Clinical trial NCT00835328: 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
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Congenital Hyperinsulinism
Keywords: Congenital Hyperinsulinism
Hyperinsulinism
Hypoglycemia
KATP channel
Metabolic Diseases
Pancreatic Disease
Glucose Metabolism Disorders
Infant, Newborn, Diseases
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
First posted: 2009-02-03
Enrollment: 14
Sex: ALL
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Mean Glucose Infusion Rate (GIR)
timeFrame: Up to 9 hours after the initiation of infusion
measure: To Determine the Pharmacokinetics of Exendin (9-39)
timeFrame: Up to 12 hours after the initiation of infusion
Secondary outcomes:
measure: Safety and Tolerability of Exendin (9-39)
timeFrame: Up to 24 hours post-infusion
measure: Mean Plasma Insulin
timeFrame: Up to 9 hours after the initiation of infusion
measure: Mean Plasma Glucose
timeFrame: Up to 9 hours after the initiation of infusion
measure: Mean Betahydroxybutyrate Levels
timeFrame: Up to 12 hours after the initiation of infusion
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Diva D De Leon, MD MSCE
role: PRINCIPAL_INVESTIGATOR
References: