Type 2 Diabetes Mellitus
Conditions
Brief summary
This study aims to assess how glimepiride affects the recovery from hypoglycemia in participants with type 2 diabetes mellitus. The primary objective is to estimate the time taken by participants to recover from hypoglycemia to euglycemia after treatment with either 2 mg or 4 mg of glimepiride when compared to placebo.
Interventions
DRUGPlacebo
Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.
DRUGGlimepiride 2 mg
One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.
DRUGGlimepiride 4 mg
Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.
PROCEDUREHypoglycemic Clamp
On Day 1 of the three treatment periods, 180 minutes after drug treatment, a fixed-rate insulin infusion is combined with a variable-rate dextrose infusion to maintain plasma glucose concentrations at close to 50 mg/dL for 30 minutes.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Has clinically confirmed diagnosis of type 2 diabetes mellitus (T2DM) controlled by diet and exercise alone, or treated by metformin only with same dose for \>= 12 weeks prior to screening visit. * Females of reproductive potential who demonstrate nongravid state, agree to use (and/or have partner use) two acceptable methods of birth control starting at least two weeks prior to study, throughout study, and at least two weeks after last dose of study drug. * Females of non-reproductive potential, post menopausal, status post hysterectomy, oophorectomy or tubal ligation. * Is in good health, other than T2DM. * Has been a nonsmoker and/or non user of nicotine-containing products for the previous 6 months. If discontinued use for previous 3 months, may be enrolled at investigator's discretion. * Will follow American Heart Association weight maintaining diet and exercise program or equivalent beginning 2 weeks prior to study until poststudy visit. * At screening visit has a Body Mass Index (BMI) =\< 40 kg/m\^2. * At screening visit has a Hemoglobin A1c (HbA1c) of \>= 7% and \< 10% (+/- 0.1%). * On the morning of randomization at predose has fasting plasma glucose (FPG) \>= 126 mg/dL, and =\< 250 mg/dL.
Exclusion criteria
* Has a history of stroke, chronic seizures, or major neurological disorder. * Has a history of any illness that might confound the results of the study or pose additional risk to the participant. * Has a history of type 1 diabetes mellitus, ketoacidosis, C-peptide =\< 0.8 ng/mL, secondary forms of diabetes or diabetic complications. * Has a history of neoplastic disease. * Is a nursing mother. * Has been treated =\< one year of screening visit with sulfonylurea agents, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs, or insulin. * Has received treatment within =\< 12 weeks of screening visit with a peroxisome proliferator-activated receptor γ (PPARγ) agonist. * Is taking medications for a co-morbid condition or anticipates taking new medications beginning 2 weeks prior to study. * Consumes excessive amounts of alcohol or caffeinated beverages. * Is a regular user of illicit drugs, or has a history of drug abuse within the previous 6 months. * Has had major surgery, lost 500 mL of blood, or participated in another investigational study within 4 weeks prior to screening visit. * Is on a weight loss program, but not in the maintenance phase, or treated with a weight loss medication within 8 weeks of prestudy visit. * Has a history of severe allergies, anaphylactic reaction or intolerability to drugs, food, insulin, glimepiride or sulfonamide derivatives.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recovery Time From Hypoglycemia to Euglycemia | From 1 to 180 minutes post hypoglycemic clamp | Immediately after release of the hypoglycemic clamp, which maintained blood glucose close to 50 mg/dL, the time taken until glucose reached euglycemia, defined as 3 consecutive measurements \>= 70 mg/dL, is called the recovery time. |
| Rate of Recovery From Hypoglycemia to Euglycemia | From 1 to 180 minutes post hypoglycemic clamp | The rate of recovery is the difference in concentration between blood glucose at euglycemia and at the end of the hypoglycemic clamp, divided by the recovery time. |
| Incremental Weighted Average Blood Glucose Concentration Over 3 Hours of Hypoglycemic Recovery | From 1 to 180 minutes post hypoglycemic clamp | The incremental weighted average qualitatively assesses overall hypoglycemic recovery by measuring mean glycemia over the 3 hour recovery period. Blood glucose measured at the release of the hypoglycemic clamp, considered the baseline value, was subtracted from blood glucose values measured over the ensuing 3 hours of hypoglycemic recovery. These differences from baseline were averaged to calculate the incremental weighted average blood glucose concentration. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All randomized participants | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 1 | Discontinued due to Hypoglycemia | 0 | 0 | 0 | 1 | 0 | 1 |
| Period 1 | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 |
| Period 1 | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 |
| Period 3 | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 49.3 Years STANDARD_DEVIATION 5.5 |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 9 | 2 / 6 | 4 / 7 |
| serious Total, serious adverse events | 0 / 9 | 0 / 6 | 0 / 7 |
Outcome results
Primary
Incremental Weighted Average Blood Glucose Concentration Over 3 Hours of Hypoglycemic Recovery
The incremental weighted average qualitatively assesses overall hypoglycemic recovery by measuring mean glycemia over the 3 hour recovery period. Blood glucose measured at the release of the hypoglycemic clamp, considered the baseline value, was subtracted from blood glucose values measured over the ensuing 3 hours of hypoglycemic recovery. These differences from baseline were averaged to calculate the incremental weighted average blood glucose concentration.
Time frame: From 1 to 180 minutes post hypoglycemic clamp
Population: The per-protocol population consisting of participants who received drug and completed the necessary post treatment measurements for at least one treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Incremental Weighted Average Blood Glucose Concentration Over 3 Hours of Hypoglycemic Recovery | 22.61 mg/dL |
| Glimepiride 2 mg | Incremental Weighted Average Blood Glucose Concentration Over 3 Hours of Hypoglycemic Recovery | 17.58 mg/dL |
| Glimepiride 4 mg | Incremental Weighted Average Blood Glucose Concentration Over 3 Hours of Hypoglycemic Recovery | 15.34 mg/dL |
90% CI: [-11.12, 1.05]
90% CI: [-13.3, -1.24]
Primary
Rate of Recovery From Hypoglycemia to Euglycemia
The rate of recovery is the difference in concentration between blood glucose at euglycemia and at the end of the hypoglycemic clamp, divided by the recovery time.
Time frame: From 1 to 180 minutes post hypoglycemic clamp
Population: The per-protocol population consisting of participants who received drug and completed the necessary post treatment measurements for at least one treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Rate of Recovery From Hypoglycemia to Euglycemia | 0.32 mg/dL/minute |
| Glimepiride 2 mg | Rate of Recovery From Hypoglycemia to Euglycemia | 0.22 mg/dL/minute |
| Glimepiride 4 mg | Rate of Recovery From Hypoglycemia to Euglycemia | 0.19 mg/dL/minute |
90% CI: [-0.21, 0]
90% CI: [-0.24, -0.03]
Primary
Recovery Time From Hypoglycemia to Euglycemia
Immediately after release of the hypoglycemic clamp, which maintained blood glucose close to 50 mg/dL, the time taken until glucose reached euglycemia, defined as 3 consecutive measurements \>= 70 mg/dL, is called the recovery time.
Time frame: From 1 to 180 minutes post hypoglycemic clamp
Population: The per-protocol population consisting of participants who received drug and completed the necessary post treatment measurements for at least one treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Recovery Time From Hypoglycemia to Euglycemia | 74.49 Minutes |
| Glimepiride 2 mg | Recovery Time From Hypoglycemia to Euglycemia | 88.90 Minutes |
| Glimepiride 4 mg | Recovery Time From Hypoglycemia to Euglycemia | 109.81 Minutes |
90% CI: [-22.98, 51.8]
90% CI: [-2.08, 72.74]