generation and resolution, final data review, and database lock. 
12.4 Publication Policy 
All information and data obtained in the course of the study are the property of the Sponsor and 
are considered confidential.  To avoid disclosures that could jeopardize proprietary rights, the 
institution and/or the Investigator agree to certain restrictions on publications (e.g., abstracts, 
speeches, posters, manuscripts, and electronic communications), as detailed in the clinical trial 
agreement. 
The publication or presentation of any study results shall comply with all applicable privacy 
laws, including, but not limited to, HIPAA or equivalent. 
This trial will be registered in a publicly accessible database (clinicaltrials.gov) not later than 21 
days after enrollment of the first subject.  Results of this trial, including negative and 
inconclusive, as well as positive results, will be made publicly available. 
12.5 Disclosure and Confidentiality 
By signing the protocol, the Investigator agrees to keep all information provided by the Sponsor 
and Integrium in strict confidence and to request similar confidentiality from his/her staff and the 
IRB.  Study documents provided by the Sponsor and Integrium (protocols, IBs, CRFs, and other 
material) will be stored appropriately to ensure their confidentiality.  The information provided 
by the Sponsor and Integrium to the Investigator may not be disclosed to others without direct 
written authorization from the Sponsor and Integrium, except to the extent necessary to obtain 
informed consent from subjects who wish to participate in the study. 
 
 


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


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World Health Organization (2006): “Definition and Diagnosis of Diabetes Mellitus and 
Intermediate Hyperglycaemia: Report of a WHO/IDF Consultation.” World Health Organization, 
Geneva, Switzerland. 
 

SAP_001.pdf: 
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Version: 1.0 
 
 
Protocol No.: ORA-D-017 
Statistical Analysis Plan 
 
  
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THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION.   
IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
 
 
 
INTEGRIUM, LLC 
BIOMETRICS DEPARTMENT 
 
 
Clinical Study Protocol: ORA-D-017 
 
A Phase 2 Randomized, Open Label Crossover Study to Compare 
ORMD-0801 Given Once Daily at Bedtime to ORMD-0801 given 
Three Times Daily (45-90 minutes before Meals) in Subjects with 
Type 1 Diabetes 
  
 
Statistical Analysis Plan (SAP) Documentation 
 
Author(s): 
Kenneth E. Homer  
Sponsor: 
Oramed Pharmaceuticals, Inc. 
Document status: 
Version 1.0 
Dates: 
09MAR2020 
Number of pages: 
18 




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Document History 
 
Version 
Number 
Author 
Date  
Change 
0.1 
K. Homer 
08JAN2020 
Initial Draft 
 
 
 
 
 
 
 
 
 


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Glossary of Abbreviations 
 
AE 
Adverse Event 
AUC 
Area Under the Time-Concentration Curve 
CGM 
Continuous Glucose Monitoring 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
IP 
Investigational Product 
HbA1c 
Hemoglobin A1c 
kg 
Kilogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
PI 
Primary Investigator 
QD 
Once a Day 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
T1D 
Type 1 Diabetes Mellitus  
TEAE 
Treatment-Emergent Adverse Events 
TID 
Three Times a Day 
WHO 
World Health Organization  
 


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Table of Contents 
Signature Page ............................................................................................................................ 2 
Document History....................................................................................................................... 3 
Glossary of Abbreviations .......................................................................................................... 4 
1. 
Introduction ......................................................................................................................... 7 
1.1. 
Scope ........................................................................................................................ 7 
1.2. 
Study Overview ....................................................................................................... 7 
1.3. 
Study Objectives ...................................................................................................... 8 
1.3.1 Primary Objectives .................................................................................................. 8 
1.3.2 Secondary Objectives .............................................................................................. 8 
2. 
Detailed Statistical Methods ................................................................................................ 8 
2.1. 
General Statistical Methods ..................................................................................... 8 
2.2. 
Study Populations .................................................................................................... 8 
2.3. 
Patient Disposition and Characteristics ................................................................... 9 
2.4. 
Demographics and Patient Baseline Characteristics ................................................ 9 
2.5. 
Study Drug Duration and Compliance .................................................................... 9 
2.6. 
Prior and Concomitant Medications ........................................................................ 9 
2.7. 
Safety Evaluations ................................................................................................... 9 
2.7.1. Adverse Events ........................................................................................................ 9 
2.7.2. Hypoglycemic Events ............................................................................................ 10 
2.7.3. Safety Laboratory Evaluations .............................................................................. 10 
2.7.4. Vital Signs ............................................................................................................. 10 
2.7.5. Electrocardiogram .................................................................................................. 10 
2.7.6. Physical Examination ............................................................................................ 10 
2.8. 
Efficacy Evaluations .............................................................................................. 11 
2.8.1. Statistical Considerations ....................................................................................... 12 
2.8.2. Basal, Bolus and Total Exogenous Insulin ............................................................ 12 
2.8.3. Continuous Glucose Monitoring............................................................................ 12 
2.8.4. Other Endpoints of Interest .................................................................................... 13 
2.9. 
Interim Analyses .................................................................................................... 13 
2.10. Other Analyses ....................................................................................................... 13 
2.11. Sample Size and Power Considerations ................................................................ 13 
2.12. Randomization Scheme and Codes ....................................................................... 13 
2.13. Handling Missing Data .......................................................................................... 13 
2.14. Protocol Deviations ............................................................................................... 14 
2.15. Computer Systems and Packages Used for Statistical Analyses ........................... 14 


