Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia

• ClinicalTrials.gov Identifier: NCT01162499
• Recruitment Status: Completed
• First Posted: July 14, 2010
• Results First Posted: November 9, 2016
• Last Update Posted: October 23, 2017
• Sponsor: Diva De Leon
• Collaborator: Lester and Liesel Baker Foundation
• Information provided by (Responsible Party): Diva De Leon, Children's Hospital of Philadelphia

Tracking Information

• First Submitted Date: May 4, 2010
• First Posted Date: July 14, 2010
• Results First Submitted Date: July 29, 2016
• Results First Posted Date: November 9, 2016
• Last Update Posted Date: October 23, 2017
• Study Start Date: April 2010
• Actual Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 22, 2016)

Mean Plasma Glucose Area Under the Curve (AUC 0-3h) [ Time Frame: 3 hours ]

To examine the effect of Exendin-(9-39) on plasma 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 30 minutes until 3 hours after the start of the meal. Using this information, the mean plasma glucose area under the curve (AUC) from the start of the infusion to the end of the infusion (3 hours) was calculated for both doses of Exendin-(9-39) [300pmol/kg/min & 500pmol/kg/min] and compared with the vehicle.

Original Primary Outcome Measures (submitted: July 13, 2010)

Nadir blood glucose levels [ Time Frame: -60 to 180 minutes ]

Hypoglycemia sometimes occurs without being preceded by hyperglycemia but in association with high insulin levels. GLP-1 stimulated by the rapid emptying of liquid meals into the intestine may be responsible for the exaggerated insulin rise and subsequent hypoglycemia.

• Change History: Complete list of historical versions of study NCT01162499 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: September 22, 2016)

• Mean Plasma Insulin Area Under the Curve (AUC 0-3h) [ Time Frame: 3 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 30 minutes until 3 hours after the start of the meal. Using this information, the mean plasma insulin area under the curve (AUC) from the start of the infusion to the end of the infusion (3 hours) was calculated for both doses of Exendin-(9-39) [300pmol/kg/min & 500pmol/kg/min] and compared with the vehicle.
• Mean Acetaminophen Plasma Concentration Area Under the Curve (AUC 0-3h) [ Time Frame: 3 hours ]
  The effect of gastric emptying was examined using the acetaminophen method whereby acetaminophen (30mg/kg or maximum of 1500mg) was mixed into the Pediasure/formula during the meal tolerance testing. Blood samples were collected every 30 minutes and the absorption of acetaminophen was determined by the gastric emptying rate, as the serum concentrations correlate with gastric emptying of liquids. Mean acetaminophen levels for each group at each time point were used to calculate the Area Under the Concentration versus Time Curve (AUC expressed in μg*min/l) after the consumption of formula for each of the two Exendin-(9-39) dose levels and normal saline vehicle.
• Peak Plasma Glucagon-like Peptide-1 (GLP-1) Concentration During Infusion [ Time Frame: 60 minutes before the start of the infusion, again at the start of the infusion (time 0), and then every 30 minutes until 3 hours after the start of the infusion ]
  To examine the effect of Exendin-(9-39) on plasma glucagon-like peptide-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 30 minutes until 3 hours after the start of the infusion. The mean peak glucagon-like peptide-1 concentration for both Exendin-(9-39) doses were compared with the peak glucagon-like peptide-1 during vehicle infusion.
• Peak Glucagon Concentration During Infusion [ Time Frame: 60 minutes before the start of the infusion, again at the start of the infusion (time 0), and then every 30 minutes until 3 hours after the start of the infusion ]
  To examine the effect of Exendin-(9-39) on plasma glucagon levels, samples were collected at various 3 hours after the start of the infusion. The mean peak glucagon concentration for both Exendin-(9-39) doses were compared with the peak glucagon during vehicle infusion.

Original Secondary Outcome Measures (submitted: July 13, 2010)

• Plasma insulin and glucagon levels. [ Time Frame: 0 to 180 minutes ]
  glucagon will only be obtained in subjects that weight is > or equal to 9kg
• acetaminophen levels [ Time Frame: samples taken every 30 minutes after ingestion of mixed meal (pediasure/formula) ]
  evaluation fo gastric emptying- acetaminophen levels
• plasma GLP1 [ Time Frame: 0 to 180 minutes ]
  collection of GLP1 after ingestion of Mixed meal

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia
• Official Title: Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia After Nissen Fundoplication: Studies With the GLP-1 Receptor Antagonist Exendin-(9-39)

Brief Summary

It has been proposed that the rapid gastric emptying of carbohydrate containing fluids into the intestine causes hyperglycemia followed by reactive hypoglycemia. The investigators have shown that glucagon-like peptide-1 (GLP-1) secretion in response to a glucose load is increased in children with Post-prandial hypoglycemia (PPH). This is a proof of concept study to investigate the causative role of GLP-1 in the pathophysiology of PPH after fundoplication by evaluating the effects of GLP-1 receptor antagonism on metabolic variables after a mixed meal.

