An Open-Label Pilot Study to Assess the Safety, Pharmacokinetics, Pharmacodynamics and Potential of Oral Insulin to Reduce Liver Fat Content and Fibrosis in Patients With Nonalcolholic Steatohepatitis (NASH)
Phase: PHASE2
Conditions: Non-Alcoholic Steatohepatitis (NASH), Type2 Diabetes Mellitus
Sponsor: Oramed, Ltd.

ORA-D-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
Clinical Protocol 07 January, 2018 – Version 3.1 
 
 
An Open-Label Pilot Study to Assess the Safety and Potential of Oral Insulin to 
Reduce Liver Fat Content in Patients with Nonalcoholic Steatohepatitis (NASH) 
 
 
 
 
 
 
 
ORA-D-N01 
INVESTIGATOR STUDY CENTER 
Rifat Safadi, MD (PI) 
Liver Unit, Dept. of Gastroenterology and Liver Diseases, Division of Medicine 
Hadassah University Medical Center 
Jerusalem, Israel   91120 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential  
 
 

 
Page 2 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
 
INTRODUCTION 
 
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are 
global public health issues closely associated with the worldwide epidemics of diabetes 
and obesity.1-3 NAFLD encompasses the spectrum of liver disease in patients with no 
significant alcohol consumption ranging from fatty liver to steatohepatitis and cirrhosis.1 
Nonalcoholic fatty liver (NAFL) is characterized by the presence of liver infiltration of fat 
(hepatic steatosis) with no evidence of hepatocellular injury in the form of ballooning of 
hepatocytes or no evidence of cirrhosis.1 The risk for progression to cirrhosis and liver 
failure in these patients is minimal. NASH is defined by the presence of hepatic steatosis 
and inflammation with hepatocyte injury (ballooning) with or without cirrhosis.1 NASH 
can progress to cirrhosis, liver failure and occasionally liver cancer. 
 
NAFLD is now considered to be the commonest cause of chronic liver disease in 
developed countries with as high as 30% of the general population affected.2, 4 In newly 
identified cases of chronic liver disease in a US survey, 39% had NAFLD.2 A high 
prevalence of NASH among NAFLD cases has been reported2: up to 55% in patients with 
elevated aminotransferases5, 6, as high as 49% in morbidly obese patients7, 8, and 67% in a 
subset of patients with incident chronic liver disease.9  
 
Half a billion adults worldwide are estimated to be obese and 1.5 billion are overweight 
or obese.10, 11 Overall, about two-thirds of the population in the developed world have a 
BMI greater than 25 kg/m2.12 Primary NAFLD/NASH is associated with insulin 
resistance (IR) and its phenotypic manifestations. There are clear relationships between 
NAFLD and obesity13 and between NAFLD and diabetes independent of obesity.14 
Systemic IR is considered to be the key risk factor for development of NAFLD.15  
The close relationship between NAFLD/NASH and type 2 diabetes mellitus (DM) leads 
to overlapping risk and complications and attendant economic burden for health care 
systems. 
 
Despite the high prevalence of NAFLD, no safe and effective treatment is currently 
available.16 Management strategies for NAFLD/NASH rely primarily on non-
pharmacologic measures. Since patients with NAFLD without steatohepatitis have 
excellent prognoses from a liver standpoint, treatments aimed at improving liver disease 
should be limited to those with NASH.1  
 
Life-style modifications are effective but adherence is difficult to maintain.17 Bariatric 
surgery can be performed in selective obese patients, but is too drastic to be the treatment 
of choice and thus it is not recommended for treating NASH.18 Vitamin E has been 
effective in treating nondiabetic NASH patients without cirrhosis.19 The long-term safety 
and efficacy of pioglitazone are not clear in NASH.20, 21 Metformin22, ursodeoxycholic 
acid, omega 3 fatty acids, and statins are not considered as therapy for NAFLD/NASH 
patients.1, 21 
 
 

 
Page 3 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
TYPE 2 DIABETES and NAFLD/NASH 
 
Type 2 DM involves failure of the action and utilization of insulin within the body. Type 
2 sufferers have an endogenous resistance to insulin. The disease appears when they fail 
to manufacture sufficient insulin levels to overcome this resistance. This relative lack of 
insulin eventually leads to chronic hyperglycemia. 
 
Traditionally, type 2 was known as “adult-onset diabetes” (with type 1 being referred to 
as “juvenile-onset” diabetes) as it generally struck adults, usually overweight, of age 45 
and over. However, in recent years, the incidence of type 2 DM has skyrocketed—to the 
extent that it is now being termed a global “pandemic.” Type 2 DM is strongly correlated 
with obesity, and so this disproportionate increase is considered a reflection of the twin 
ills of modern life—overeating/obesity and decreased physical activity. 
 
The 2014 CDC National Diabetes Statistics Report estimated that 29.1 million people or 
9.3% of the US population have diabetes; 21 million diagnosed and 8.1 million 
undiagnosed.23 Another 86 million (37% of US adults aged 20 years and older) people 
were estimated to suffer from pre-diabetes, a condition that increases the risk of 
developing type 2 DM—the more common form of the disease—as well as heart disease 
and stroke. 
 
Comparable statistics may be found in both developed and developing countries around 
the world as the frequency of diabetes continues to rise. Global prevalence of diabetes is 
now estimated at more than 380 million, or about 8% of the worldwide adult population 
according to the International Diabetes Federation. Type 2 DM represents 85-95% of 
both present and future cases.24 
 
As noted above, the prevalence of NAFLD can be as high as 90–95% in obese 
individuals and up to 70% of patients with type 2 DM develop NAFLD.25 In addition, 
they share similarities in their risk factors, pathogenic mechanisms and complications. 
 
INSULIN TREATMENT  
 
There is no known cure for diabetes. Treatment of the disease requires constant care and 
monitoring, along with some form of insulin or drug therapy coupled with diet and 
exercise.  
 
Patients with type 2 DM have generally been prescribed a diet and exercise program as 
well as oral medication in order to control blood glucose levels. However, diet and oral 
hyperglycemic agents have failed to provide a satisfactory control of type 2 DM in a 
progressively larger proportion of these patients. Therefore, there is now an increasing 
trend to treat type 2 diabetic patients with insulin as well, in order to avoid the potential 
complications from hyperglycemia. 
 
 
 

 
Page 4 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
 
New Approaches To Insulin Therapy 
 
In the past decade, several major studies (DCCT, UKPDS and others) have focused 
attention on the need for strict control of glycemia to prevent and/or reduce the risk of 
both the specific microvascular and the less specific macrovascular complications.26,27 
The mounting numbers of type 2 sufferers worldwide, coupled with the growing 
tendency to treat this form of diabetes with insulin therapy, means that there are currently 
millions of individuals, adults as well as children, who must inject themselves several 
times each day throughout their entire lives. Injections are painful, inconvenient, and 
frightening for many patients. Over time reluctance to carry out injections increases and 
many patients become non-adherent to therapy. 
 
In addition, the subcutaneous administration of insulin does not provide, in most cases, 
the fine continuous metabolic regulation that occurs normally with insulin secreted from 
the pancreas directly into the liver via the portal vein. 
 
An ideal solution for treating these diabetics would be to transplant healthy insulin 
producing cells (pancreatic islets) into the patient. However, direct transplantation has not 
yet been practical. The immune system of the recipient recognizes the cells as foreign and 
rejects them. The side effects of drugs necessary to suppress the immune system are too 
severe to justify their use in otherwise healthy patients. 
 