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3. 
Data Listing Shells ............................................................................................................ 15 
3.1. 
Data Listings Table of Contents ............................................................................ 15 
3.2. 
Data Listings .......................................................................................................... 16 
4. 
Summary Table and Figure Shells .................................................................................... 16 
4.1. 
Post-text Table of Contents ................................................................................... 16 
4.2. 
Summary Tables .................................................................................................... 17 
4.3. 
Post-text Figures Tables of Contents ..................................................................... 17 
4.4. 
Post-Text Figures ................................................................................................... 18 
4.5. 
Table Shells ........................................................................................................... 18 
 


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1. 
Introduction 
1.1. 
Scope 
This document contains detailed information to aid the production of the Clinical Study 
Report (CSR) including summary tables and listings for trial ORA-D-017.  The contents of 
this document were reviewed by the sponsor, Oramed Pharmaceuticals, Inc., and the trial 
biostatistician at Integrium. 
1.2. 
Study Overview 
This study is designed to compare ORMD-0801 given once a day (QD) versus three times a 
day (TID) in subjects with Type 1 Diabetes (T1D). The study will consist of seven visits 
(including Screening Visit). 
Subjects will come in for a screening visit to determine eligibility for participation in the 
study. Eligible subjects will be scheduled to return to the clinic approximately 1 week later. 
Subjects fulfilling all inclusion/exclusion criteria will have a Continuous Glucose Monitor 
(CGM) placed, provided with a diary, dispensed placebo capsules and asked to return to the 
clinic in approximately 10 days for randomization. 
At the randomization visit (Visit 3), data from the CGM will be downloaded and diaries will 
be collected and reviewed. Subjects will be randomized to receive either ORMD-0801 24 mg 
given once daily at bedtime, or ORMD-0801 8 mg given three times a day, 45-90 minutes 
before meals.  
Subjects will be instructed to return to the clinic in eighteen days for the next visit (Day 18). 
On Day 18 (Visit 4), a CGM will be placed and a diary will be provided. 
Subjects will return to the clinic ten days following Visit 4, on Day 28 (Visit 5). Compliance 
will be assessed, data from the CGM will be downloaded, the diary will be collected, and 
subjects will be crossed over to the alternate treatment regimen.  
Subjects will be instructed to return to the clinic in 18 days for the next visit (Day 46). On 
Day 46 (Visit 6), a CGM will be placed and a diary will be provided. 
Subjects will return to the clinic on Day 56 (Visit 7) compliance will be assessed, data from 
the CGM will be downloaded and diary will be collected. 
 
 


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1.3. Study Objectives 
1.3.1 
Primary Objectives 
The primary objectives of the study are: 
1. To compare the impact of Oral Insulin dosed QD to Oral Insulin dosed TID on 
exogenous basal and bolus insulin requirements in subjects with T1D during the 
last 10 days of each treatment period. 
2. To compare the impact of Oral Insulin dosed QD to Oral Insulin dosed TID and 
associated adjustments of basal and bolus insulin on mean 24-hour glucose and 
parameters of glycemic variability as measured by a CGM over the last 10 days 
of each treatment period. 
1.3.2 
Secondary Objectives  
The secondary objectives of this study are: 
1. To compare the change from baseline in number of hypoglycemic episodes in subjects 
treated with Oral Insulin dosed QD to Oral insulin dosed TID in subjects with T1D 
over the last 10 days of each treatment period. 
2. To compare the change from baseline in HbA1c levels in subjects with T1D treated 
with Oral Insulin dosed QD or Oral Insulin dosed TID as measured at the end of each 
treatment period. 
3. To explore differences in glucodynamic between the different dosing regimens during 
the last 10 days of each treatment period. 
4. To evaluate the safety of Oral Insulin through the recording of adverse events, clinical 
laboratory tests results (hematology, chemistry and urinalysis) and vital signs. 
2. 
Detailed Statistical Methods 
2.1. 
General Statistical Methods 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics. For descriptive statistics summary tables will include by 
study group summaries of sample size, arithmetic mean, standard deviation, median, 
minimum and maximum values, and 95% Confidence Intervals (if appropriate). For 
categorical variables summary tables will include by study group summaries of frequency 
counts. 
2.2. 
Study Populations 
Safety Population 
All randomized subjects who receive at least one dose of study treatment will be 
included in the safety analysis population. 


