Clinical trial NCT02535715: A Euglycemic Insulin Clamp Study in Type 1 Diabetic Patients With Oral Insulin (ORAMED)
Official title: A Euglycemic Insulin Clamp Study in Type 1 Diabetic Patients With Oral Insulin (ORAMED)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 1 Diabetes
Keywords: Oral Insulin
Lead sponsor: The University of Texas Health Science Center at San Antonio
Sponsor class: OTHER
Collaborators: name: Oramed, Ltd.
First posted: 2015-08-31
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Hepatic Glucose Production (Co-primary Outcome)
timeFrame: Participants will be followed during the procedures, until all 3 procedures are completed, an average of 1 month
Secondary outcomes:
measure: Plasma Insulin Concentrations
timeFrame: Participants will be followed during the procedures, until all 3 procedures are completed, an average of 1 month
measure: Plasma Glucose Concentrations
timeFrame: Participants will be followed during the procedures, until all 3 procedures are completed, an average of 1 month
measure: Plasma Glucagon Concentrations
timeFrame: Participants will be followed during the procedures, until all 3 procedures are completed, an average of 1 month
measure: Plasma Free Fatty Acid Concentrations
timeFrame: Participants will be followed during the procedures, until all 3 procedures are completed, an average of 1 month
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: The University of Texas Health Science Center at San Antonio
state: Texas
Study officials:
affiliation: University of Texas
name: Ralph A DeFronzo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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 Oct;28(10):2543-5. doi: 10.2337/diacare.28.10.2543. No abstract available.
citation: 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 Apr;38(4):387-95. doi: 10.1016/0026-0495(89)90129-7.
citation: STEELE R. Influences of glucose loading and of injected insulin on hepatic glucose output. Ann N Y Acad Sci. 1959 Sep 25;82:420-30. doi: 10.1111/j.1749-6632.1959.tb44923.x. No abstract available.