Consequently, research is underway to develop a new and different approach that would 
both improve the administration of insulin and provide a way by which the hormone can 
reach the liver in a physiological manner, namely, oral administration of insulin. 
 
ORAL ADMINISTRATION OF INSULIN 
 
Insulin injections are, intrinsically unpleasant and patients may cease to perform them, 
leading to a multitude of possible complications. In addition, subcutaneous injection is 
not the most physiologically efficient mode of insulin transfer to the body. Hence, the 
search for an oral form of insulin has been underway since Banting and Best’s discovery 
of insulin in 1922. Oral insulin would free patients of the pain and inconvenience of 
injections while providing a more physiologically advantageous route of administration.  
 
Proposed Mechanism 
 
Any attempt to develop an oral insulin modality must take into account two major 
obstacles that result from insulin’s biochemical characteristics as a polypeptide: 1) Its 
direct transfer across the mucosal barrier is restricted; 2) it is subject to degradation by 
the proteolytic enzymes located in the stomach and intestinal lumen.  
 
To overcome these barriers, Oramed has proposed a mechanism to prevent the digestion 
of the introduced hormone in the gastrointestinal tract and to facilitate its physiological 
absorption. After performance of a range of studies for optimization of co-factors to 

 
Page 5 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
prevent the digestion of insulin, Oramed has identified the most efficacious formulation 
of encapsulated oral insulin. The proposed composition contains: (1) crystalline insulin, 
(2) EDTA as enhancer, (3) soybean trypsin (SBTI), and (4) omega 3-rich fish oil, in a 
coated capsule. These components are expanded upon in greater detail below. Each has a 
target function, which promotes the goals of our treatment modality. The chelating agent 
EDTA functions as an effective enhancer of the mixture. The SBTI prevents enzymatic 
degradation of the insulin by mucosal enzymes. 
 
Modality Components 
 
Insulin: 
Structure: 
Insulin is a polypeptide hormone produced by cells in the islets of Langerhans in 
the pancreas. Human insulin consists of two different peptide chains, the A 
(acidic) chain of 21 amino acids and the B (basic) chain of 30 amino acids, 
connected by two disulfide bridges. The A chain contains a third disulfide bond.  
 
 
The structure of insulin: The left hand side of the panel is a space-filling model of the insulin 
monomer, believed to be biologically active. Carbon is green, hydrogen white, oxygen red, and 
nitrogen blue. On the right hand side is a cartoon of the hexamer, believed to be the stored form. 
A monomer unit is highlighted with the A chain blue and the B chain cyan. Yellows denote 
disulfide bonds, and magenta spheres are zinc ions. 
Source: Created by Isaac Yonemoto.  Created with Pymol, Inkscape, and Gimp from NMR structure 1ai0 in the pdb. Ref: Chang, X., 
Jorgensen, A.M., Bardrum, P., Led, J.J. 
 
ORAL INSULIN FOR NAFLD/NASH 
 
The similarities between type 2 DM and NAFLD/NASH in risk factors, pathogenic 
mechanisms and complications suggest common approaches to therapeutic intervention. 
Recall that 70% of type 2 DM patients will develop NAFLD/NASH and that 85% of new 
cases of diabetes will be type 2 patients. The key component of insulin resistance shared 
by diabetes and NAFLD/NASH makes direct insulin intervention an attractive option. 
The oral insulin formulation has the potential advantage of first pass metabolism in the 
liver allowing local availability and concentration of insulin at the affected liver fat cells. 
 

 
Page 6 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
ORAL INSULIN DEMONSTRATIONS OF EFFICACY IN TYPE 2 DIABETES 
 
Oramed’s research and development team has performed multiple studies on pigs and 
canines over the last decade. The studies were designed to optimize the composition and 
functionality of our oral insulin modality and to demonstrate its safety and efficacy for 
use in animals and humans. The completed studies in humans are briefly described in 
Appendix A. 
 
ORA-H-N01 NASH STUDY DESIGN 
 
This is an open, pilot study using the oral ORMD-0801 insulin formulation in patients 
with NASH and confirmed type 2 DM. The study will consist of a Screening, Placebo 
run-in, Treatment Phase and End-of-Study Phase.  
 
 
STUDY OBJECTVIES  
 
Primary Objective 
• To evaluate the safety of oral insulin in patients with nonalcoholic 
steatohepatitis (NASH) and type 2 DM. 
 
Secondary Objective 
• To assess whether oral insulin may be effective in reducing liver fat content and 
inflammation in patients with NASH and type 2 DM. 
 
 
Study Duration 
 
Screening Phase: up to 14 days prior to placebo run-in period 
Placebo run-in Phase: 2 weeks  
Treatment Phase: 12 weeks 
End-of-Study (EOS): After completion of 4 weeks after end of treatment 
 
Study Population and Size 
 
This exploratory study will first enroll 10 patients with NASH and type 2 DM.  
At the completion of their 4-week follow-up period, results will be presented to the 
Helsinki Committe. Following approval, an additional 20 patients will be enrolled.  The 
size of the study population was determined by the investigator (with literature review) to 
be sufficient to show trends of reducing liver fat content by MRI PDFF (MRI-Proton 
Density Fat Fraction) images, the FibroMax Test  and Fibroscan including CAP. 
 
 
 
 
 

 
Page 7 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
Inclusion Criteria: 
 
1. Male or female aged 18-70 years. 
2. BMI ≥25  
3. Known type 2 DM according to American Diabetic Association (one of the three 
needed): Fasting Plasma Glucose ≥126 mg/dl or 2h postprandial (PG) following 
75g OGTT ≥200 mg/dl or HbA1C > 5.7%28 or on treatment with metformin 
4. Abdominal ultrasound (US) proven fatty liver performed within 6 months before 
randomization. 
5. Fat concentration in the liver of S2 (moderate steatosis, 6–32% hepatocytes with 
steatosis) or more as measured by Fibromax (SteatoTest and NASHTest 
Components, BioPredictive, Paris, France29).1 Or MRI PDFF >10%.  
6. Liver enzyme abnormalities: Up to 5 times ULN. 
7. Evidence of ≥stage 3 fibrosis, as determined by FibroScan 
8. Signature of the written informed consent. 
9. Negative pregnancy test at study entry for females of child bearing potential. 
10. Females must have a negative urine pregnancy test result at screening, prior to the 
start of the run-in period, and at initiation of active dosing. A negative urine and 
serum pregnancy test must be obtained prior to active dosing. Males and females 
of childbearing potential must use two methods of contraception (double barrier 
method), one of which must be an acceptable barrier method from the time of 
screening to the last study visit (12 weeks). Barrier methods of contraception 
include male condoms plus spermicide, diaphragm with spermicide plus male 
condom, cap with spermicide plus male condom, or oral contraceptives. 
Acceptable methods of birth control include abstinence, oral contraceptives, 
surgical sterilization, vasectomy, the contraceptive patch, and the contraceptive 
ring. If a subject is not usually sexually active but becomes active, he or his 
partner should use medically accepted forms of contraception. Sperm donations 
will not be allowed for the duration of the study and for 90 days after the last dose 
of study drug. 
Females of non-childbearing potential are defined as postmenopausal who a) had 
more than 24 months since last menstrual cycle with menopausal levels of FSH, 
b) who are surgically menopausal (surgical sterility defined by tubal occlusion, 
bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
11. For hypertensive patients, hypertension must be controlled by stable dose of anti-
hypertensive medication for at least 2 months prior to screening (and the stable 
dose can be maintained throughout the study) with BP < 150/<95 mmHg 
12. Patients previously treated with vitamin E (>400IU/day), Polyunsaturated fatty 
acid (>2g/day) or Ursodeoxycholic acid fish oil can be included if drugs are 
stopped at least 3 months prior to diagnostic liver biopsy and up to the end of the 
study. 
13. Glycaemia must be controlled (Glycosylated Hemoglobin A1C ≤8.5%) while any 
HbA1C increment should not exceed 1% during 6 months prior to enrolment). 
                                                 
1 FibroMax consists of algorithms based on results from the following set of biochemical tests: alpha-2 
macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, ALT, AST, GGT, fasting glucose, 
triglycerides and total cholesterol. See Poynard, et al., 2005 for discussion of diagnostic value.  

