Congenital Hyperinsulinism
Conditions
Keywords
Congenital Hyperinsulinism, Hyperinsulinism, Hypoglycemia, KATP channel, Metabolic Diseases, Pancreatic Disease, Glucose Metabolism Disorders, Infant, Newborn, Diseases
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.
Interventions
DRUGExendin (9-39)
A short-term intravenous infusion of the investigational drug, Exendin (9-39), will be administered over up to 9 hours.
DRUGVehicle
A short-term intravenous infusion of normal saline (0.9% NaCl), or the vehicle, will be administered over up to 9 hours.
Sponsors
Diva De Leon
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
No minimum to 12 Months
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Glucose Infusion Rate (GIR) | Up to 9 hours after the initiation of infusion | To assess the effect of Exendin (9-39) on glucose infusion rate, glucose infusion rate (GIR) over the last 2 hours of the treatment period was calculated by adding the total amount of intravenous glucose (mg) received over 2 hours divided by the weight (kg) and by time (120 min) during infusion of Exendin (9-39) and normal saline vehicle. |
| To Determine the Pharmacokinetics of Exendin (9-39) | Up to 12 hours after the initiation of infusion | The following PK variables of interest include AUC0-∞, AUC0-t, maximal concentration (Cmax), time to maximal concentration (Tmax), concentration at end of infusion (Ceoi), steady state volume of distribution (Vss), clearance (CL) and half-life (t1/2) of Exendin (9-39). These will be derived through both non-compartmental and model-based methods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Exendin (9-39) | Up to 24 hours post-infusion | Number of participants with adverse events as a measure of safety and tolerability \[evaluated by the result of laboratory safety tests (hematology, chemistry, urinalysis), vital signs, physical examinations, and 12-lead ECG\] |
| Mean Plasma Insulin | Up to 9 hours after the initiation of infusion | To assess the effect of Exendin (9-39) on plasma insulin levels, samples were collected at various time points during the infusion \[Exendin (9-39) or vehicle\] including: at the start of the infusion (T=0) and at 1, 5, and 9 hours post initiation of the infusion. |
| Mean Plasma Glucose | Up to 9 hours after the initiation of infusion | To assess the effect of Exendin (9-39) on plasma glucose levels, samples were collected at various time points during the infusion \[Exendin (9-39) or vehicle\] including: at the start of the infusion (T=0) and at 1, 5, and 9 hours post initiation of the infusion. |
| Mean Betahydroxybutyrate Levels | Up to 12 hours after the initiation of infusion | To assess the effect of Exendin (9-39) on mean betahydroxybutyrate levels, samples were collected at various time points during the infusion \[Exendin (9-39) or vehicle\] including: at the start of the infusion (T=0) and hourly up to 12-hours post initiation of the infusion. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on a confirmed clinical diagnosis of congenital hyperinsulinism at 1 academic medical center between August 2009 and October 2019. The first participant was enrolled on August 26, 2008 and the last participant was enrolled in January 25, 2017.
Pre-assignment details
Of the 14 enrolled participants, 13 met inclusion criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Exendin (9-39) 0.02 mg/kg/hr 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). | 5 |
| Exendin (9-39) 0.04 mg/kg/hr 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). | 2 |
| Exendin (9-39) 0.10 mg/kg/hr 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). | 2 |
| Exendin (9-39) 0.20 mg/kg/hr 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). | 4 |
| Total | 13 |
Baseline characteristics
| Characteristic | Exendin (9-39) 0.02 mg/kg/hr | Exendin (9-39) 0.04 mg/kg/hr | Exendin (9-39) 0.10 mg/kg/hr | Exendin (9-39) 0.20 mg/kg/hr | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 2 Participants | 2 Participants | 4 Participants | 13 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 2 Participants | 2 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 01 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 4 Participants | 2 Participants | 2 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 1 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 2 | 0 / 2 | 0 / 4 | 0 / 13 |
| other Total, other adverse events | 1 / 5 | 2 / 2 | 2 / 2 | 4 / 4 | 10 / 13 |
| serious Total, serious adverse events | 0 / 4 | 0 / 2 | 0 / 2 | 0 / 4 | 0 / 13 |
Outcome results
Primary
Mean Glucose Infusion Rate (GIR)
To assess the effect of Exendin (9-39) on glucose infusion rate, glucose infusion rate (GIR) over the last 2 hours of the treatment period was calculated by adding the total amount of intravenous glucose (mg) received over 2 hours divided by the weight (kg) and by time (120 min) during infusion of Exendin (9-39) and normal saline vehicle.
Time frame: Up to 9 hours after the initiation of infusion
Population: Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures.
Primary
To Determine the Pharmacokinetics of Exendin (9-39)
The following PK variables of interest include AUC0-∞, AUC0-t, maximal concentration (Cmax), time to maximal concentration (Tmax), concentration at end of infusion (Ceoi), steady state volume of distribution (Vss), clearance (CL) and half-life (t1/2) of Exendin (9-39). These will be derived through both non-compartmental and model-based methods.
Time frame: Up to 12 hours after the initiation of infusion
Population: Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures.
Secondary
Mean Betahydroxybutyrate Levels
To assess the effect of Exendin (9-39) on mean betahydroxybutyrate levels, samples were collected at various time points during the infusion \[Exendin (9-39) or vehicle\] including: at the start of the infusion (T=0) and hourly up to 12-hours post initiation of the infusion.
Time frame: Up to 12 hours after the initiation of infusion
Population: Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures.
Secondary
Mean Plasma Glucose
To assess the effect of Exendin (9-39) on plasma glucose levels, samples were collected at various time points during the infusion \[Exendin (9-39) or vehicle\] including: at the start of the infusion (T=0) and at 1, 5, and 9 hours post initiation of the infusion.
Time frame: Up to 9 hours after the initiation of infusion
Population: Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures.
Secondary
Mean Plasma Insulin
To assess the effect of Exendin (9-39) on plasma insulin levels, samples were collected at various time points during the infusion \[Exendin (9-39) or vehicle\] including: at the start of the infusion (T=0) and at 1, 5, and 9 hours post initiation of the infusion.
Time frame: Up to 9 hours after the initiation of infusion
Population: Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures.
Secondary
Safety and Tolerability of Exendin (9-39)
Number of participants with adverse events as a measure of safety and tolerability \[evaluated by the result of laboratory safety tests (hematology, chemistry, urinalysis), vital signs, physical examinations, and 12-lead ECG\]
Time frame: Up to 24 hours post-infusion
Population: Subjects served as their own control for comparison between the effects of Exendin (9-39) and the normal saline vehicle. The trial was terminated after 14 participants enrolled in the study. No data is available for any outcome measures.