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2.3. 
Patient Disposition and Characteristics 
An account of the patients by disposition will be tabulated overall.  The number of patients 
included in each analysis population will be summarized. Patients not completing the study will 
be summarized and listed with the reason for their premature discontinuation.   
2.4. 
Demographics and Patient Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all subjects. Summary 
statistics (e.g., number of subjects, mean, median, standard deviation, minimum and 
maximum) will be generated for continuous variables (e.g., age and weight) and the number 
and percentage of subjects within each category will be presented for categorical variables 
(e.g., sex, ethnicity and race). 
2.5. 
Study Drug Duration and Compliance  
This is a two-period crossover study. A table summarizing the number of days on study 
medication, the number of tablets taken and the percent compliance (100*number of tablets 
taken / expected number of tablets) by treatment regimen will be presented. 
2.6. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization (WHO) 
Drug dictionary March 2018 version.  
Prior medications will be defined as any medication that stops prior to the day of first dose.  
Concomitant medications will be defined as any medication that stops on or after the day of 
first dose.  
Section 2.13 describes the imputation rules for partial dates. All medications will be presented 
in a data listing. 
2.7. 
Safety Evaluations 
2.7.1. Adverse Events 
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Affairs 
(MedDRA) version 21.0 and tabulated, including categorical information of interest such as 
onset and resolution times, time of onset relative to dose, severity at onset, maximum severity, 
causal relationship to study medication, and action taken.  
Treatment-emergent adverse events (TEAEs) are defined as any AE that starts or increases in 
severity after the first randomized dose of study treatment.   The incidence of TEAEs will be 
tabulated by MedDRA preferred term, system organ class, treatment group, severity, and 
assigned relationship to study treatment.  Adverse events will also be summarized by severity 
and relationship to the investigational product (IP).  


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The incidence of serious AEs, drug-related AEs, serious and drug-related AEs, and any AEs 
resulting in discontinuation from the study will be listed.  
2.7.2. Hypoglycemic Events 
The proportion (percentage) of patients affected by hypoglycemia will be reported by treatment 
regimen. The hypoglycemic information will come from the data entered in the Hypoglycemic 
/ Hyperglycemic log. 
2.7.3. Safety Laboratory Evaluations 
Screening, pre-dose values (Day 1 of treatment), post-dose values (Day 28 of treatment) and 
change from pre-dose to post-dose will be described using summary statistics for each 
parameter for each treatment regimen. All laboratory results will be presented in listings. 
 
A clinically significant abnormal value or clinically significant change from baseline 
(Screening), may be recorded as an AE, if deemed appropriate by the PI or sponsor. 
2.7.4. Vital Signs 
Screening, pre-dose values (Day 1 of treatment), Day 18 of treatment, Day 28 of treatment 
and change from pre-dose to Days 18 and 28 will be described using summary statistics for 
each parameter for each treatment regimen. All vital sign results will be presented in listings. 
A clinically significant change from baseline may be recorded as an AE, if deemed 
appropriate by the PI or sponsor.  
2.7.5. Electrocardiogram 
ECG was collected at screening only. All ECG results will be presented in listings. 
2.7.6. Physical Examination 
The Screening and end of study results will be described using frequency counts for each 
body system.  
All physical exam findings will be presented in the data listings. 
 


