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

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

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.

Study Overview

• Status: Terminated
• Conditions: Congenital Hyperinsulinism
• Intervention / Treatment: Drug: Exendin (9-39); Drug: Vehicle

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.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Confirmed clinical diagnosis of congenital hyperinsulinism
2. Infants less than 12 months of age at study enrollment
3. Failure to respond to treatment with diazoxide

Exclusion Criteria:

1. Evidence of a medical condition that might alter results, including kidney failure, severe liver dysfunction, severe respiratory or cardiac failure

2. Treatment with medications that may affect glucose metabolism at the time of initiation of study procedures, including:

   1. Treatment with glucagon 4 hours prior to infusion (T=0)
   2. Treatment with octreotide 24 hours prior to infusion (T=0)
   3. Treatment with diazoxide 72 hours prior to infusion (T=0)
3. Suspected Beckwith-Wiedemann syndrome or other syndromic forms of congenital hyperinsulinism.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exendin (9-39) 0.02 mg/kg/hr; 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); A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours.; Drug: Vehicle; A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours.; Other Names: Placebo
Experimental: Exendin (9-39) 0.04 mg/kg/hr; 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); A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours.; Drug: Vehicle; A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours.; Other Names: Placebo
Experimental: Exendin (9-39) 0.10 mg/kg/hr; 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); A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours.; Drug: Vehicle; A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours.; Other Names: Placebo
Experimental: Exendin (9-39) 0.20 mg/kg/hr; 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); A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours.; Drug: Vehicle; A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours.; 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

Collaborators and Investigators

• Sponsor: Diva De Leon
• Investigators: Principal Investigator: Diva D De Leon, MD MSCE, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2009
• Primary Completion (Actual): January 28, 2017
• Study Completion (Actual): January 28, 2017

Study Registration Dates

• First Submitted: February 2, 2009
• First Submitted That Met QC Criteria: February 2, 2009
• First Posted (Estimate): February 3, 2009

Study Record Updates

• Last Update Posted (Actual): June 1, 2020
• Last Update Submitted That Met QC Criteria: May 16, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Hypoglycemia; Infant, Newborn, Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Pancreatic Disease; Congenital Hyperinsulinism; Hyperinsulinism; KATP channel
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Infant, Newborn, Diseases; Pancreatic Diseases; Hypoglycemia; Hyperinsulinism; Congenital Hyperinsulinism; Nesidioblastosis
• Other Study ID Numbers: 2008-10-6256

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO