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| ID | Type | Description | Link |
|---|---|---|---|
| R03DK078535-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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The purpose of this study is to determine if Exendin-(9-39), an antagonist of the glucagon-like peptide-1 (GLP-1) receptor with effects on the pancreatic beta cell, increases fasting blood glucose levels in subjects with congenital hyperinsulinism.
This is an open-label, pilot study , to determine if Exendin-(9-39), an antagonist of the glucagon-like peptide-1 (GLP-1) receptor with effects on the pancreatic beta cells, increases fasting blood glucose levels in subjects with congenital hyperinsulinism. Our overall hypothesis is that abnormal GLP-1 secretion resulting from dysfunctional nutrient sensing in intestinal L-cells plays a role in the dysregulated insulin secretion characteristic of this disorder, and that antagonism of the GLP-1 receptor will increase fasting blood glucose levels.
Aim 1. To evaluate the dose of exendin-(9-39) required to elevate fasting blood glucose levels in subjects with congenital hyperinsulinism due to KATP channel mutations.
Aim 2. To determine therapeutic plasma levels, plasma half-life and pharmacokinetics of exendin-(9-39) during an intravenous short-term infusion in subjects with congenital hyperinsulinism due to Adenosine triphosphate (ATP)-sensitive potassium channel (KATP) mutations.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Exendin-(9-39) first, the Vehicle | Experimental | Exendin-(9-39) will be administered intravenously (IV) after an overnight fast. Exendin-(9-39) will be infused over 6 hours with the dose slowly escalating from 100pmol/kg/min for 2 hours, then 300pmol/kg/min for another 2 hours followed by 500pmol/kg/min for the last 2 hours of the infusion. The following day, after another overnight fast, normal saline (control) vehicle infusion will be administered intravenously (IV) over 6 hours. During both infusions, blood glucose levels will be measured every 20 minutes. |
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| Vehicle first, then Exendin-(9-39) | Placebo Comparator | Normal saline vehicle infusion will be administered intravenously (IV) after an overnight fast. The infusion will be given over 6 hours. The following day, after another overnight fast, Exendin-(9-39) will be infused over 6 hours with the dose slowly escalating from 100pmol/kg/min for 2 hours, then 300pmol/kg/min for another 2 hours followed by 500pmol/kg/min for the last 2 hours of the infusion. During both infusions, blood glucose levels will be measured every 20 minutes. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Exendin-(9-39) | Drug | A short term intravenous infusion of the study drug, exendin-(9-39), will be given over 6 hours. |
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| Measure | Description | Time Frame |
|---|---|---|
| Mean Blood Glucose Area Under the Curve (AUC 0-6h) | To examine the effect of Exendin-(9-39) on fasting blood 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean blood glucose area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. | 6 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Plasma Insulin Area Under the Curve (AUC 0-6h) | 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean plasma insulin area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Diva D 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 |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22855730 | Derived | Calabria AC, Li C, Gallagher PR, Stanley CA, De Leon DD. GLP-1 receptor antagonist exendin-(9-39) elevates fasting blood glucose levels in congenital hyperinsulinism owing to inactivating mutations in the ATP-sensitive K+ channel. Diabetes. 2012 Oct;61(10):2585-91. doi: 10.2337/db12-0166. Epub 2012 Aug 1. |
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Subjects with confirmed genetic and clinical diagnosis of Adenosine triphosphate (ATP)-sensitive potassium channels (KATP) hyperinsulinism were recruited from the Hyperinsulinism Center at the Children's Hospital of Philadelphia
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| ID | Title | Description |
|---|---|---|
| FG000 | Exendin-(9-39) First, the Vehicle | Exendin-(9-39) was administered intravenously (IV) after an overnight fast. Exendin-(9-39) was infused over 6 hours with the dose slowly escalating from 100pmol/kg/min for 2 hours, then 300pmol/kg/min for another 2 hours followed by 500pmol/kg/min for the last 2 hours of the infusion. The following day, after another overnight fast, normal saline (control) vehicle infusion was administered intravenously (IV) over 6 hours. During both infusions, blood glucose levels were measured every 20 minutes. |
| FG001 | Vehicle First, Then Exendin-(9-39) | Normal saline vehicle infusion was administered intravenously (IV) after an overnight fast. The infusion was given over 6 hours. The following day, after another overnight fast, Exendin-(9-39) was infused over 6 hours with the dose slowly escalating from 100pmol/kg/min for 2 hours, then 300pmol/kg/min for another 2 hours followed by 500pmol/kg/min for the last 2 hours of the infusion. During both infusions, blood glucose levels were measured every 20 minutes. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Intervention 1 (7 Hours) |
