A Euglycemic Insulin Clamp Study in Type 1 Diabetic Patients With Oral Insulin (ORAMED)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Euglycemic Insulin Clamp Study in Type 1 Diabetic Patients With Oral Insulin (ORAMED)

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: ORMD-0801 capsules- 2x8mg
* Drug: ORMD-0801 capsules- 3x8mg
* Drug: ORMD-0801 capsules- 1x16mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be between 18 and 70 years of age Must have type 1 diabetes Must be in good general health by routine history and physical exam A1c <10.0% BMI = 18-40 kg/m2 On no medications known to affect glucose metabolism other than insulin Hematocrit ≥ 34 vol% Liver Function Tests < 3 x Upper Normal Limit Plasma creatinine < 1.8 mg/dl Exclusion Criteria: Under 18 years of age and over 70 years of age Does not have type 1 diabetes A1c > 10.0% BMI < 18 or > 40 kg.m2 On medications known to affect glucose metabolism other than insulin Hematocrit ≤ 34 vol% Liver Function Tests >3 x Upper Normal Limit Plasma creatinine > 1.8 mg/dl

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ORAMED ORMD-0801 capsules- 2x8mg 1st; 3x8mg 2nd, 1x16mg 3rd<br>Two 8 mg ORAMED capsules containing insulin then 3X8mg ORAMED capsules containing insulin, second study then 1X16mg ORAMED capsules containing insulin, third study | Drug: ORMD-0801 capsules- 2x8mg<br>* 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.<br>* Other names: Oral Insulin Capsules;Drug: ORMD-0801 capsules- 3x8mg<br>* 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.<br>* Other names: Oral Insulin Capsules;Drug: ORMD-0801 capsules- 1x16mg<br>* 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.<br>* Other names: Oral Insulin Capsules;|
| Experimental: ORAMED ORMD-0801 capsules- 3x8mg 1st, 1x16mg 2nd, 2x8mg 3rd<br>Three 8mg ORAMED capsules containing insulin then 1X16mg ORAMED capsules containing insulin, second study then 2X8mg ORAMED capsules containing insulin, third study | Drug: ORMD-0801 capsules- 2x8mg<br>* 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.<br>* Other names: Oral Insulin Capsules;Drug: ORMD-0801 capsules- 3x8mg<br>* 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.<br>* Other names: Oral Insulin Capsules;Drug: ORMD-0801 capsules- 1x16mg<br>* 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.<br>* Other names: Oral Insulin Capsules;|
| Experimental: ORAMED ORMD-0801 capsules-1x16mg 1st, 2x8mg 2nd, 3x8mg 3rd<br>One 16mg ORAMED capsule containing insulin then 2X8mg ORAMED capsule containing insulin, second study then 3X8mg ORAMED capsule containing insulin, third study | Drug: ORMD-0801 capsules- 2x8mg<br>* 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.<br>* Other names: Oral Insulin Capsules;Drug: ORMD-0801 capsules- 3x8mg<br>* 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.<br>* Other names: Oral Insulin Capsules;Drug: ORMD-0801 capsules- 1x16mg<br>* 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.<br>* Other names: Oral Insulin Capsules;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic Glucose Production (Co-primary Outcome) | Tritiated glucose infusion during procedures (Baseline and every 30 minutes during procedures) Calculated from plasma(mg/kg-minute). Averaged every 30 minutes. | Participants will be followed during the procedures, until all 3 procedures are completed, an average of 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Insulin Concentrations | Baseline and every 15 minutes during procedures (microIU/mL). | Participants will be followed during the procedures, until all 3 procedures are completed, an average of 1 month | 
| Plasma Glucose Concentrations | Measured at baseline and every 5 minutes during the procedures(mg/dL), Averaged over 30 minute intervals during the procedure | Participants will be followed during the procedures, until all 3 procedures are completed, an average of 1 month | 
| Plasma Glucagon Concentrations | Measured at baseline and every 30 minutes during the procedures (pg/mL) | Participants will be followed during the procedures, until all 3 procedures are completed, an average of 1 month | 
| Plasma Free Fatty Acid Concentrations | Measured at baseline and every 30 minutes during the procedures (micro mol/L) | Participants will be followed during the procedures, until all 3 procedures are completed, an average of 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oral Insulin