The Methodology Assessment of Glucose Dependent Insulin Secretion
Conditions
Brief summary
This study will compare graded glucose infusion (GGI) to the hyperglycemic clamp (HGC) for assessment of glucose-dependent insulin secretion (GDIS) using exenatide as a probe.
Interventions
DRUGComparator: exenatide
exenatide in two 5mcg subcutaneous doses 120 minutes apart, followed by either HGC or GGI. After a 14 day washout period two additional 5mcg doses will be administered, followed by HCG or GGI.
DRUGComparator: Placebo
5% osmitrol in two 60 mcL subcutaneous doses 120 minutes apart, followed by either HGC or GGI. After a 14 day washout period two additional 60 mcL doses will be administered, followed by HCG or GGI.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject has a Body Mass Index (BMI) of less than or equal to 26 kg/m2 at screening * Subject is judged to be in good health * Subject has been a nonsmoker for at least 3 months * Subject is willing to avoid strenuous physical activity for the duration of the study
Exclusion criteria
* Subject has a history of high blood pressure requiring treatment * Subject has a history of diabetes or a family history of diabetes mellitus * Subject is unable to discontinue all prescription and non-prescription drugs for duration of study * Subject consumes more than 3 alcoholic beverages per day * Subject consumes more than 6 servings of caffeinated beverages per day (1 serving = 120mg caffeine) * Subject has had major surgery or has donated or loss 1 unit of blood within 4 weeks of screening * Subject has multiple and/or severe allergies to foods or drugs * Subject is a regular user of illegal drugs * Subject is unwilling or unable to consume the standardized meals during the study and/or is on a carbohydrate restricted diet
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Insulin Concentration | Pre and Post glucose infusion | — |
| Change From Baseline in Insulin Secretion Rate (ISR) Normalized to Ambient Plasma Glucose | Steady-state of HGC: 90 - 120 minutes post dose; highest glucose infusion rate of GGI: 120 - 160 minutes post dose | Comparison of Glucose Dependent Insulin Secretion (GDIS) measured after HGC at steady-state to GDIS measured after GGI at the highest glucose infusion rate. Insulin Secretion Rate (ISR)/ Blood Glucose (BG) |
| Change From Baseline in C-peptide Concentration | Pre and Post glucose infusion | — |
Participant flow
Recruitment details
First Patient Entered: 19-Sep-2008 Last Patient, Last Visit: 05-Mar-2009 1 site
Pre-assignment details
Inclusion criteria: Subjects with a Body Mass Index (BMI) of ≤26 kg/m2 Exclusion criteria: History of diabetes or family history of diabetes. Subjects on a carbohydrate restricted diet. An amendment added 8 subjects to go before study completion and instituted down dosing for subjects assigned to exenatide 5 μg in the HGC period to placebo
Participants by arm
| Arm | Count |
|---|---|
| All Patients All patients from all arms | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Period 1 Procedure/Treatment Groups | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period 1 Procedure/Treatment Groups | Study placed on temporary hold | 1 | 0 | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 29.3 years STANDARD_DEVIATION 9.1 |
| Body Mass Index | 23.3 kg/m^2 STANDARD_DEVIATION 2.1 |
| Gender Female | 0 Participants |
| Gender Male | 27 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 9 | 4 / 9 | 4 / 10 | 6 / 7 | 3 / 8 | 2 / 11 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 0 / 10 | 1 / 7 | 0 / 8 | 0 / 11 |
Outcome results
Primary
Change From Baseline in C-peptide Concentration
Time frame: Pre and Post glucose infusion
Population: All subjects treated
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| HGC - Exenatide 5 μg | Change From Baseline in C-peptide Concentration | 29.3 ng/mL |
| HGC - Exenatide 1.5 μg | Change From Baseline in C-peptide Concentration | 22.6 ng/mL |
| HGC - Placebo | Change From Baseline in C-peptide Concentration | 6.24 ng/mL |
p-value: <0.00190% CI: [19.2, 27]ANOVA
p-value: <0.00190% CI: [12.6, 20.1]ANOVA
Primary
Change From Baseline in Insulin Concentration
Time frame: Pre and Post glucose infusion
Population: All subjects treated
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| HGC - Exenatide 5 μg | Change From Baseline in Insulin Concentration | 592 μIU(insulin)/mL |
| HGC - Exenatide 1.5 μg | Change From Baseline in Insulin Concentration | 293 μIU(insulin)/mL |
| HGC - Placebo | Change From Baseline in Insulin Concentration | 46.5 μIU(insulin)/mL |
p-value: <0.00190% CI: [451.4, 638.7]ANOVA
p-value: <0.00190% CI: [160.9, 323.3]ANOVA
Primary
Change From Baseline in Insulin Secretion Rate (ISR) Normalized to Ambient Plasma Glucose
Comparison of Glucose Dependent Insulin Secretion (GDIS) measured after HGC at steady-state to GDIS measured after GGI at the highest glucose infusion rate. Insulin Secretion Rate (ISR)/ Blood Glucose (BG)
Time frame: Steady-state of HGC: 90 - 120 minutes post dose; highest glucose infusion rate of GGI: 120 - 160 minutes post dose
Population: All subjects treated
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| HGC - Exenatide 5 μg | Change From Baseline in Insulin Secretion Rate (ISR) Normalized to Ambient Plasma Glucose | 2.14 (ng/min) / (mg/dL) |
| HGC - Exenatide 1.5 μg | Change From Baseline in Insulin Secretion Rate (ISR) Normalized to Ambient Plasma Glucose | 1.49 (ng/min) / (mg/dL) |
| HGC - Placebo | Change From Baseline in Insulin Secretion Rate (ISR) Normalized to Ambient Plasma Glucose | 0.53 (ng/min) / (mg/dL) |
| GGI - Exenatide 5 μg | Change From Baseline in Insulin Secretion Rate (ISR) Normalized to Ambient Plasma Glucose | 2.95 (ng/min) / (mg/dL) |
| GGI - Exenatide 1.5 μg | Change From Baseline in Insulin Secretion Rate (ISR) Normalized to Ambient Plasma Glucose | 2.07 (ng/min) / (mg/dL) |
| GGI - Placebo | Change From Baseline in Insulin Secretion Rate (ISR) Normalized to Ambient Plasma Glucose | 0.71 (ng/min) / (mg/dL) |
p-value: <0.00190% CI: [1.29, 1.92]ANOVA
p-value: <0.00190% CI: [0.66, 1.24]ANOVA
p-value: <0.00190% CI: [1.57, 3.06]ANOVA
p-value: <0.00190% CI: [0.64, 2.12]ANOVA