 
Page 8 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
 
 
Exclusion Criteria 
 
1. Patients with active (acute or chronic) liver disease other than NASH (e.g. viral 
hepatitis, genetic hemochromatosis, Wilson disease, alpha-1 antitrypsin 
deficiency, alcohol liver disease, drug induced liver disease) at the time of 
randomization. 
2. ALT or AST > 5 times ULN 
3. Abnormal synthetic liver function (serum albumin ≤3.5gm%, INR >1.3). 
4. Known alcohol and/or any other drug abuse or dependence in the last five years. 
5. Weight >120 Kg 
6. Known history or presence of clinically significant, cardiovascular, 
gastrointestinal, metabolic (other than diabetes mellitus), neurologic, pulmonary, 
endocrine, psychiatric, neoplastic disorder or nephrotic syndrome. 
7. History or presence of any disease or condition known to interfere with the 
absorption, distribution, metabolism or excretion of drugs including bile salt 
metabolites (e.g. inflammatory bowel disease (IBD), previous intestinal (ileal or 
colonic) operation, chronic pancreatitis, celiac disease or previous vagotomy. 
8. Weight loss of more than 5% within 6 months prior to randomization. 
9. History of bariatric surgery. 
10. Uncontrolled blood pressure BP ≥150/≥95. 
11. Non type 2 DM (type 1, endocrinopathy, genetic syndromes etc). 
12. Patients with HIV. 
13. Daily alcohol intake >20 g/day for women and >30 g/day for men. 
14. Treatment with anti-diabetic medications other than metformin, such as 
sulfonylurea, DPP-4 inhibitors, GLP-1 receptor agonists, TZDs, etc. 
15. Metformin, fibrates, statins, not provided on a stable dose in the last 6 months. 
16. Patients who are treated with valproic acid, Tamoxifen, methotrexate, 
amiodarone. 
17. Chronic treatment with antibiotics (e.g. Rifaximin). 
18. Homeopathic and/or Alternative treatments. Any treatment must be stopped 
before the screening period.  
19. Uncontrolled hypothyroidism defined as Thyroid Stimulating Hormone >2X the 
upper limit of normal (UNLN). Thyroid dysfunction controlled for at least 6 
months prior to screening is permitted. 
20. Patients with renal dysfunction: eGFR< 40 ml/min. 
21. Unexplained serum creatinine phosphokinase (CPK) >3X the upper limit of 
normal (UNL). Patients with a reason for CPK elevation may have the 
measurement repeated prior to randomization; a CPK retest > 3X ULN leads to 
exclusion. 
 
 
 
STUDY PERIODS 
 

 
Page 9 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
The following parameters will be measured and recorded taken at each of the visits, 
as specified below:  
  
 
Screening Phase 
 
Screening process will take place at Visit 1, up to 14 days prior to placebo run in 
treatment.   
 
Visit 1 (up to week -4) 
• Medical history  
• Medication history 
• Complete Physical examination (PE)  
• ECG 
• Vital signs (blood pressure, heart rate). Vital signs will be measured in the sitting 
position after at least 5 minutes of rest.   
• Clinical laboratory evaluations 
o Chemistry: Electrolytes, BUN, creatinine, glucose level, liver function 
tests (LFT) including transaminases (ALT, AST), albumin, and alkaline 
phosphatases, creatine phosphokinase (CPK) 
o Hematology: Complete blood count (CBC)  
 
 
Run-in Phase (to week -2) 
 
The run-in phase will consist of 2 weeks period starting at visit (Visit 2) week -2  
 
Visit 2 
• Informed consent 
• Medication history 
• Brief physical examination 
• Treatment (run in placebo) 
• Vital Signs 
• Self-monitored fasting morning blood glucose (finger-stick) of fasting blood 
glucose will be recorded in the patient diaries 3 days weekly in the morning. 
 
 
 
 
 
 
Treatment Phase (week 0) 
 
The Treatment Phase will consist of a treatment period of 12 weeks that will start at visit 
3 (week 0) and outpatient visits at week 1, 2, 4, 8, and 12 (final visit).  
At each visit patients will have 

 
Page 10 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
 
• Medication history 
• Brief Physical examination (PE)- at Visits 4,5, 6, and 7 
• Treatment  
• Medication Compliance  
• Vital signs (blood pressure, heart rate). Vital signs will be measured in the sitting 
position after at least 5 minutes of rest. 
 
At Visits 3 (baseline), 6, 7, and 8, patients will have  
• Clinical laboratory evaluations (chemistry, hematology) 
• Fasting blood glucose and insulin (also used for HOMA estimates)2 
• Self-monitored fasting morning blood glucose (finger-stick) of fasting blood 
glucose will be recorded in the patient diaries 3 days weekly in the morning. 
• Adiponectin 
 
At Visits 3 and 8 Patients will have 
• Complete PE 
• FibroMax Test 
• Fibroscan 
• MRI PDFF 
 
End-of-Study (EOS) (week 16) /Early Discontinuations  
 
The EOS visit (Visit 9) will be conducted 4 weeks following the last scheduled treatment 
visit. Patients will complete the following EOS evaluations: 
• Medication history 
• Complete PE, only if the investigator deems it necessary. 
• EOS ECG, only if the investigator deems it necessary. 
• Vital signs (blood pressure, heart rate) will be measured in the sitting position 
after at least 5 minutes of rest, only if the investigator deems it necessary.   
• Clinical laboratory evaluations (chemistry, hematology) 
• Fasting blood glucose 
• Fasting blood Insulin 
• Adiponectin 
 
Patients who are discontinued early from the study will complete the EOS evaluations at 
the time of early discontinuation. 
 
 
Unscheduled visit  
The patient may be required to return for an unscheduled visit for a repeat measurement 
of fasting blood glucose, if the investigator deems it necessary.   
 
                                                 
2 HOMA = The Homeostasis Model Assessment 

 
Page 11 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
Self-Monitoring Fasting Blood Glucose and Patient Diaries 
 
All patients will self-monitor fasting morning blood glucose levels three (3) times weekly 
during the run-in and treatment period.  Monitoring must be performed at the same time 
each designated day (± 10 minutes) prior any caloric intake.  Patients will be required to 
record the values in a patient diary and bring the diary to each clinic visit; Information 
recorded for the fasting blood glucose will be reviewed by the clinical research 
coordinator for completeness and transcribed onto CRF’s. During the study, both fasting 
finger stick glucose and laboratory fasting plasma glucose will be obtained. 
 