Hypothesis: In children with post-prandial hypoglycemia after fundoplication, antagonism of the GLP-1 receptor by exendin-(9-39) will elevate nadir blood glucose levels after a meal challenge and prevent post-prandial hypoglycemia.

• Detailed Description: PPH is a frequent complication of fundoplication in children. The mechanism responsible for the PPH is poorly understood, but involves an exaggerated insulin response to a meal and subsequent hypoglycemia. We have shown that children with PPH after Nissen fundoplication have abnormally exaggerated secretion of GLP-1, an incretin hormone with multiple glucose lowering effects including stimulation of insulin secretion and suppression of glucagon secretion. In this study we seek to examine the causal role of endogenous GLP-1 in PPH after fundoplication by evaluating the effects of antagonizing the GLP-1 receptor with exendin-(9-39) on key metabolic features of PPH.
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Postprandial Hypoglycemia

Intervention

• Drug: Exendin-(9-39)
  IV infusion of exendin-(9-39) for 5 hours
• Other: Vehicle
  Normal saline (vehicle) infusion for 5 hours at 0.06 mL/kg/hr
  Other Name: Normal Saline

Study Arms

• Experimental: Exendin-(9-39) first, then Vehicle

  After an overnight fast, an intravenous (IV) infusion of Exendin-(9-39) will be started 1 hour prior to the meal challenge and continued for 5 hours. After the first hour of the infusion, subjects will undergo a mixed meal tolerance test in which Pediasure (10cc/kg) will be consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes (for infants under 12 months, Pediasure will be replaced by the infant's formula). Blood samples will be drawn at different time points during the infusion to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1). The Exendin-(9-39) dose for the first 3 subjects will be 300pmol/kg/min and, if tolerated, the dose will be increased to 500pmol/kg/min for subsequent subjects.

  The next day, all procedures will be repeated except subjects will receive an IV infusion of normal saline (vehicle) over 6 hours.

  Interventions:

  • Drug: Exendin-(9-39)
  • Other: Vehicle
• Active Comparator: Vehicle first, then Exendin-(9-39)

  After an overnight fast, an intravenous (IV) infusion of normal saline (vehicle) will be started 1 hour prior to the meal challenge and continued for 5 hours. After the first hour of the infusion, subjects will undergo a mixed meal tolerance test in which Pediasure (10cc/kg) will be consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes (for infants under 12 months, Pediasure will be replaced by the infant's formula). Blood samples will be drawn at different time points during the infusion to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1).

  The next day, all procedures will be repeated except subjects will receive an IV infusion of Exendin-(9-39) which will be started 1 hour prior to the meal challenge and continue for 5 hours. The dose for the first 3 subjects will be 300pmol/kg/min and, if tolerated, the dose will be increased to 500pmol/kg/min for subsequent subjects.

  Interventions:

  • Drug: Exendin-(9-39)
  • Other: Vehicle

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 12, 2015): 7
• Original Estimated Enrollment (submitted: July 13, 2010): 16
• Actual Study Completion Date: December 2014
• Actual Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Children (6 months-18 years) who have had fundoplication or other gastric surgeries, irrespective of duration of postoperative period
• Weight > 6.5 Kg
• Signs and/or symptoms of PPH: post-prandial blood glucose levels of < 70 mg/dL ; symptoms including but not limited to feeding difficulties, irritability, nausea, diarrhea, pallor, diaphoresis, weakness, and lethargy after meals

Exclusion Criteria:

• Evidence of a medical condition that might alter results or compromise the elimination of the peptide, including, but not limited to: active infection, kidney failure (creatinine ≥ 2x above upper limit for age), severe liver dysfunction (AST or ALT ≥ 5x upper limit of normal for AST or ALT), severe respiratory or cardiac failure
• Other disorders of glucose regulation such as diabetes mellitus, congenital hyperinsulinism, glycogen storage disease
• Current use (within 1 week) of medications that may alter glucose homeostasis such as glucocorticoids, diazoxide, octreotide
• Use of antihistaminics within 10 days prior to the study
• Moderate and severe anemia defined as a hemoglobin < 10g/dL
• Pregnancy
• Milk and soy protein allergy

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 18 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01162499
• Other Study ID Numbers: 09-007372
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Diva De Leon, Children's Hospital of Philadelphia
• Study Sponsor: Diva De Leon
• Collaborators: Lester and Liesel Baker Foundation

Investigators

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

• PRS Account: Children's Hospital of Philadelphia
• Verification Date: September 2017