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| Intervention 2 (7 Hours) |
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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 Blood Glucose Area Under the Curve (AUC 0-6h) | To examine the effect of Exendin-(9-39) on fasting blood 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean blood glucose area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. | Subjects served as their own control for comparison between effects of Exendin-(9-39) and the normal saline vehicle. | Posted | Mean | Standard Error | mmol*min/L | 6 hours |
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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) | Exendin-(9-39) was administered intravenously (IV) after an overnight fast. Exendin-(9-39) was infused over 6 hours with the dose slowly escalating from 100pmol/kg/min for 2 hours, then 300pmol/kg/min for another 2 hours followed by 500pmol/kg/min for the last 2 hours of the infusion. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypoglycemia | Endocrine disorders | Systematic Assessment |
Due to safety concerns subjects with symptomatic hypoglycemia were rescued with dextrose to maintain glucose levels >60mg/dL limiting detectable treatment effect.
| 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 |
|---|---|
| D044903 | Congenital Hyperinsulinism |
| D006946 | Hyperinsulinism |
| D007003 | Hypoglycemia |
| ID | Term |
|---|---|
| D010182 | Pancreatic Diseases |
| D004066 | Digestive System Diseases |
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| ID | Term |
|---|---|
| C083773 | exendin (9-39) |
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| Vehicle | Other | A short term intravenous infusion of normal saline, or the vehicle, will be given over 6 hours. |
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| 6 hours |
| Mean Plasma Glucagon Area Under the Curve (AUC 0-6h) | To examine the effect of Exendin-(9-39) on plasma glucagon 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean plasma glucagon area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. | 6 hours |
| Mean Plasma Intact Glucagon-Like Peptide-1 (GLP-1) Area Under the Curve (AUC 0-6h) | To examine the effect of Exendin-(9-39) on plasma intact glucagon-like Peptide-1 (GLP-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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean intact GLP-1 area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. | 6 hours |
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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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| Mutation (ABCC8) | Number | participants |
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| Pancreatectomy | Whether subject has undergone prior pancreatectomy during infancy and if so, what percent of the pancreas was removed. | Number | participants |
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| OG001 | Vehicle | Normal saline vehicle infusion was administered intravenously (IV) after an overnight fast. The infusion was given over 6 hours. |
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| Secondary | Mean Plasma Insulin Area Under the Curve (AUC 0-6h) | 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean plasma insulin area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. | Subjects served as their own control for comparison between effects of Exendin-(9-39) and the normal saline vehicle. | Posted | Mean | Standard Error | pmol*min/L | 6 hours |
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|
|
| Secondary | Mean Plasma Glucagon Area Under the Curve (AUC 0-6h) | To examine the effect of Exendin-(9-39) on plasma glucagon 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean plasma glucagon area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. | Subjects served as their own control for comparison between effects of Exendin-(9-39) and the normal saline vehicle. | Posted | Mean | Standard Error | pg*min/dL | 6 hours |
|
|
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| Secondary | Mean Plasma Intact Glucagon-Like Peptide-1 (GLP-1) Area Under the Curve (AUC 0-6h) | To examine the effect of Exendin-(9-39) on plasma intact glucagon-like Peptide-1 (GLP-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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean intact GLP-1 area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. | Subjects served as their own control for comparison between effects of Exendin-(9-39) and the normal saline vehicle. | Posted | Mean | Standard Error | pmol*min/L | 6 hours |
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| 0 |
| 9 |
| 0 |
| 9 |
| EG001 | Vehicle | Normal saline vehicle infusion was administered intravenously (IV) after an overnight fast. The infusion was given over 6 hours. | 0 | 9 | 4 | 9 |
| Headache | General disorders | Systematic Assessment |
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| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |