Effect of Exendin-(9-39) on Fasting Adaptation and Protein Sensitivity

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to examine the effects of exendin-(9-39) on fasting blood glucose and protein induced hypoglycemia on subjects with Congenital Hyperinsulinism. Funding Source - FDA Office of Orphan Products Development (OODP).

Detailed Description
-----------------
This is a placebo controlled study with randomized crossover design to evaluate the effect of the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin-(9-39), on fasting blood glucose levels, protein-induced hypoglycemia, and fasting tolerance of subjects with congenital hyperinsulinism due to mutations in the ATP- sensitive potassium channel (KATP) channel.

Official Title
-----------------
Role of GLP-1 in Congenital Hyperinsulinism:Effect of Exendin-(9-39) on Fasting Adaptation and Protein Sensitivity

Conditions
-----------------
Congenital Hyperinsulinism

Intervention / Treatment
-----------------
* Drug: Exendin-(9-39)
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed diagnosis of hyperinsulinism Mutation analysis results demonstrating KATP channel defect Age 6 months to 18 years with Persistent hypoglycemia Exclusion Criteria: Current therapy with medications that may affect glucose metabolism such as octreotide, diazoxide, high dose glucocorticoids, adrenergic agents, etc. Subjects will be eligible to participate if the last dose of octreotide is given 48 hrs before study day 1 and the last dose of diazoxide is given 72 hours before study day 1 Evidence of a medical condition that might alter results or compromised the elimination of the peptide, including active infection, kidney failure, severe liver dysfunction, severe respiratory or cardiac failure Pregnancy Subjects with milk protein allergy will be excluded for participating in studies involving protein tolerance test

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: In a random crossover design, subjects were assigned to either intervention (6 hour infusion of exendin( 9-39) at a dose range of 100-500pmol/kg/min) or vehicle (6hr infusion of 0.9%NaCl)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Vehicle first, then Exendin-(9-39)<br>An infusion of vehicle (0.9%NaCl) will run for 60 minutes(time -60 to 0) before starting the study infusion of vehicle or exendin-(9-39). At time 0, vehicle (0.9%NaCl) will be started and will continue for 6 hours. The following day, at time 0, exendin-(9-39) at a dose ranging from 100-500pmol/kg/min will be started and continue for 6 hours. During both infusions, blood glucose, insulin, c-peptide, GLP-1, and glucagon will be measured every 30 minutes. | Drug: Exendin-(9-39)<br>* 100-500pmol/kg/min<br>Drug: placebo<br>* placebo (0.9% NaCl)<br>* Other names: (0.9% NaCl);|
| Other: Exendin-(9-39) first then Vehicle.<br>An infusion of vehicle (0.9%NaCl) will run for 60 minutes(time -60 to 0) before starting the study infusion of vehicle or exendin-(9-39). . At time 0, exendin-(9-39) at a dose ranging from 100-500pmol/kg/min will be started and continue for 6 hours. The following day, at time 0, vehicle (0.9%NaCl) will be started and will continue for 6 hours. During both infusions, blood glucose, insulin, c-peptide, GLP-1, and glucagon will be measured every 30 minutes. . | Drug: Exendin-(9-39)<br>* 100-500pmol/kg/min<br>Drug: placebo<br>* placebo (0.9% NaCl)<br>* Other names: (0.9% NaCl);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) Plasma Glucose | Area under the curve plasma glucose from the initiation of infusion of vehicle or exendin-(9-39) to end of the infusion | Time 0 min - time 360 min | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) Plasma Insulin | Area under the curve plasma insulin from the initiation of infusion of vehicle or exendin-(9-39) to end of the infusion | time 0 min to time 360 min | 
| Area Under the Curve (AUC) Plasma C-peptide | Area under the curve plasma C-peptide from the beginning of the infusion of vehicle or exendin-(9-39) to the end of the infusion | time 0 min to time 360 min | 
| Area Under the Curve (AUC) Plasma Glucagon | Area under the curve plasma glucagon from the beginning of the infusion of vehicle or exendin-(9-39) to the end of the infusion | time 0 min to time 360 min | 
| Area Under the Curve ( AUC) Plasma Total GLP-1 (Glucagon-like Peptide-1) | Area under the curve plasma total GLP-1 (glucagon-like peptide-1) from the beginning of the infusion of vehicle or exendin-(9-39) to the end of the infusion | time 0 to time 360 min | 
| Area Under the Curve ( AUC) Plasma Active GLP-1 (Glucagon-like Peptide-1) | Area under the curve plasma active GLP-1 (glucagon-like peptide-1) from the beginning of the infusion of vehicle or exendin-(9-39) to the end of the infusion | time 0 min to time 360 min | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hyperinsulinism, Hypoglycemia, KATP channel