Effect of Exendin (9-39) on Glucose Requirements to Maintain Euglycemia

Study Overview
=================
Brief Summary
-----------------
The primary aim of this study is to evaluate the effect of Exendin (9-39) on glucose requirements to maintain euglycemia in pediatric patients with congenital hyperinsulinism (CHI) who have failed medical therapy. The secondary aims are to determine the therapeutic plasma levels, plasma half-life and pharmacokinetics of Exendin (9-39) during a 9-hour intravenous infusion.

Detailed Description
-----------------
This study will enroll infants with congenital hyperinsulinism owing to KATP channel mutations who are unresponsive to medical therapy and will require a pancreatectomy to control hypoglycemia from a single academic medical center in the United States. An open-label, two-period, two-treatment crossover study design with a dose-escalation component will be implemented. Successive cohorts of patients (up to 5 participants/cohort) will each receive a fixed dose of Exendin (9-39) infusion and normal saline vehicle on two separate days in random order. The protocol specifies 0.02 mg/kg/hr, via continuous intravenous infusion, administered over 9-hours for the first cohort. The volume of saline to be infused will be calculated to match the volume of Exendin (9-39). Successive cohorts will be given doses that are increased in up to 1/2 log increments. Overall, the investigators hypothesize that antagonism of the GLP-1 receptor by Exendin (9-39) will increase fasting blood glucose levels, prevent protein-induced hypoglycemia and decrease glucose requirement to maintain euglycemia in infants with CHI. Aim 1. To examine the effect of Exendin (9-39) on glucose requirements to maintain euglycemia in infants with congenital hyperinsulinism unresponsive to medical therapy. Aim 2. To determine therapeutic plasma levels, plasma half-life and pharmacokinetics of Exendin-(9-39) during an intravenous infusion.

Official Title
-----------------
Role of Glucagon-Like Peptide-1 (GLP-1) in Congenital Hyperinsulinism: Effect of Exendin (9-39) on Glucose Requirements to Maintain Euglycemia

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

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed clinical diagnosis of congenital hyperinsulinism Infants less than 12 months of age at study enrollment Failure to respond to treatment with diazoxide Exclusion Criteria: Evidence of a medical condition that might alter results, including kidney failure, severe liver dysfunction, severe respiratory or cardiac failure Treatment with medications that may affect glucose metabolism at the time of initiation of study procedures, including: Treatment with glucagon 4 hours prior to infusion (T=0) Treatment with octreotide 24 hours prior to infusion (T=0) Treatment with diazoxide 72 hours prior to infusion (T=0) Suspected Beckwith-Wiedemann syndrome or other syndromic forms of congenital hyperinsulinism.

Ages Eligible for Study
-----------------
Maximum Age: 12 Months

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: This is a two-period, two-treatment cross-over clinical study with a dose-escalation component. Each subject, in random order, will receive an intravenous (IV) infusion of Exendin (9-39) and normal saline vehicle for up to 9 hours on two separate days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exendin (9-39) 0.02 mg/kg/hr<br>Cohort 1: Participants will be administered 0.02 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. | Drug: Exendin (9-39)<br>* A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours.<br>Drug: Vehicle<br>* A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours.<br>* Other names: Placebo;|
| Experimental: Exendin (9-39) 0.04 mg/kg/hr<br>Cohort 2: Participants will be administered 0.04 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. | Drug: Exendin (9-39)<br>* A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours.<br>Drug: Vehicle<br>* A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours.<br>* Other names: Placebo;|
| Experimental: Exendin (9-39) 0.10 mg/kg/hr<br>Cohort 3: Participants will be administered 0.10 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 6 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. | Drug: Exendin (9-39)<br>* A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours.<br>Drug: Vehicle<br>* A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours.<br>* Other names: Placebo;|
| Experimental: Exendin (9-39) 0.20 mg/kg/hr<br>Cohort 4: Participants will be administered 0.20 mg/kg/hr of Exendin (9-39) and vehicle (normal saline), via continuous intravenous infusion, over 9 hours on two separate days in random order, with 3 hours of follow-up after the last dose is administered or until blood glucose is < 70 mg/dL (whichever comes first). Glucose infusion rates (GIR) will be titrated three hours prior to infusions to keep blood glucose in the range of 70-90 mg/dL. During both infusions, blood glucose will be measured every 30 minutes. | Drug: Exendin (9-39)<br>* A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours.<br>Drug: Vehicle<br>* A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours.<br>* Other names: Placebo;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Glucose Infusion Rate (GIR) | To assess the effect of Exendin (9-39) on glucose infusion rate, glucose infusion rate (GIR) over the last 2 hours of the treatment period was calculated by adding the total amount of intravenous glucose (mg) received over 2 hours divided by the weight (kg) and by time (120 min) during infusion of Exendin (9-39) and normal saline vehicle. | Up to 9 hours after the initiation of infusion | 
| To Determine the Pharmacokinetics of Exendin (9-39) | The following PK variables of interest include AUC0-∞, AUC0-t, maximal concentration (Cmax), time to maximal concentration (Tmax), concentration at end of infusion (Ceoi), steady state volume of distribution (Vss), clearance (CL) and half-life (t1/2) of Exendin (9-39). These will be derived through both non-compartmental and model-based methods. | Up to 12 hours after the initiation of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of Exendin (9-39) | Number of participants with adverse events as a measure of safety and tolerability [evaluated by the result of laboratory safety tests (hematology, chemistry, urinalysis), vital signs, physical examinations, and 12-lead ECG] | Up to 24 hours post-infusion | 
| Mean Plasma Insulin | To assess the effect of Exendin (9-39) on plasma insulin levels, samples were collected at various time points during the infusion [Exendin (9-39) or vehicle] including: at the start of the infusion (T=0) and at 1, 5, and 9 hours post initiation of the infusion. | Up to 9 hours after the initiation of infusion | 
| Mean Plasma Glucose | To assess the effect of Exendin (9-39) on plasma glucose levels, samples were collected at various time points during the infusion [Exendin (9-39) or vehicle] including: at the start of the infusion (T=0) and at 1, 5, and 9 hours post initiation of the infusion. | Up to 9 hours after the initiation of infusion | 
| Mean Betahydroxybutyrate Levels | To assess the effect of Exendin (9-39) on mean betahydroxybutyrate levels, samples were collected at various time points during the infusion [Exendin (9-39) or vehicle] including: at the start of the infusion (T=0) and hourly up to 12-hours post initiation of the infusion. | Up to 12 hours after the initiation of infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Congenital Hyperinsulinism, Hyperinsulinism, Hypoglycemia, KATP channel, Metabolic Diseases, Pancreatic Disease, Glucose Metabolism Disorders, Infant, Newborn, Diseases