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2.8. 
Efficacy Evaluations 
The primary endpoints for the study are: 
1. To compare the amount of basal, bolus and total (basal + bolus) exogenous insulin 
utilized over the final 10 days of each treatment period. 
2. To compare the impact of Oral Insulin dosed QD to Oral Insulin dosed TID and 
associated adjustments of basal and bolus insulin on mean 24-hour CGM glucose levels 
during the final 10 days of each treatment period. 
The secondary endpoints for the study are: 
1. Glucodynamics over the final 10 days of each treatment period as measured by CGM: 
a. Time in range 70 – 180 mg/dL 
b. Time <70 mg/dL 
c. Time >180 mg/dL 
d. Time >250 mg/dL 
e. Glucose Coefficient of Variation 
f. Low Blood Glucose Index (LBGI) 
g. Glucose below 70 mg/dL Area Over the Curve (AOC70) 
2. Total daily non-oral insulin requirements in units per kilogram (kg) body weight over 
the last 10 days of each treatment period. 
The exploratory endpoints for the study are: 
1. HbA1c measured at the end of each treatment period 
2. Patient diary-reported carbohydrate intake over the final 10 days of each treatment 
period 
3. Changes in body weight from baseline (Visit 3) to the end of each treatment period 
4. Other measures of hypoglycemia 
a. Severe hypoglycemia events (impaired or loss of consciousness requiring 
assistance of another) 
b. Documented symptomatic hypoglycemia (an event during which typical 
symptoms of hypoglycemia are accompanied by a measured plasma glucose 
concentration <70 mg/dL) 
c. Total time <70 mg/dL by CGM 
d. Nocturnal hypoglycemia, severe or documented symptomatic episodes (as 
defined above) occurring after the subject has retired for the primary sleeping 
period. 
 
 


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2.8.1. Statistical Considerations 
Subjects will be analyzed under 3 treatment regimens: Standard of Care (Baseline), Once a Day 
Dosing (QD) and Three Times a Day Dosing (TID). 
Information collected in the daily diaries or via the Continuous Glucose Monitor (CGM) on the 
final 10 days of treatment will be analyzed using a Repeated Measures Analysis of Covariance 
with subject as a random effect with each of the 10 days being a single measurement. When 
analyzing the exogenous insulin variables, the CGM parameters (mean 24 hour glucose value 
and 24 hour time within 70-180 mg/dL range) and the patient reported carbohydrate intake will 
be included as covariates. When analyzing CGM parameters, the exogenous insulin (basal and 
bolus insulin amounts) and patient reported carbohydrate intake will be included as covariates. 
Treatment least squares means and change from baseline estimates will be derived using this 
linear model. 
Information collected at the day 28 visits (Day 28 and Day 56) will be analyzed using an 
Analysis of Covariance model with subject as a random effect. Treatment least squares means 
and change from baseline estimates will be derived using this linear model. 
2.8.2. Basal, Bolus and Total Exogenous Insulin 
The amount of basal, bolus and total exogenous insulin will be analyzed using the Repeated 
Masures Analysis of Covariance model indicated in Section 2.8.1. Least squares mean, standard 
error and 95% confidence intervals will be presented for each treatment regimen and changes 
between treatment regimens. 
Total daily non-oral insulin requirements in units per kilogram (kg) body weight will also be 
analyzed in a fashion similar to basal, bolus and total exogenous insulin. 
2.8.3. Continuous Glucose Monitoring 
Continuous Glucose Monitoring (CGM) will be summarized using 3 different time intervals: 
• Daytime (6AM to 10PM), 
• Nighttime (10PM to 6AM) and 
• 24 Hour (6AM to 6AM). 
The area under the curve (AUC) will be derived for each of the time periods for each of the 10 
days for each treatment regimen. The average glucose measurement will be derived by 
dividing the AUC by the number of observed hours. 
In addition to the mean values, the following CGM parameters will be derived for each time 
interval: 
• Time that Glucose Value is Between 70 and 180, 
• Time that Glucose Value is Less Than 70,  
• Time that Glucose Value is Greater Than 180,  