If a fasting blood glucose measures greater than or equal to 270 mg/dL (15 mmol/L) 
during daily self-monitoring or during any in-clinic visit, the patient will be required to 
contact the clinic to report the value.  Blood will be drawn and sent to lab for plasma 
glucose determination.   The patient may be required to return for an unscheduled visit to 
the clinic for a repeat measurement of fasting blood glucose within one week after the 
original measurement.   If the repeat measurement is also greater than or equal to 270 
mg/dL, the patient will be discontinued from treatment with study drug and offered 
rescue medication.  The patient will continue to be seen for all remaining study visits, if 
possible. 
 
Fingerstick glucose values of <50 mg/dL (2.78 mmol/L) should be confirmed by 
laboratory plasma glucose measurements and if three or more are observed within 12 
hours subsequent to administration of study drug without a reasonable explanation (such 
as increased physical activity and/or skipped meal), the patient will be discontinued from 
treatment with study drug and rescued with glucose administration (20g of glucose 
tablets) which will be available at all times at the study site.  This information will be 
recorded in the patient’s diary and the patient will be instructed to contact the study site if 
this occurs.  The patient will continue to be seen for all remaining study visits. 
Sites will instruct patients to immediately perform a finger stick glucose measurement if 
any symptoms occur that may be related to hypoglycemia (e.g., weakness, dizziness, 
shakiness, increased sweating, palpitations, or confusion), and to avoid delay in treating 
these symptoms.  The measurements will be recorded in the patient diary. Patients will 
always carry glucose tablets with them and ingests 3-4 tablets if hypoglycemia occurs. 
 
Hypoglycemia and associated symptoms (e.g., weakness, dizziness, shakiness, increased 
sweating, palpitations, or confusion), have been associated with insulin administration, 
including ORMD-0801. 
 
 
 
 
 
 
 
 

 
Page 12 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
Table 1: Schedule of Assessments 
Assessments 
Screening 
Placebo 
 
Treatment 
 
Un Scheduled 
Visit  
End-of-Study / 
Early 
Termination 
Week 
up to -4 
-2 
0 
1 
2 
4 
8 
12 
Not Defined 
16 
Days 
Up to -28 
-14 
7± 
2 
7±
2 
14±
2 
28±
2 
56±
2 
84±
2 
 
112±2 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Un 
Scheduled  
9 
Written informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Medication history 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Complete 
physical 
examination 
X 
 
X 
 
 
 
 
X 
 
(X1 ) 
Brief physical 
examination 
 
X 
X 
X 
X 
X 
X 
 
 
 
Treatment  
 
X 
X 
X 
X 
X 
X 
 
 
 
Medication 
compliance check 
 
 
X 
X 
X 
X 
X 
X 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
(X1 ) 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X1 ) 
Clinical laboratory 
evaluations2 
X 
 
X 
 
 
X 
X 
X 
(X1 ) 
X 
Fasting blood 
glucose3 
 
X 
X 
 
 
X 
X 
X 
(X1 ) 
X 
Fasting Insulin3 
 
X 
X 
 
 
X 
X 
X 
 
X 
Self-monitored 
fasting morning 
blood glucose4 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Adiponectin 
 
 
X 
 
 
X 
X 
X 
 
X 
FibroMax Test 
 
 
X 
 
 
 
 
X 
 
 
Fibroscan Test 
 
 
X 
 
 
 
 
X 
 
 
MRI PDFF 
 
 
 
X 
 
 
 
 
X 
 
 
1Only if investigator deems necessary 
2Chemistry (electrolytes, BUN, creatinine, glucose, LFTs) and CBC 
3Fasting blood glucose and insulin will be used to determine HOMA estimates. 
4Self-monitoring (finger-stick) of fasting blood glucose will required 3 days weekly in the morning and recorded in patient 
diaries. 
 
TREATMENT REGIMEN 
 
The treatment regimen will consist of a soft gelatin capsule containing 8 mg insulin, and 
75 mg SBTI. Patients will take 2 capsules daily in the morning with or without food. 
 

 
Page 13 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
SAFETY EVALUATIONS 
 
See complete instructions about Safety and Adverse Events evaluation and reporting in 
Appendix B.  
 
• Adverse events will be collected throughout the study beginning from the time the 
patient signs the consent form until the EOS evaluations  
• Concomitant medications/therapies will be recorded throughout the duration of 
study, beginning from the time the patient signs the informed consent.  
• Vital signs (blood pressure, heart rate) will be measured in the sitting position 
after at least 5 minutes of rest at all visits 
• Clinical laboratory evaluations (chemistry, hematology) will be performed at 
screening and at weeks 0, 4, 8, 12, and 16. 
• Treatment of significant hyperglycemia, will be tailored to the medical history 
and needs of the patient, as per recommended treatment guidelines. 
• Symptomatic hypoglycemia - Hypoglycemia as noted by a feeling of 
hypoglycaemia with concomitant blood glucose measurements below 70.  
o All occurrences of hypoglycemia will be treated with orange juice, 3-4 
glucose tablets, or a 20% glucose solution via an I.V. bolus injection over 
1 to 2 minutes and the subject will be monitored until symptoms have 
resolved. 
o If three or more finger stick glucose values of <50 mg/dL (2.78 mmol/L) 
are observed in one week within 12 hours subsequent to administration of 
study drug without a reasonable explanation (such as increased physical 
activity and/or skipped meal), the patient will be discontinued from 
treatment with study drug. This information will be recorded in the 
patient’s diary and the patient will be instructed to contact the study site if 
this occurs. The patient will continue to be seen for all remaining study 
visits. 
o The site will instruct patients to immediately perform a finger stick 
glucose measurement if any symptoms occur that may be related to 
hypoglycemia (e.g., weakness, dizziness, shakiness, increased sweating, 
palpitations, or confusion), and to avoid delay in treating these symptoms. 
The measurements will be recorded in the patient diary.  
o Patients will always carry glucose tablets with them and ingests 3-4 tablets 
if hypoglycemia necessitates it.  
 
 
 

