Effect of Exendin-(9-39) on Glycemic Control in Subjects With Congenital Hyperinsulinism

NCT ID: NCT00571324

Last Updated: 2017-12-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 9 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-08-31
• Study Completion Date: 2014-12-31

Brief Summary

The purpose of this study is to determine if Exendin-(9-39), an antagonist of the glucagon-like peptide-1 (GLP-1) receptor with effects on the pancreatic beta cell, increases fasting blood glucose levels in subjects with congenital hyperinsulinism.

Detailed Description

This is an open-label, pilot study , to determine if Exendin-(9-39), an antagonist of the glucagon-like peptide-1 (GLP-1) receptor with effects on the pancreatic beta cells, increases fasting blood glucose levels in subjects with congenital hyperinsulinism. Our overall hypothesis is that abnormal GLP-1 secretion resulting from dysfunctional nutrient sensing in intestinal L-cells plays a role in the dysregulated insulin secretion characteristic of this disorder, and that antagonism of the GLP-1 receptor will increase fasting blood glucose levels.

Aim 1. To evaluate the dose of exendin-(9-39) required to elevate fasting blood glucose levels in subjects with congenital hyperinsulinism due to KATP channel mutations.

Aim 2. To determine therapeutic plasma levels, plasma half-life and pharmacokinetics of exendin-(9-39) during an intravenous short-term infusion in subjects with congenital hyperinsulinism due to Adenosine triphosphate (ATP)-sensitive potassium channel (KATP) mutations.

Conditions

Congenital Hyperinsulinism

Keywords

hyperinsulinism; hypoglycemia; KATP channel; Kir6.2

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Exendin-(9-39) first, the Vehicle

Exendin-(9-39) will be administered intravenously (IV) after an overnight fast. Exendin-(9-39) will be infused over 6 hours with the dose slowly escalating from 100pmol/kg/min for 2 hours, then 300pmol/kg/min for another 2 hours followed by 500pmol/kg/min for the last 2 hours of the infusion. The following day, after another overnight fast, normal saline (control) vehicle infusion will be administered intravenously (IV) over 6 hours. During both infusions, blood glucose levels will be measured every 20 minutes.

Group Type: EXPERIMENTAL

Exendin-(9-39)

Intervention Type: DRUG

A short term intravenous infusion of the study drug, exendin-(9-39), will be given over 6 hours.

Vehicle

Intervention Type: OTHER

A short term intravenous infusion of normal saline, or the vehicle, will be given over 6 hours.

Vehicle first, then Exendin-(9-39)

Normal saline vehicle infusion will be administered intravenously (IV) after an overnight fast. The infusion will be given over 6 hours. The following day, after another overnight fast, Exendin-(9-39) will be infused over 6 hours with the dose slowly escalating from 100pmol/kg/min for 2 hours, then 300pmol/kg/min for another 2 hours followed by 500pmol/kg/min for the last 2 hours of the infusion. During both infusions, blood glucose levels will be measured every 20 minutes.

Group Type: PLACEBO_COMPARATOR

Exendin-(9-39)

Intervention Type: DRUG

A short term intravenous infusion of the study drug, exendin-(9-39), will be given over 6 hours.

Vehicle

Intervention Type: OTHER

A short term intravenous infusion of normal saline, or the vehicle, will be given over 6 hours.

Interventions

Exendin-(9-39)

A short term intravenous infusion of the study drug, exendin-(9-39), will be given over 6 hours.

Intervention Type: DRUG

Vehicle

A short term intravenous infusion of normal saline, or the vehicle, will be given over 6 hours.

Intervention Type: OTHER

Other Intervention Names

Placebo

Eligibility Criteria

Inclusion Criteria

• Subjects with congenital hyperinsulinism

Exclusion Criteria

• Acute medical illness
• History of other systemic chronic disease such as cardiac failure, renal insufficiency, hepatic insufficiency, chronic obstructive pulmonary disease, anemia, or uncontrolled hypertension
• Pregnancy
• Diabetes mellitus
• Use of medications that affect glucose metabolism, such as glucocorticoids, beta agonists, diazoxide and octreotide.
• Subjects will be eligible to participate 48 hrs after the last dose of octreotide and 72 hrs after last dose of diazoxide

• Minimum Eligible Age: 7 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Diva De Leon

OTHER

Sponsor Role: lead

Responsible Party

Diva De Leon

M.D. Assistant Professor of Pediatrics

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Diva D De Leon, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia

Locations

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Countries

United States

References

Calabria AC, Li C, Gallagher PR, Stanley CA, De Leon DD. GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the ATP-sensitive K+ channel. Diabetes. 2012 Oct;61(10):2585-91. doi: 10.2337/db12-0166. Epub 2012 Aug 1.

Reference Type: DERIVED

PMID: 22855730 (View on PubMed)

Other Identifiers

R03DK078535-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2007-1-5131

Identifier Type: -

Identifier Source: org_study_id