Conditions: Type 1 Diabetes
Keywords: Oral Insulin
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 11
Healthy volunteers: no

Brief summary:
ORAMED has developed an oral insulin that, in preliminary studies, has shown promise. In the present study investigators will perform a pharmacodynamic/pharmacokinetic study to evaluate this novel insulin preparation as a potential therapeutic option in diabetic patients.

Detailed description:
Insulin therapy is an absolute requirement in type 1 diabetic patients. Multiple injections present a barrier to achieving normal/near-normal glucose control in diabetic patients (1). Therefore, there has been considerable interest in developing alternative routes of insulin administration. ORAMED has developed an oral insulin that, in preliminary studies, has shown promise. In the present study investigators will perform a pharmacodynamic/pharmacokinetic study to evaluate this novel insulin preparation as a potential therapeutic option in type 1 diabetic patients.

10 type 1 diabetic subjects will be studied.

Each subject will be studied on three occasions with an interval of 3 days to 4 weeks between each study. During each study subjects will receive one intervention at a time in random order: (i) two 8 mg ORAMED capsule containing insulin; (ii) three 8 mg ORAMED capsules containing insulin; (iii) one 16 mg ORAMED capsule containing insulin. If the fasting plasma glucose is \>200mg/dl on the procedure day, the procedure will be rescheduled.

Prior to each study subjects will refrain from eating (except water) after 10 at night and report to the Clinical Research Center at approximately 7 in the morning. A catheter will be placed in an antecubital vein and a prime (40 microCuries x fasting plasma glucose/100) - continuous (0.4 microCuries/min) infusion of tritiated glucose will be started and continued until the end of the study. Plasma glucose will be monitored and if necessary during the 1st hour of tracer equilibration, a small amount of IV regular insulin will be administered to obtain a fasting plasma glucose of 100-130mg/dl. After a 3-hour tracer equilibration, subjects will ingest the ORAMED capsule containing insulin and a variable infusion of 20% glucose will be started to maintain the plasma glucose concentration between 100-120 mg/dl. Plasma samples for glucose, insulin, glucagon, and free fatty acid (FFA) concentrations and tritiated glucose radioactivity will be obtained every 5-15 minutes for 4 hours following the ingestion of the ORAMED capsule containing insulin.

Calculations: Following an overnight fast, steady state conditions prevail and the basal rate of glucose appearance equals the rate of glucose disappearance and is calculated as the tritiated glucose infusion rate divided by the tritiated glucose specific activity. Under postabsorptive conditions, Basal rate of glucose appearance primarily reflects hepatic glucose production (2). Following the ingestion of oral insulin, non-steady state conditions prevail and Ra and Rd are calculated using Steele's equation (3). Endogenous (primarily reflects liver) glucose production is calculated by subtracting the exogenous glucose infusion rate from the tracer-derived rate of glucose appearance. Endogenous rate of glucose disappearance reflects glucose uptake by all tissues in the body, but primarily reflects skeletal muscle (4).

Sample Size: The present study represents a pilot study to gain information about the absorption of oral insulin and its effect on hepatic and peripheral (skeletal muscle) glucose metabolism. This information will be used to determine whether the ORAMED oral insulin preparation represents a viable option to treat diabetic subjects, to gain information about the dose response effect of ORAMED insulin on glucose metabolism, and to provide quantitative data about the effect of oral insulin on hepatic and peripheral (muscle) glucose metabolism. Therefore, the investigators conservatively have set the sample size at 10.

Arms:
arm 1: Two 8 mg ORAMED capsules containing insulin then 3X8mg ORAMED capsules containing insulin, second study then 1X16mg ORAMED capsules containing insulin, third study arm 2: Three 8mg ORAMED capsules containing insulin then 1X16mg ORAMED capsules containing insulin, second study then 2X8mg ORAMED capsules containing insulin, third study arm 3: One 16mg ORAMED capsule containing insulin then 2X8mg ORAMED capsule containing insulin, second study then 3X8mg ORAMED capsule containing insulin, third study