 
Page 14 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
REFERENCES 
 
1. 
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of 
non-alcoholic fatty liver disease: practice Guideline by the American Association for the 
Study of Liver Diseases, American College of Gastroenterology, and the American 
Gastroenterological Association. Hepatology. 2012;55(6):2005-23. 
2. 
Ratziu V, Bellentani S, Cortez-Pinto H, et al. A position statement on 
NAFLD/NASH based on the EASL 2009 special conference. Journal of hepatology. 
2010;53(2):372-84. 
3. 
Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and 
natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in 
adults. Alimentary pharmacology & therapeutics. 2011;34(3):274-85. 
4. 
Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Alimentary 
pharmacology & therapeutics. 2007;25(8):883-9. 
5. 
de Ledinghen V, Ratziu V, Causse X, et al. Diagnostic and predictive factors of 
significant liver fibrosis and minimal lesions in patients with persistent unexplained 
elevated transaminases. A prospective multicenter study. Journal of hepatology. 
2006;45(4):592-9. 
6. 
Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated 
liver function tests during a 28-year follow-up. Hepatology. 2010;51(2):595-602. 
7. 
Campos GM, Bambha K, Vittinghoff E, et al. A clinical scoring system for 
predicting nonalcoholic steatohepatitis in morbidly obese patients. Hepatology. 
2008;47(6):1916-23. 
8. 
Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese 
patients undergoing bariatric surgery. Journal of hepatology. 2006;45(4):600-6. 
9. 
Weston SR, Leyden W, Murphy R, et al. Racial and ethnic distribution of 
nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. 
Hepatology. 2005;41(2):372-9. 
10. 
Pappachan JM, Antonio FA, Edavalath M, et al. Non-alcoholic fatty liver disease: 
a diabetologist's perspective. Endocrine. 2014;45(3):344-53. 
11. 
Finucane MM, Stevens GA, Cowan MJ, et al. National, regional, and global 
trends in body-mass index since 1980: systematic analysis of health examination surveys 
and epidemiological studies with 960 country-years and 9.1 million participants. Lancet. 
2011;377(9765):557-67. 
12. 
Pappachan MJ. Increasing prevalence of lifestyle diseases: high time for action. 
The Indian journal of medical research. 2011;134:143-5. 
13. 
Bellentani S, Marino M. Epidemiology and natural history of non-alcoholic fatty 
liver disease (NAFLD). Annals of hepatology. 2009;8 Suppl 1:S4-8. 
14. 
Brindisi MC, Guiu B, Duvillard L, et al. Liver fat content is associated with an 
increase in cholesterol synthesis independent of statin therapy use in patients with type 2 
diabetes. Atherosclerosis. 2012;224(2):465-8. 
15. 
Kotronen A, Juurinen L, Tiikkainen M, et al. Increased liver fat, impaired insulin 
clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. 
Gastroenterology. 2008;135(1):122-30. 
16. 
Malinowski SS, Byrd JS, Bell AM, et al. Pharmacologic therapy for nonalcoholic 
fatty liver disease in adults. Pharmacotherapy. 2013;33(2):223-42. 

 
Page 15 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
17. 
Benjamin SM, Valdez R, Vinicor F. Diabetes prevention. The New England 
journal of medicine. 2002;346(23):1829-30; author reply -30. 
18. 
Lassailly G, Caiazzo R, Pattou F, et al. Bariatric surgery for curing NASH in the 
morbidly obese? Journal of hepatology. 2013;58(6):1249-51. 
19. 
Bell LN, Wang J, Muralidharan S, et al. Relationship between adipose tissue 
insulin resistance and liver histology in nonalcoholic steatohepatitis: a pioglitazone 
versus vitamin E versus placebo for the treatment of nondiabetic patients with 
nonalcoholic steatohepatitis trial follow-up study. Hepatology. 2012;56(4):1311-8. 
20. 
Mahady SE, Wong G, Craig JC, et al. Pioglitazone and vitamin E for 
nonalcoholic steatohepatitis: a cost utility analysis. Hepatology. 2012;56(6):2172-9. 
21. 
Dufour JF, Oneta CM, Gonvers JJ, et al. Randomized placebo-controlled trial of 
ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clinical 
gastroenterology and hepatology : the official clinical practice journal of the American 
Gastroenterological Association. 2006;4(12):1537-43. 
22. 
Schwimmer JB, Middleton MS, Deutsch R, et al. A phase 2 clinical trial of 
metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. 
Alimentary pharmacology & therapeutics. 2005;21(7):871-9. 
23. 
National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the 
United States. Atlanta, GA, US Department of Health and Human Services: Centers for 
Disease Control and Prevention; 2014. 
24. 
Federation ID. IDF Diabetes Atlas. Brussels, Belgium: International Diabetes 
Federation; 2013 [cited 2014 November]; 6th edn.:[Available from: 
http://www.idf.org/diabetesatlas. 
25. 
Bellentani S, Scaglioni F, Marino M, et al. Epidemiology of non-alcoholic fatty 
liver disease. Digestive diseases. 2010;28(1):155-61. 
26. 
The effect of intensive treatment of diabetes on the development and progression 
of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control 
and Complications Trial Research Group. The New England journal of medicine. 
1993;329(14):977-86. 
27. 
Intensive blood-glucose control with sulphonylureas or insulin compared with 
conventional treatment and risk of complications in patients with type 2 diabetes 
(UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 
1998;352(9131):837-53. 
28. 
Association AD. Standards of Medical Care in Diabetes—2014. Diabetes care. 
2014;37(Supplement 1):S14-S80. 
29. 
Poynard T, Ratziu V, Charlotte F, et al. Diagnostic value of biochemical markers 
(NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-
alcoholic fatty liver disease. BMC gastroenterology. 2006;6:34. 
 
 
 

 
Page 16 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
APPENDIX A: Studies of Oramed Oral Insulin in Humans 
 
Phase 1A Clinical Trial 
 
The encouraging outcome of the pre-clinical studies set the stage for Phase 1a clinical 
trials that evaluated oral insulin on eight healthy male volunteers during four separate 
visits. The study was completed in August of 2007. The results of this study clearly 
demonstrated that the insulin administered by Oramed’s capsules was absorbed and 
retained its biologically activity. Additionally, it exhibits unique PK and PD effects 
characterized by the delayed onset of action and a prolonged metabolic effect as 
compared with other oral or inhaled formulations currently under study. 
 
Phase 1B Clinical Trial 
 
Oramed then continued with a formulation optimization (Phase 1b) clinical trial which 
included eight healthy male volunteers studied during five visits. The trials were 
completed in March of 2008 and the results showed again that insulin combined with 
Oramed’s drug delivery enhancers and formulated in a capsule dosage form was absorbed 
and resulted in plasma glucose reduction, a decrease in c-peptide and an increase in 
insulin. A lead formulation was identified as a result of this study. 
 
Phase 2A– Type 2 Diabetes Mellitus Clinical Trial 
 
In August 2008, Oramed completed Phase 2a clinical trials of ORMD 0801. The trial 
included ten Type 2 diabetic patients studied over the course of seven visits. The goal of 
these trials was to evaluate the safety and efficacy of oral insulin on patients with 
diabetes.  The results of this clinical trial showed that Oramed’s oral insulin capsule can 
effectively deliver insulin to people with diabetes and result in lowering blood glucose 
levels. Furthermore oral insulin (ORMD 0801) was found safe and was well tolerated. 
 

 
Page 17 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
 
 
Figures A-D: A. Representative glucose and insulin recordings of an ORMD 0801 responder over the 5hrs 
of testing.  B. Representative glucose and insulin recordings of a placebo-treated subject over the 5 hrs of 
testing.  C. Representative c-peptide and insulin recordings of an ORMD 0801 responder.  D. AUC120-180 
and AUC180-240 calculations presented as ratios of AUC0-60 of both glucose and c-peptide levels 
following ORMD 0801 and placebo treatments. 
 
Phase 2A– Type 1 Diabetes Mellitus – Clinical Trial 
 
Oramed then proceeded with a Phase 2A clinical trial assessing the safety, tolerability 
and food effect study of ORMD-0801, in patients with type 1 diabetes.  ORMD-0801 was 
well tolerated by patients with Type 1 diabetes mellitus and no adverse events were 
encountered during the study. The insulin absorption was not perturbed when given 
shortly (10 minutes) before meal ingestion. 
 
 
 

 
Page 18 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
 
 
 
 
 
 
 
 
Figure 1.  ORMD 0801 levels after administration of two single-dose capsules:  Subjects were 
administered two capsules of a specific ORMD 0801 formulation at three independent treatment sessions.  
Meals were served either 10, 45 or 90 minutes post-administration.  Blood samples were drawn throughout 
the monitoring sessions and insulin levels were measured.  Moving averages of normalized insulin 
recordings were graphed as a function of time. 
 
