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| Name | Class |
|---|---|
| Lester and Liesel Baker Foundation | UNKNOWN |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Exendin-(9-39) first, then Vehicle | Experimental | 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. |
|
| Vehicle first, then Exendin-(9-39) | Active Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Exendin-(9-39) | Drug | IV infusion of exendin-(9-39) for 5 hours |
|
| Measure | Description | Time Frame |
|---|---|---|
| Mean Plasma Glucose Area Under the Curve (AUC 0-3h) | 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. | 3 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Plasma Insulin Area Under the Curve (AUC 0-3h) | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Diva De Leon, MD | Children's Hospital of Philadelphia | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
One subject signed consent but they were excluded from study participation after the study team was unable to establish IV access.
Children were recruited from the Division of Endocrinology and Diabetes at The Children's Hospital of Philadelphia.
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| ID | Title | Description |
|---|---|---|
| FG000 | Exendin-(9-39) First, Then Vehicle | After an overnight fast, an intravenous (IV) infusion of Exendin-(9-39) was started 1 hour prior to the meal challenge and continued for 4 hours. After the first hour of the infusion, subjects underwent a mixed meal tolerance test in which Pediasure (10cc/kg) was consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes. Blood samples were drawn 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 was 300pmol/kg/min and, as planned, it was increased to 500pmol/kg/min for subsequent subjects. The next day, all procedures were repeated except subjects received an IV infusion of normal saline (vehicle) over 4 hours. |
| FG001 | Vehicle First, Then Exendin-(9-39) | After an overnight fast, an intravenous (IV) infusion of normal saline (vehicle) was started 1 hour prior to the meal challenge and continued for 4 hours. After the first hour of the infusion, subjects underwent a mixed meal tolerance test in which Pediasure (10cc/kg) was consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes. Blood samples were drawn to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1). The next day, all procedures were repeated except subjects received an IV infusion of Exendin-(9-39) which was started 1 hour prior to the meal challenge and continued for 4 hours. The dose for the first 3 subjects was 300pmol/kg/min and, as planned, it was increased to 500pmol/kg/min for subsequent subjects. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Intervention 1 (4 Hours) |
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| Intervention 2 (4 Hours) |
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Baseline analysis population includes all subjects who were randomized and began treatment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Subject Population | All subjects enrolled and treated in the protocol served as their own control. Because of this and the small sample size, baseline characteristic data is presented together. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Mean Plasma Glucose Area Under the Curve (AUC 0-3h) | 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. | Changes were compared between the two dose levels of Exendin-(9-39) of 300pmol/kg/min (3 subjects) and 500pmol/kg/min (3 subjects) were compared to the vehicle infusion (all 6 subjects). | Posted | Mean | Standard Error | mg*min/dl | 3 hours |
|
30 days following the last administration of study treatment (either Exendin-(9-39) or vehicle)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Exendin-(9-39) 300pmol/kg/Min Dose | After an overnight fast, an intravenous (IV) infusion of Exendin-(9-39) was started 1 hour prior to the meal challenge and continued for 4 hours. After the first hour of the infusion, subjects underwent a mixed meal tolerance test in which Pediasure (10cc/kg) was consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes. Blood samples were drawn during the infusion to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1). The Exendin-(9-39) dose was 300pmol/kg/min, infused over 4 total hours. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Muscle Spasm | Musculoskeletal and connective tissue disorders | Systematic Assessment |
The primary limitation in addition to small sample size, relates to the fact that none of the subjects experienced significant hypoglycemia during the 3 hour post-meal period.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Diva De Leon, MD | Children's Hospital of Philadelphia | 267-426-5529 | DELEON@email.chop.edu |
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| ID | Term |
|---|---|
| D007003 | Hypoglycemia |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C083773 | exendin (9-39) |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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| Vehicle | Other | Normal saline (vehicle) infusion for 5 hours at 0.06 mL/kg/hr |
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| 3 hours |
| Mean Acetaminophen Plasma Concentration Area Under the Curve (AUC 0-3h) | 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. | 3 hours |
| Peak Plasma Glucagon-like Peptide-1 (GLP-1) Concentration During 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. | 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 |
| Peak Glucagon Concentration During 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. | 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 |
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| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Previous Surgery | Number | participants |
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| Feeding Regimen | Number | participants |
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| Post-Prandial Hypoglycemia Treatment | Subjects with feeding manipulations had feedings which were modified to decrease volume and slow the rate of delivery. | Number | participants |
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| Post-Prandial Hypoglycemia Treatment Frequency | Number | participants |
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| Age at Post-Prandial Hypoglycemia Diagnosis | Number | participants |
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After an overnight fast, an intravenous (IV) infusion of Exendin-(9-39) was started 1 hour prior to the meal challenge and continued for 4 hours. After the first hour of the infusion, subjects underwent a mixed meal tolerance test in which Pediasure (10cc/kg) was consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes. Blood samples were drawn during the infusion to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1). The Exendin-(9-39) dose was 300pmol/kg/min, infused over 4 total hours.
