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

Diva De Leon

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Congenital Hyperinsulinism

Treatments: Drug: Vehicle; Drug: Exendin (9-39)

Study type: Interventional

Funder types: Other

Identifiers

NCT00835328

2008-10-6256

Details and patient eligibility

About

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.

Full 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.

Enrollment: 14 patients

Sex: All

Ages: Under 12 months old

Volunteers: No 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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14 participants in 4 patient groups

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

Experimental group

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.

Treatment:

Drug: Exendin (9-39)

Drug: Vehicle

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

Experimental group

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.

Treatment:

Drug: Exendin (9-39)

Drug: Vehicle

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

Experimental group

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.

Treatment:

Drug: Exendin (9-39)

Drug: Vehicle

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

Experimental group

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.

Treatment:

Drug: Exendin (9-39)

Drug: Vehicle