Figure 2. Averaged normalized glucose readings 
for all seven subjects: Two glucose recordings were 
obtained for each subject at each blood sample 
drawing.  An average was calculated and moving 
averages were determined for each individual subject 
for each treatment session.  An average of the moving 
averages of all seven subjects was then computed and 
graphed as glucose readings as a function of time. 
 
 
 
 
 
 
Figure 3. Classic influential relationship of insulin 
on post-meal glucose levels: Moving averages of 
insulin and glucose levels of subject #7 were co-plotted 
to illustrate the temporal relationship between the 
insulin peak and glucose rise and decline post-meal 
served 10 minutes after drug administration 
 
 
 
 
 
 
 
 
Subject 3 -
-50
-40
-30
-20
-10
0
10
20
30
40
0
100
200
300
time (min)
insulin
v
Subject 6
-25
-20
-15
-10
-5
0
5
10
15
20
0
100
200
300
time (min)
insulin
Subject 7
0
2
4
6
8
10
12
14
16
18
20
0
100
200
300
time (min)
insulin
Subject 8
-60
-40
-20
0
20
40
60
80
100
120
0
100
200
300
time (min)
insulin
Subject 9
-25
-20
-15
-10
-5
0
5
0
100
200
300
time (min)
insulin
Subject 4
-6
-4
-2
0
2
4
6
8
10
0
100
200
300
time (min)
insulin
Subject 5
0
20
40
60
80
100
120
140
160
0
100
200
300
time (min)
insulin
meal 45 min post-ORMD 0801
meal 10 min post-ORMD 0801
meal 90 min post-ORMD 0801
time (min)
time (min)
time (min)
time (min)
time (min)
time (min)
time (min)
Subject 3 -
-50
-40
-30
-20
-10
0
10
20
30
40
0
100
200
300
time (min)
insulin
v
Subject 6
-25
-20
-15
-10
-5
0
5
10
15
20
0
100
200
300
time (min)
insulin
Subject 7
0
2
4
6
8
10
12
14
16
18
20
0
100
200
300
time (min)
insulin
Subject 8
-60
-40
-20
0
20
40
60
80
100
120
0
100
200
300
time (min)
insulin
Subject 9
-25
-20
-15
-10
-5
0
5
0
100
200
300
time (min)
insulin
Subject 4
-6
-4
-2
0
2
4
6
8
10
0
100
200
300
time (min)
insulin
Subject 5
0
20
40
60
80
100
120
140
160
0
100
200
300
time (min)
insulin
meal 45 min post-ORMD 0801
meal 10 min post-ORMD 0801
meal 90 min post-ORMD 0801
time (min)
time (min)
time (min)
time (min)
time (min)
time (min)
time (min)
-20
0
20
40
60
80
100
120
0
100
200
300
time (min)
Glucose 
meal 10 min post-ORMD 0801
meal 90 min post-ORMD 0801
meal 45 min post-ORMD 0801
-20
0
20
40
60
80
100
120
0
100
200
300
time (min)
Glucose 
-20
0
20
40
60
80
100
120
0
100
200
300
time (min)
Glucose 
meal 10 min post-ORMD 0801
meal 90 min post-ORMD 0801
meal 45 min post-ORMD 0801
time (min)
0
5
10
15
-80
-60
-40
-20
0
20
40
0
100
200
300
insulin
glucose
time (min)
0
5
10
15
-80
-60
-40
-20
0
20
40
0
100
200
300
0
5
10
15
-80
-60
-40
-20
0
20
40
0
100
200
300
insulin
glucose

 
Page 19 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
 
Figure 4. Slight plasma insulin peaks suffice for 
post-meal glucose concentration regulation: 
Moving averages of insulin and glucose levels of 
subject #8 were co-plotted to illustrate the temporal 
relationship between the insulin peak and glucose 
rise and decline post-meal served 45 minutes after 
drug administration 
 
 
 
 
 
In contrast, subjects with undetectable insulin levels following ORMD 0801 
administration, demonstrated elevation of blood sugar concentrations following food 
consumption, with slow or no (Figure 5) significant decrease within the 360 minute 
monitoring session. 
 
 
Figure 5. Glucose levels follwoing undetectable 
insulin peaks: Moving averages of insulin and 
glucose levels of subject #9 were co-plotted to 
illustrate the lack of decline in postmeal glucose 
concentrations despite drug administration. 
 
 
 
 
 
 
 
Phase IIb – Type 2 Diabetes Mellitus - Clinical Trial 
 
This multi-site, placebo-controlled, randomized, double-blinded study, conducted in 
South Africa, focused on the responses of 29 Type II diabetes (T2DM) patients to 
ORMD-0801.  Volunteers received a once-daily, fixed dose of oral insulin capsules (8 
mg/capsule, 2 capsules = 16 mg/day) for a period of six weeks.  Three of the subjects 
were otherwise on diet, while 27 were on diet+Metformin (≥ 2.5 g/day) diabetes 
management programs before the study. The primary objective of this trial was to assess 
the safety and tolerability of the investigational product, by monitoring adverse events, 
hypoglycemia and other safety parameters throughout the study.  Secondary endpoints 
evaluated the effectiveness of ORMD-0801 in providing glycemic control, as determined 
by comparison of baseline fasting blood glucose (FBG), insulin, fructosamine, c-peptide, 
C-reactive protein (CRP) and Hb1Ac levels to those measured after the 6-week treatment 
period.  
 
The 6-week ORMD-0801 treatment regimen proved safe and tolerable, with no reports of 
serious AEs throughout the study period.  No cumulative effects of extended exposure to 
time (min)
0
100
200
300
-60
-50
-40
-30
-20
-10
0
10
20
-40
-20
0
20
40
60
insulin
glucose
time (min)
0
100
200
300
-60
-50
-40
-30
-20
-10
0
10
20
-40
-20
0
20
40
60
0
100
200
300
0
100
200
300
-60
-50
-40
-30
-20
-10
0
10
20
-40
-20
0
20
40
60
insulin
glucose
insulin
glucose
0
100
200
300
-14
-12
-10
-8
-6
-4
-2
0
time (min)
-20
0
20
40
60
80
100
120
140
160
insulin
glucose
0
100
200
300
0
100
200
300
-14
-12
-10
-8
-6
-4
-2
0
time (min)
-20
0
20
40
60
80
100
120
140
160
insulin
glucose

 
Page 20 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
ORMD-0801 were observed, and only two mild hypoglycemic events were recorded in 
patient diaries (Table 1). 
 
Table 1: Adverse Events ORMD-0801 Cohort* 
 
Event 
Severity 
Action 
Outcome 
Notes 
Hypoglycaemia 
Mild 
Dose not changed 
Recovered 
Blood sugar: 12.0 
mmol/L 
Hypoglycaemia 
Unknown 
Unknown 
Unknown 
Hypoglycaemic on 
clinical symptoms 
Constipation 
Mild 
Dose not changed 
Not recovered 
 
Diarrhoea and skin rash 
Mild 
Dose not changed 
Recovered 
 
Diarrhoea 
Mild 
Dose not changed 
Recovered 
 
Increased bowel movement 
Mild 
Not applicable 
Recovered 
 
* no AEs were reported in the placebo cohort 
 
Efficacy evaluations were performed on blood samples of 21 patients on oral insulin and 
8 patients on placebo. Mean decreases in insulin and CRP levels were found to be 
statistically significant following the 6-week, once-daily ORMD-0801 treatment period, 
when compared to the placebo group (Figure 6A).  These findings suggest that ORMD-
0801 offered temporary relief to insulin-secreting beta cells. Moreover, the percentage of 
subjects demonstrating clinically relevant reductions in insulin, c-peptide, FBG and 
Hb1Ac levels was always higher in the ORMD-0801 cohort, when compared to the 
placebo (Figure 6B). 
 
