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

Primary Purpose

Congenital Hyperinsulinism

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Exendin (9-39)
Vehicle
Sponsored by
Diva De Leon
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Congenital Hyperinsulinism focused on measuring Congenital Hyperinsulinism, Hyperinsulinism, Hypoglycemia, KATP channel, Metabolic Diseases, Pancreatic Disease, Glucose Metabolism Disorders, Infant, Newborn, Diseases

Eligibility Criteria

undefined - 12 Months (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • The Children's Hospital of Philadelphia

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Exendin (9-39) 0.02 mg/kg/hr

Exendin (9-39) 0.04 mg/kg/hr

Exendin (9-39) 0.10 mg/kg/hr

Exendin (9-39) 0.20 mg/kg/hr

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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]
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.
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.
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.

Full Information

First Posted
February 2, 2009
Last Updated
May 16, 2020
Sponsor
Diva De Leon
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1. Study Identification

Unique Protocol Identification Number
NCT00835328
Brief Title
Effect of Exendin (9-39) on Glucose Requirements to Maintain Euglycemia
Official Title
Role of Glucagon-Like Peptide-1 (GLP-1) in Congenital Hyperinsulinism: Effect of Exendin (9-39) on Glucose Requirements to Maintain Euglycemia
Study Type
Interventional

2. Study Status

Record Verification Date
May 2020
Overall Recruitment Status
Terminated
Why Stopped
Study stopped prematurely to test a new formulation of Exendin (9-39)
Study Start Date
August 26, 2009 (Actual)
Primary Completion Date
January 28, 2017 (Actual)
Study Completion Date
January 28, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Diva De Leon

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Congenital Hyperinsulinism
Keywords
Congenital Hyperinsulinism, Hyperinsulinism, Hypoglycemia, KATP channel, Metabolic Diseases, Pancreatic Disease, Glucose Metabolism Disorders, Infant, Newborn, Diseases

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Crossover Assignment
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)
Allocation
Randomized
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Exendin (9-39) 0.02 mg/kg/hr
Arm Type
Experimental
Arm Description
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.
Arm Title
Exendin (9-39) 0.04 mg/kg/hr
Arm Type
Experimental
Arm Description
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.
Arm Title
Exendin (9-39) 0.10 mg/kg/hr
Arm Type
Experimental
Arm Description
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.
Arm Title
Exendin (9-39) 0.20 mg/kg/hr
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Exendin (9-39)
Intervention Description
A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours.
Intervention Type
Drug
Intervention Name(s)
Vehicle
Other Intervention Name(s)
Placebo
Intervention Description
A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours.
Primary Outcome Measure Information:
Title
Mean Glucose Infusion Rate (GIR)
Description
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.
Time Frame
Up to 9 hours after the initiation of infusion
Title
To Determine the Pharmacokinetics of Exendin (9-39)
Description
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.
Time Frame
Up to 12 hours after the initiation of infusion
Secondary Outcome Measure Information:
Title
Safety and Tolerability of Exendin (9-39)
Description
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]
Time Frame
Up to 24 hours post-infusion
Title
Mean Plasma Insulin
Description
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.
Time Frame
Up to 9 hours after the initiation of infusion
Title
Mean Plasma Glucose
Description
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.
Time Frame
Up to 9 hours after the initiation of infusion
Title
Mean Betahydroxybutyrate Levels
Description
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.
Time Frame
Up to 12 hours after the initiation of infusion

10. Eligibility

Sex
All
Maximum Age & Unit of Time
12 Months
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Diva D De Leon, MD MSCE
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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

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