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• Time that Glucose Value is Greater Than 250, 
• Low Blood Glucose Index, and 
• Glucose below 70 mg/dL Area Over the Curve (AOC70) 
All of the CGM parameters will be analyzed for each of the time periods (24-hour, daytime 
and nighttime) using the Repeated Measures Analysis of Covariance Model indicated in 
section 2.8.1.  
Individual and mean figures will be generated to present the glucose curves / data for the 24-
hour, daytime and nighttime measurements. 
2.8.4. Other Endpoints of Interest 
HbA1c, average patient reported carbohydrate intake and body weight will be summarized 
using an Analysis of Covariance Model as indicated in Section 2.8.1. 
2.9. 
Interim Analyses 
There are no interim analyses planned for this study. 
2.10. Other Analyses 
No other analyses are planned at this time. 
2.11. Sample Size and Power Considerations 
An estimated total of approximately 26 subjects are planned to be randomized to participate in 
the two dosing conditions in a randomized order. The study objectives (primary and secondary) 
have not been previously explored, so there are no estimates of means or standard deviations to 
perform power calculations. 
2.12. Randomization Scheme and Codes 
The randomization details for this study are presented in a separate randomization plan. 
2.13. Handling Missing Data 
Listings will be provided for all data. Descriptive statistics will be provided for all planned 
visits as provided on the electornic Case Report Forms (eCRFs).  
Dates related to the adverse events and medications will be imputed using the rules below in 
an effort to categorize them properly into the summary tables.  
Imputing partial or missing start dates: 
• If the year is unknown, then the start date will not be imputed. The date will remain 
missing. 


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• If the month is unknown and the year is the same as the first dose date of the study, 
then impute the month and day of the date to be equal to the first dose month and day. 
Otherwise, impute the month as January. 
• If the day is unknown and the month and year are the same as the first dose date of the 
study, then impute the day to be equal to the day of the first dose. Otherwise, impute 
the day as ‘01’. 
Impute partial or missing stop dates: 
• If the year is unknown, then the stop date will not be imputed. The date will remain 
missing. 
• If the month is unknown, impute the month as December. 
• If the day is unknown, impute the day to be the last day of the month. 
If an imputed stop date is greater than the date of study completion/discontinuation date of the 
study, then the imputed stop date will be set equal to the date of completion/discontinuation 
date.  
There is no plan to impute missing CGM data. 
2.14. Protocol Deviations 
Protocol deviations will be displayed in a data listing as provided by the clinical team.  
2.15. Computer Systems and Packages Used for Statistical Analyses 
Server SAS® version 9.4 on the Microsoft Windows Server 2008R2 64-bit platform will be 
used for all analyses.  All computations will be performed using SAS®.  The exact form of the 
various algorithms will be the SAS® defaults.  The output from any SAS® procedure will be 
used in the tables using SAS® macros. 
 
 


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3. 
Data Listing Shells 
3.1. 
Data Listings Table of Contents 
The following post-text listings will be generated.  
16.1.7 
Randomization Schedule 
16.2.1 
Subject Completion/Discontinuation 
16.2.2 
Protocol Deviations  
16.2.3 
Population Status 
16.2.4.1 
Demographics and Baseline Characteristics 
16.2.4.2 
Childbearing Status 
16.2.4.3 
Inclusion / Exclusion Criteria and Informed Consent 
16.2.4.4 
Medical History 
16.2.4.5.1 
Prior and Concomitant Medications 
16.2.4.5.2 
Non-Drug Treatment 
16.2.5.1 
Study Drug Accountability 
16.2.5.2 
Study Drug Dosing Time – Final 10 Days of Treatment 
16.2.6.1 
Exogenous Insulin Usage – Final 10 Days of Treatment 
16.2.6.2.1 
Continuous Glucose Monitoring – Daytime Parameters 
16.2.6.2.2 
Continuous Glucose Monitoring – Nighttime Parameters 
16.2.6.2.3 
Continuous Glucose Monitoring – 24 Hour Parameters 
16.2.6.4 
Carbohydrate Intake – Final 10 Days of Treatment 
16.2.6.5 
HbA1c Values 
16.2.6.6 
Weight Values 
16.2.7.1.1 
Adverse Events 
16.2.7.1.2 
Serious Adverse Events 
16.2.7.1.3 
Adverse Events Leading to Study Treatment Discontinuation 
16.2.7.2 
Hypoglycemic / Hyperglycemic Log 
16.2.8.1 
Laboratory Test Results - Chemistry 
16.2.8.2 
Laboratory Test Results - Hematology 
16.2.8.3 
Laboratory Test Results – Urinalysis 
16.2.9.1 
Vital Signs 
16.2.9.2 
Electrocardiogram Results 


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16.2.9.3 
Physical Examination Results 
3.2. 
Data Listings 
All subjects and all data will be presented in the listings. The listings will be sorted by treatment 
and subject number.  
There are currently 29 listings that are planned to be generated. The 29 listings are broken down 
as follows: 16 Standard Unique, 4 Standard Repeat, 9 Non-Standard Unique and 0 Non-
Standard Repeat. 
 
4. 
Summary Table and Figure Shells 
4.1. 
Post-text Table of Contents 
The following post-text tables will be generated. 
 