 
 
 
Figure 6.  Plasma marker responses and percent responders to a six-week, daily oral ORMD-0801 
regimen  T2DM patients were treated once daily with a 16 mg insulin ORMD-0801 formulation or placebo 
capsule.  Blood samples drawn at the start of the study and after a 6-week treatment period were tested for 
marker levels.  A. Mean changes (±SD) in plasma insulin and CRP levels between the samples of day 0 and 
samples taken after the 6-wk treatment period are presented.  B.  Subjects demonstrating a decrease of  ≥0.5 
mmol/L in FBG, ≥40 µmol/L fructose-amine, ≥0.6% Hb1Ac, ≥1 mU/L insulin, ≥100 pmol/L c-peptide or 
≥1 mg/L CRP were considered responders for that specific marker.  The number of responders for each 
tested marker is presented as the percent of the total number of subjects analyzed for the given parameter. 
 
0
5
10
15
20
25
30
35
40
45
50
FBG
Fructose-
amine
HbA1c
Insulin c-peptide
CRP
Responders (% of cohort)
ORMD-0801
placebo
-4
-2
0
2
4
6
8
ORMD-0801
placebo
ORMD-0801
placebo
Insulin
CRP
0.031
p value
*
0.042
*
A
B
Mean changes
(Insulin: mU/L; CRP: pmol/L)

 
Page 21 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
Further investigation involving univariate, covariate and multivariate analyses, 
demonstrated positive correlations between above-average recordings of subject baseline 
triglyceride, BMI, insulin, HbA1c, c-peptide or blood pressure and/or below borderline-
high levels of baseline cholesterol or LDL, and increased CRP responses (Table 2). When 
only considering individuals presenting these predictors (72.4-75.9% of the original study 
population), more significant decreases in CRP levels than those obtained for the full 
intent-to-treat (ITT) population, were observed following insulin-based treatment, when 
compared to placebo. In these cases, mean intercohort differences in CRP levels ranged 
between 73.9-87.6% (p-values: 0.022-0.007), demonstrating a strong impact of the oral 
insulin preparation on inflammatory response with expected influence on insulin 
sensitivity. 
 

ORA-D-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
 
Table 2.  Clinically relevant predictors for heightened CRP responses among T2DM patients 
  
Predictor 
ORMD-
0801 
(N) 
Placebo 
(N) 
Percent of 
ITT 
population 
(%) 
Mean 
change 
ORMD-
0801 
Mean 
change 
placebo 
SD 
change 
ORMD-
0801 
SD 
change 
placebo 
Difference 
between 
cohorts 
using the 
optimal 
rule (%) 
p-Value 
Under 
Optimal 
Rule 
Adjusted 
p-Value 
Optimal 
Rule 
1 
0.86 <= BASELINE_TRI <= 3.11  
13 
8 
72.4 
-1.3385 
3.05 
2.032 
3.1625 
-73.90% 
0.0138 
0.0036 
2 
7.5 <= BASELINE_HBA1C <= 
10.1 
16 
7 
79.3 
-0.9875 
3.5571 
2.3984 
3.1796 
-76.50% 
0.014 
0.0056 
3 
27.1 <= VS_BMI  
15 
7 
75.9 
-1.0533 
3.5571 
2.4969 
3.1796 
-77.60% 
0.0153 
0.0052 
4 
BASELINE_CHOLESTEROL <= 
6.15 
17 
5 
75.9 
-0.4647 
4.54 
2.2803 
3.408 
-84.30% 
0.0159 
0.0054 
5 
1.39 <= BASELINE_LDL <= 4.17 
16 
5 
72.4 
-0.3125 
4.54 
2.2516 
3.408 
-81.70% 
0.0217 
0.0067 
6 
123 <= VS_BP_SYS  
16 
6 
75.9 
-0.3438 
4.1167 
1.8812 
3.15 
-75.10% 
0.0076 
0.0021 
7 
123 <= VS_BP_SYS  AND 
BASELINE_HDL <= 1.73  
16 
5 
72.4 
-0.3438 
4.86 
1.8812 
3.152 
-87.60% 
0.0038 
0.0006 
8 
123 <= VS_BP_SYS AND 493 <= 
BASELINE_CPEP  
15 
6 
72.4 
-0.5333 
4.1167 
1.8089 
3.15 
-78.30% 
0.0065 
0.0013 
9 
123 <= VS_BP_SYS AND 
BASELINE_HDL <= 1.73 
16 
5 
72.4 
-0.3438 
4.86 
1.8812 
3.152 
-87.60% 
0.0038 
0.0006 
10 
123 <= VS_BP_SYS AND 6.4 <= 
BASELINE_INSULIN  
16 
5 
72.4 
-0.3438 
4.86 
1.8812 
3.152 
-87.60% 
0.0038 
0.0006 
11 
123 <= VS_BP_SYS AND 493 <= 
BASELINE_CPEP  
15 
6 
72.4 
-0.5333 
4.1167 
1.8089 
3.15 
-78.30% 
0.0065 
0.0013 
12 
7.5 <= BASELINE_HBA1C <= 
10.1 AND 30 <= AGE  
15 
7 
75.9 
-1.3733 
3.5571 
2.1982 
3.1796 
-83.00% 
0.0071 
0.0019 
13 
123 <= VS_BP_SYS  AND 1 YR 
<= METFORMIN_DURATION  
16 
5 
72.4 
-0.3438 
4.54 
1.8812 
3.408 
-82.20% 
0.0073 
0.0015 

ORA-D-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
The reported results substantiate the safety and tolerability of ORMD-0801 and 
demonstrate a relevant clinical impact of ORMD-0801 at the tested dose. The small 
sample size and placebo effect, thoroughly described in the literature for diabetes 
management studies, contributed to the often nonsignificant outcomes in baseline vs. 
post-treatment marker levels. However, this first analysis of long-term exposure to 
ORMD-0801, proved its safety and tolerability, and will lay the foundation for further 
testing in larger populations. In addition, the findings related to CRP responses present 
factors which may be essential in further understanding interpatient insulin response 
variability, which to date, has challenged healthcare providers in outlining effective 
glucose control protocols. Definition of highly responsive subject subpopulations is 
expected to enhance insulin-based treatment efficacy. 
 
 

 
Page 24 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
APPENDIX B: Adverse Event Reporting 
 
Adverse Events 
 
Information about all adverse events, whether volunteered by the patient, recorded in the 
patient’s diary, discovered by Investigator questioning, or detected through physical 
examination, laboratory test or other means, will be collected and recorded on the 
Adverse Event Case Report Form and followed-up as appropriate. 
Medical conditions present at study entry are considered pre-existing conditions and will 
be documented as medical history in the study source and CRF documents. All adverse 
events, including worsening of pre-existing conditions, must be reported and documented 
as described below. 
 
Definitions 
An adverse event is any untoward medical event that occurs in a patient or patient 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including abnormal laboratory findings), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
Assessment of Adverse Events 
Volunteered, observed, and elicited reports of adverse events must be recorded. This 
includes adverse events the patient reports spontaneously, those the Investigator observes, 
and those the study staff elicits in response to open-ended questions during study visits. 
Each adverse event will be assessed by the Investigator with regard to seriousness, 
severity, and relatedness to the study treatment for recording in the CRF. 
 
Seriousness 
International Conference on Harmonization (ICH) Guidelines define a serious adverse 
event (SAE) as any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening.  
• Requires or prolongs existing hospitalization.  
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Important medical events that may not result in death, be life-threatening or 
require hospitalization, but that may jeopardize the patient or require medical 
intervention to prevent one of the above outcomes, should also be considered 
serious when based upon the Investigator’s medical judgment.  
 
Events not to be reported as SAEs are the following:  
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition. 

 
Page 25 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
• Treatment, including hospitalization, which was elective or pre-planned for a pre-
existing condition that is unrelated to the indication under study and did not 
worsen. 
• Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
aforementioned definitions of “serious” and not resulting in hospital admission. 
 
Severity 
The Principal Investigator will provide an assessment of the severity of each adverse 
reaction by recording a severity rating on the appropriate AE reporting page of the 
subject’s CRF. Severity will be assessed according to the following scale: 
 
Mild – events are usually transient and easily tolerated, requiring no special treatment and 
causing no disruption of the subject’s normal daily activities. 
 
Moderate – events introduce a low level of inconvenience or concern to the subject and 
may interfere with daily activities, but are usually improved by simple therapeutic 
measures. Moderate experiences may cause some interference with functioning. 
 
Severe – events interrupt the subject’s normal daily activities and generally require 
systemic drug therapy or other treatment. They are usually incapacitating. 
 
Relationship to Study Medication 
The Investigator will assess the relationship between the study medication and the 
adverse event and document as follows: 
 
Unrelated:  The event is clearly due to causes other than the active study drug. 
 
Unlikely: The event is doubtfully related to active study drug.  The event was most likely 
related to other factors such as the patient’s clinical state, concomitant drugs or other 
therapeutic interventions. 
 
Possible: The event follows a reasonable temporal sequence from the time of active study 
drug administration, but could have been produced by other factors such as the patient’s 
clinical state, therapeutic interventions or concomitant drugs. 
 
Probable: The event follows a reasonable temporal sequence from the time of active 
study drug administration, and follows a known response pattern to the drug. The toxicity 
cannot be reasonably explained by other factors such as the patient’s clinical state, 
therapeutic interventions or concomitant drugs. 
 
Definite: The event follows a reasonable temporal sequence from the time of active study 
drug administration, follows a known response pattern to the drug, cannot be reasonably 
explained by other factors such as the patient’s condition, concomitant drugs or 
therapeutic interventions, AND either occurs immediately following active study drug 
administration, improves on stopping the study drug, or reappears on re-exposure.  
 

 
Page 26 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
Adverse Events of Hypoglycemia 
The CTCAE (version 4.0) criteria for mild, moderate, and severe hypoglycemia based on 
blood glucose will be used, as shown below: 
Mild: < 70 – 55 mg/dL (< 3.8 - 3.0 mmol/L) 
Moderate: < 55 – 40 mg/dL (< 3.0 - 2.2 mmol/L) 
Severe: < 40 – 30 mg/dL (< 2.2 - 1.7 mmol/L) 
Life Threatening: < 30 mg/dL (< 1.7 mmol/L) 
 
Recording Adverse Events 
All adverse events experienced during the trial, regardless of relationship to study 
medication, must be recorded on the Adverse Event CRF from the time of patient consent 
until completion of patients End of Study visit (Visit 9). All serious adverse events will 
be collected through Visit 9. The Investigator must continue to follow all non-serious 
events possibly related to the study medication and all serious adverse events until they 
resolve or until the Investigator assesses them in writing as chronic or stable.  
Regardless of relationship to study medication, the event must be recorded on the 
Adverse Event CRF. Adverse event documentation should include the following 
information: 
• Standard medical terminology for the AE  
• Description of adverse event 
• Date and time of onset 
• Date and time of resolution of the adverse event  
• Whether or not the event is ongoing 
• Severity of the event  
• Relationship between the adverse event and the investigational product 
• Description of any actions taken (e.g., medications, treatments) 
• Outcome of the AE 
• Whether or not the effect was serious and/or unanticipated 
 
Whenever possible, a diagnosis should be given when signs and symptoms are due to 
common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion 
should be reported as "upper respiratory infection"). For the purposes of this study, 
hypoglycemic events will be considered adverse events and should be recorded in source 
and CRF records.  
When a diagnosis is not available, each adverse event should be reported separately. For 
example, “nausea and vomiting” should be split into two separate events. 
 
Reporting Serious Adverse Events 
In accordance with Federal regulations, Investigators will be notified of the occurrence of 
serious, unexpected and related adverse events. 
The Investigator must report all serious adverse events to Sponsor within 24 hours of the 
site being notified of the event. Investigators must also report these events to the 
Institutional Review Board (IRB) in accordance with the IRB’s reporting guidelines, 
within the IRB specified timeframe, or no later than 48 hours after knowledge of the 
event. 

 
Page 27 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
For submission of these events to the Israeli Regulatory Agency? the Sponsor will follow 
FDA regulations 21 CFR 312.32. If the event is determined to meet the requirements of 
IND Safety Reporting then expedited reporting requirements to the FDA will be 
followed. The Sponsor may need to issue an Investigator notification, to inform all 
Investigators involved in any study with the same drug (or therapy) that this serious 
unexpected suspected adverse reaction (SUSAR) has occurred.  
Investigator Reporting Procedures 
The PI or other study personnel must immediately (within 24 hours) inform Sponsor of 
any AE considered serious (as defined above) or otherwise medically significant. 
Notification should be via facsimile transmission of a written report signed by the PI. 
Notification must include the PI’s assessment as to whether the event was or was not 
related to the use of the study medication. The Sponsor contact information is as follows: 
 
Oramed Ltd. 
Hi-Tech Park 2/4 Givat Ram 
PO Box 39098 
Jerusalem, 91390, Israel  
 
The Principal Investigator must also promptly inform the governing IRB of the serious 
adverse event per the governing IRB’s requirements. 
 
The CRO will notify Oramed within 24 hours of receipt. Any SAE that occurred within 
30 days after last dose will be followed and reported as above. 
 
Pregnancy Reporting 
If the subject or partner of a subject participating in the study becomes pregnant during 
the study or within 30 days or discontinuing study medication, the Investigator should 
report the pregnancy to Oramed within 24 hours of being notified. The Exposure In Utero 
form to the Investigator for completion. 
 
The subject or partner should be followed by the Investigator until completion of the 
pregnancy. If the pregnancy ends for any reason before the anticipated date, the 
Investigator should notify the Sponsor. At the completion of the pregnancy, the 
investigator will document the outcome of the pregnancy. If the outcome of the 
pregnancy meets the criteria for immediate classification as an SAE (i.e., postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly), the 
Investigator should follow the procedures for reporting an SAE. 
 
Reporting Unanticipated Problems to the IRB 
The Investigator must promptly report to his or her IRB all unanticipated problems 
involving risks to patients.  Investigators must consult FDA regulations and IRB/ethics 
committee guidance for reporting requirements. 
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 

 
Page 28 of 28 
 
ORA-H-N01 Clinical Protocol 07 January, 2018 – Version 3.1  
 
 
 
Confidential  
 
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.