| OG001 | Exendin-(9-39) 500pmol/kg/Min Dose | After an overnight fast, an intravenous (IV) infusion of Exendin-(9-39) was started 1 hour prior to the meal challenge and continued for 4 hours. After the first hour of the infusion, subjects underwent a mixed meal tolerance test in which Pediasure (10cc/kg) was consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes. Blood samples were drawn during the infusion to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1). The Exendin-(9-39) dose was 500pmol/kg/min, infused over 4 total hours. |
| OG002 | Vehicle | After an overnight fast, an intravenous (IV) infusion of normal saline (vehicle) was started 1 hour prior to the meal challenge and continued for 4 hours. After the first hour of the infusion, subjects underwent a mixed meal tolerance test in which Pediasure (10cc/kg) was consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes. Blood samples were drawn during the infusion to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1). The vehicle was infused over 4 total hours. |
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| Secondary | Mean Plasma Insulin Area Under the Curve (AUC 0-3h) | 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. | Changes were compared between the two dose levels of Exendin-(9-39) of 300pmol/kg/min (3 subjects) and 500pmol/kg/min (3 subjects) were compared to the vehicle infusion (all 6 subjects). | Posted | Mean | Standard Error | pmol*min/l | 3 hours |
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|
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| Secondary | Mean Acetaminophen Plasma Concentration Area Under the Curve (AUC 0-3h) | 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. | AUC were compared between the two dose levels of Exendin-(9-39) of 300pmol/kg/min (3 subjects) and 500pmol/kg/min (3 subjects) were compared to the vehicle infusion (all 6 subjects). | Posted | Mean | Standard Error | μg*min/l | 3 hours |
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| Secondary | Peak Plasma Glucagon-like Peptide-1 (GLP-1) Concentration During 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. | Differences were compared between the two dose levels of Exendin-(9-39) of 300pmol/kg/min (3 subjects) and 500pmol/kg/min (3 subjects) were compared to the vehicle infusion (all 6 subjects). | Posted | Mean | Standard Error | pmol/l | 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 |
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| Secondary | Peak Glucagon Concentration During 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. | Differences in peak glucagon concentration were compared between the two dose levels of Exendin-(9-39) of 300pmol/kg/min (3 subjects) and 500pmol/kg/min (3 subjects) were compared to the vehicle infusion (all 6 subjects). | Posted | Mean | Standard Error | pg/ml | 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 |
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| 0 |
| 3 |
| 0 |
| 3 |
| EG001 | Exendin-(9-39) 500pmol/kg/Min Dose | After an overnight fast, an intravenous (IV) infusion of Exendin-(9-39) was started 1 hour prior to the meal challenge and continued for 4 hours. After the first hour of the infusion, subjects underwent a mixed meal tolerance test in which Pediasure (10cc/kg) was consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes. Blood samples were drawn during the infusion to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1). The Exendin-(9-39) dose was 500pmol/kg/min, infused over 4 total hours. | 0 | 3 | 0 | 3 |
| EG002 | Vehicle | After an overnight fast, an intravenous (IV) infusion of normal saline (vehicle) was started 1 hour prior to the meal challenge and continued for 4 hours. After the first hour of the infusion, subjects underwent a mixed meal tolerance test in which Pediasure (10cc/kg) was consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes. Blood samples were drawn during the infusion to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1). The vehicle was infused over 4 total hours. | 0 | 6 | 2 | 6 |
| Hypoglycemia | Endocrine disorders | Systematic Assessment |
|
| Gastrostomy-tube discharge | Gastrointestinal disorders | Systematic Assessment | Subject reported discharge from G-tube at home, after completion of study infusions |
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