Table 
Number 
Table title 
14.1.1 
Summary of Subject Disposition (Safety Population) 
14.1.2 
Summary of Demographics and Baseline Characteristics (Safety Population) 
14.1.3 
Summary of Medical History (Safety Population) 
14.1.4.1 
Summary of Prior Medications (Safety Population) 
14.1.4.2 
Summary of Concomitant Medications (Safety Population) 
14.1.5 
Summary of Study Medication Compliance (Safety Population) 
14.2.1 
Summary of Exogenous Insulin Usage (Safety Population) 
14.2.2.1 
Summary of Continuous Glucose Measurement Parameters – Daytime (Safety 
Population) 
14.2.2.2 
Summary of Continuous Glucose Measurement Parameters – Nighttime 
(Safety Population) 
14.2.2.3 
Summary of Continuous Glucose Measurement Parameters – 24-Hour (Safety 
Population) 
14.2.3 
Summary of Carbohydrate Intake (Safety Population) 
14.2.4 
Summary of HbA1c (Safety Population) 
14.2.5 
Summary of Weight (Safety Population) 
14.3.1.1 
Adverse Events Overall Summary (Safety Population) 


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Table 
Number 
Table title 
14.3.1.2 
Summary of Treatment Emergent Adverse Events by System Organ Class, 
and Preferred Term (Safety Population)  
14.3.1.3 
Summary of Treatment Emergent Adverse Events Leading to Discontinuation 
of Study (Safety Population)  
14.3.1.4 
Summary of Serious Treatment Emergent Adverse Events (Safety Population) 
14.3.1.5 
Summary of Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Severity (Safety Population) 
14.3.1.6 
Summary of Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship to Study Treatment (Safety Population) 
14.3.2.1 
Summary of Laboratory Values – Chemistry (Safety Population) 
14.3.2.2 
Summary of Laboratory Values – Hematology (Safety Population) 
14.3.2.3 
Summary of Laboratory Values – Urinalysis (Safety Population) 
14.3.3 
Summary of Vital Signs (Safety Population) 
14.3.4 
Summary of Hypoglycemic Events (Safety Population) 
14.3.5 
Summary of Physical Examination Findings (Safety Population) 
4.2. 
Summary Tables 
There are currently 25 tables that are planned to be generated. The 25 tables are broken down 
as follows: 9 Standard Unique, 4 Standard Repeat, 12 Non-Standard Unique and 0 Non-
Standard Repeat. 
4.3. 
Post-text Figures Tables of Contents 
The following post-text figures will be generated. 
Figure 
Number 
Figure Title 
14.2.1.1.1 
Exogenous Insulin Usage - Basal – Individual Observed Values 
14.2.1.1.2 
Exogenous Insulin Usage - Basal – Mean Observed Values 
14.2.1.2.1 
Exogenous Insulin Usage - Bolus – Individual Observed Values 
14.2.1.2.2 
Exogenous Insulin Usage - Bolus – Mean Observed Values 
14.2.1.3.1 
Exogenous Insulin Usage - Total – Individual Observed Values 
14.2.1.3.2 
Exogenous Insulin Usage - Total – Mean Observed Values 
14.2.2.1.1 
Continuous Glucose Measurements - Individual Observed Values – 24-Hours 
14.2.2.1.2 
Continuous Glucose Measurements - Mean Observed Values – 24-Hours 


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Figure 
Number 
Figure Title 
14.2.2.2.1 
Continuous Glucose Measurements - Individual Observed Values – Daytime 
14.2.2.2.2 
Continuous Glucose Measurements - Mean Observed Values – Daytime 
14.2.2.3.1 
Continuous Glucose Measurements - Individual Observed Values – Nighttime 
14.2.2.3.2 
Continuous Glucose Measurements - Mean Observed Values – Nighttime 
 
4.4. 
Post-Text Figures 
There are currently 12 figures that are planned to be generated. The 12 figures are broken down 
as follows: 0 Standard Unique, 0 Standard Repeat, 8 Non-Standard Unique and 4 Non-Standard 
Repeat. 
4.5. 
Table Shells 
The table shells can be found in a separate file. The following number of decimal places will be 
used when presenting summary statistics: 
• N to 0 decimal places 
• Minimum and maximum to the same number of decimal places as recorded in the raw data. 
• Means and medians to 1 more decimal place than is recorded in the raw data. Standard 
deviations to 2 more decimal places than is recorded in the raw data. 
• Percentages to 1 decimal place. 
 
The precision may be changed for individual endpoints as needed.