Interventions: intervention 1: ORMD-0801 capsules- 2x8mg intervention 2: ORMD-0801 capsules- 3x8mg intervention 3: ORMD-0801 capsules- 1x16mg
Intervention descriptions: intervention 1: Participants who receive this intervention first, then receive either ORMD-0801- 3x8mg or 1x16mg dose after a 3 day to 4 week interval. Participants receiving this drug as the second drug intervention will then receive the third intervention after a 3 day to 4 week interval. ORMD-0801 capsules are an oral insulin that has shown promise in preliminary studies. Investigators will evaluate this novel insulin preparation as a potential therapeutic option in diabetic patients. intervention 2: Participants who receive this intervention first, then receive either ORMD-0801- 2x8mg or 1x16mg dose after a 3 day to 4 week interval. Participants receiving this drug as the second drug intervention will then receive the third intervention after a 3 day to 4 week interval. ORMD-0801 capsules are an oral insulin that has shown promise in preliminary studies. Investigators will evaluate this novel insulin preparation as a potential therapeutic option in diabetic patients. intervention 3: Participants who receive this intervention first, then receive either ORMD-0801- 2x8mg or 3x8mg dose after a 3 day to 4 week interval. Participants receiving this drug as the second drug intervention will then receive the third intervention after a 3 day to 4 week interval. ORMD-0801 capsules are an oral insulin that has shown promise in preliminary studies. Investigators will evaluate this novel insulin preparation as a potential therapeutic option in diabetic patients.

Protocol document:
Prot_SAP_000.pdf: 
14-476H, DeFronzo, PI Protocol, 07-10-15, AMD 
1 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
Official Study Title: A Euglycemic Insulin Clamp Study in Type 1 Diabetic Patients With Oral 
Insulin (ORAMED 
 
NCT number: NCT02535715 
 
IRB Approval Date: 08-27-2015 
 
Unique Protocol ID: HSC20140476H 
 


14-476H, DeFronzo, PI Protocol, 07-10-15, AMD 
2 
 
TITLE:  A Euglycemic Insulin Clamp Study in Type 1 Diabetic Patients with Oral Insulin 
(ORAMED) 
BACKGROUND:  Insulin therapy is an absolute requirement in type 1 diabetic patients.  
Multiple injections present a barrier to achieving normal/near-normal glucose control in diabetic 
patients (1).  Therefore, there has been considerable interest in developing alternative routes of 
insulin administration.  ORAMED has developed an oral insulin that, in preliminary studies, has 
shown promise.  In the present study we will perform a pharmacodynamic/pharmacokinetic 
study to evaluate this novel insulin preparation as a potential therapeutic option in diabetic 
patients. 
EXPERIMENTAL PLAN: 
 
Subjects:  10 type 1 diabetic subjects between the ages of 18 to 70, in good general 
health by routine history and physical exam; A1c<10.0%; BMI = 18-40 kg/m2; on no meds 
known to affect glucose metabolism other than insulin; hematocrit  34 vol%; LFTs < 3 x ULN; 
plasma creatinine < 1.8 mg/dl. 
 
Study Design:  Each subject will be studied on three occasions with an interval of 3 days 
to 4 weeks between each study.  During each study subjects will receive:  (i) two 8 mg 
ORAMED capsule containing insulin; (ii) three 8 mg ORAMED capsules containing insulin; (iii) 
one 16 mg ORAMED capsule containing insulin.  If the fasting plasma glucose is >200mg/dl on 
the procedure day, the procedure will be rescheduled. 
 
Prior to each study subjects will refrain from eating (except water) after 10 PM and report 
to the Clinical Research Center at approximately 7 AM.  A catheter will be placed in an 
antecubital vein and a prime (40 uCi x FPG/100) – continuous (0.4 uCi/min) infusion of tritiated 
(3-3H-glucose) glucose will be started and continued until the end of the study.  Plasma glucose 


14-476H, DeFronzo, PI Protocol, 07-10-15, AMD 
3 
 
will be monitored and if necessary during the 1st hour of tracer equilibration, a small amount of 
IV regular insulin will be administered to obtain a fasting plasma glucose of 100-130mg/dl. The 
total amount of administered regular insulin will be <10 units.  After a 3-hour tracer equilibration, 
subjects will ingest the ORAMED capsule containing insulin and a variable infusion of 20% 
glucose will be started to maintain the plasma glucose concentration between 100-120 mg/dl.  
Plasma samples for glucose, insulin, glucagon, and free fatty acid (FFA) concentrations and 
tritiated glucose radioactivity will be obtained every 5-15 minutes for 4 hours following the 
ingestion of the ORAMED capsule containing insulin. 
 
Calculations:  Following an overnight fast, steady state conditions prevail and the basal 
rate of glucose appearance (Ra) equals the rate of glucose disappearance (Rd) and is calculated 
as the tritiated glucose infusion rate (DPPM/min) divided by the tritiated glucose specific activity 
(DPM/min).  Under postabsorptive conditions, Ra primarily reflects hepatic glucose production 
(2).  Following the ingestion of oral insulin, non-steady state conditions prevail and Ra and Rd 
are calculated using Steele’s equation (3).  Endogenous (primarily reflects liver) glucose 
production (EGP) is calculated by subtracting the exogenous glucose infusion rate from the 
tracer-derived Ra.  Rd reflects glucose uptake by all tissues in the body, but primarily reflects 
skeletal muscle (4). 
 
Sample Size:  The present study represents a pilot study to gain information about the 
absorption of oral insulin and its effect on hepatic and peripheral (skeletal muscle) glucose 
metabolism.  This information will be used to determine whether the ORAMED oral insulin 
preparation represents a viable option to treat diabetic subjects, to gain information about the 
dose response effect of ORAMED insulin on glucose metabolism, and to provide quantitative 


14-476H, DeFronzo, PI Protocol, 07-10-15, AMD 
4 
 
data about the effect of oral insulin on hepatic and peripheral (muscle) glucose metabolism.  
Therefore, we conservatively have set the sample size at 10. 
 


14-476H, DeFronzo, PI Protocol, 07-10-15, AMD 
5 
 
REFERENCES 
1.  
Polonsky WH, Fisher L, Guzman S, Villa-Caballero L, Edelman SV: Psychological 
insulin resistance in patients with type 2 diabetes: the scope of the problem. Diabetes 
Care 2005;28:2543-2545 
2.  
DeFronzo RA, Ferrannini E, Simonson DC: Fasting hyperglycemia in non-insulin-
dependent diabetes mellitus: contributions of excessive hepatic glucose production and 
impaired tissue glucose uptake. Metabolism 1989;38:387-395 
3.  
Steele R: Influences of glucose loading and of injected insulin on hepatic glucose output. 
Ann N Y Acad Sci 1959;82:420-430 
 


14-476H, DeFronzo, PI Protocol, 07-10-15, AMD 
6 
 
ORAL INSULIN CLAMP 
 
TIME 
GLUCOSE 
INSULIN 
GLUCAGON 
FFA 
3-3H-glucose 
(min) 
(0.5 ml) 
(2.5 ml) 
(2.5 ml) 
(2 ml) 
(2.5 ml) 
 
-180     Start 3-3H-gucose 
-30 
x 
x 
x 
x 
x 
-20 
x 
 
 
 
x 
-10 
x 
x 
x 
x 
x 
-5 
x 
 
 
 
x 
0 
x 
Oral insulin 
x 
x 
x 
x 
15 
q 5 min  
x 
 
 
x 
30 
 
x 
x 
x 
45 
 
x 
 
 
x 
60 
 
x 
x 
x 
x 
75 
 
x 
 
 
x 
90 
 
x 
x 
x 
x 
105 
 
x 
 
 
x 
120 
 
x 
x 
x 
x 
135 
 
x 
 
 
x 
150 
 
x 
x 
x 
x 
165 
 
x 
 
 
x 
180 
 
x 
x 
x 
x 
195 
 
x 
 
 
x 
210 
 
x 
x 
x 
x 
220 
 
x 
 
 
x 
230 
 
x 
 
 
x 
235 
 
x 
 
 
x 
240 
 
x 
x 
x 
x 
 
Number 
52 
21 
11 
11 
23 
Volume 
26 
50.5 
27.5 
27.5 
57.5 
 
TOTAL – 189 ml