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

• ClinicalTrials.gov Identifier: NCT00571324
• Recruitment Status: Completed
• First Posted: December 12, 2007
• Results First Posted: November 9, 2016
• Last Update Posted: December 11, 2017
• Sponsor: Diva De Leon
• Collaborators: National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Diva De Leon, Children's Hospital of Philadelphia

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Congenital Hyperinsulinism	Drug: Exendin-(9-39); Other: Vehicle	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: An Open Label Pilot Study of the Effects of the Glucagon-like Peptide-1 Receptor Antagonist, Exendin-(9-39) on Glycemic Control in Subjects With Congenital Hyperinsulinism
• Study Start Date: August 2007
• Actual Primary Completion Date: December 2014
• Actual Study Completion Date: December 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: Exendin-(9-39); A short term intravenous infusion of the study drug, exendin-(9-39), will be given over 6 hours.; Other: Vehicle; A short term intravenous infusion of normal saline, or the vehicle, will be given over 6 hours.; Other Name: Placebo
Placebo Comparator: 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.	Drug: Exendin-(9-39); A short term intravenous infusion of the study drug, exendin-(9-39), will be given over 6 hours.; Other: Vehicle; A short term intravenous infusion of normal saline, or the vehicle, will be given over 6 hours.; Other Name: Placebo

Outcome Measures

Primary Outcome Measures :

1. Mean Blood Glucose Area Under the Curve (AUC 0-6h) [ Time Frame: 6 hours ]
   To examine the effect of Exendin-(9-39) on fasting blood glucose levels, samples were collected at various time points before and during the infusion [Exendin-(9-39) or vehicle] including: 60 minutes before the start of the infusion, again at the start of the infusion (Time 0), and then every 20 minutes until 6 hours after the start of the infusion. Using this information, the mean blood glucose area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared.

Secondary Outcome Measures :

1. Mean Plasma Insulin Area Under the Curve (AUC 0-6h) [ Time Frame: 6 hours ]
   To examine the effect of Exendin-(9-39) on plasma insulin levels, samples were collected at various time points before and during the infusion [Exendin-(9-39) or vehicle] including: 60 minutes before the start of the infusion, again at the start of the infusion (Time 0), and then every 20 minutes until 6 hours after the start of the infusion. Using this information, the mean plasma insulin area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared.
2. Mean Plasma Glucagon Area Under the Curve (AUC 0-6h) [ Time Frame: 6 hours ]
   To examine the effect of Exendin-(9-39) on plasma glucagon levels, samples were collected at various time points before and during the infusion [Exendin-(9-39) or vehicle] including: 60 minutes before the start of the infusion, again at the start of the infusion (Time 0), and then every 20 minutes until 6 hours after the start of the infusion. Using this information, the mean plasma glucagon area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared.
3. Mean Plasma Intact Glucagon-Like Peptide-1 (GLP-1) Area Under the Curve (AUC 0-6h) [ Time Frame: 6 hours ]
   To examine the effect of Exendin-(9-39) on plasma intact glucagon-like Peptide-1 (GLP-1) levels, samples were collected at various time points before and during the infusion [Exendin-(9-39) or vehicle] including: 60 minutes before the start of the infusion, again at the start of the infusion (Time 0), and then every 20 minutes until 6 hours after the start of the infusion. Using this information, the mean intact GLP-1 area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared.

Eligibility Criteria

• Ages Eligible for Study: 7 Years to 60 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Pennsylvania

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Sponsors and Collaborators

Diva De Leon

National Institutes of Health (NIH)

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

Investigators

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Calabria AC, Li C, Gallagher PR, Stanley CA, De León 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. Epub 2012 Aug 1.

• Responsible Party: Diva De Leon, M.D. Assistant Professor of Pediatrics, Children's Hospital of Philadelphia
• ClinicalTrials.gov Identifier: NCT00571324
• Other Study ID Numbers: 2007-1-5131; R03DK078535-01 ( U.S. NIH Grant/Contract )
• First Posted: December 12, 2007
• Results First Posted: November 9, 2016
• Last Update Posted: December 11, 2017
• Last Verified: November 2017

Keywords provided by Diva De Leon, Children's Hospital of Philadelphia:

hyperinsulinism; hypoglycemia; KATP channel; Kir6.2

Additional relevant MeSH terms:

Congenital Hyperinsulinism; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Pancreatic Diseases; Digestive System Diseases; Infant, Newborn, Diseases; Hypoglycemia