Effects of Glimepiride on Recovery From Hypoglycemia in Participants With Type 2 Diabetes Mellitus (MK-0000-253)

Study Overview
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Brief Summary
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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.

Official Title
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A Study to Assess the Effects of Glimepiride on Recovery From Hypoglycemia in Participants With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Placebo
* Drug: Glimepiride 2 mg
* Drug: Glimepiride 4 mg
* Procedure: Hypoglycemic Clamp


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo → Glimepiride 2 mg → Glimepiride 4 mg<br>Participants received placebo in the first period, 2 mg glimepiride in the second period and 4 mg glimepiride in the third period, with a 7-day washout between each period. | Drug: Placebo<br>* Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 2 mg<br>* One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 4 mg<br>* Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Procedure: Hypoglycemic Clamp<br>* 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.<br>|
| Experimental: Glimepiride 2 mg → Glimepiride 4 mg → Placebo<br>Participants received 2 mg glimepiride in the first period, 4 mg glimepiride in the second period and placebo in the third period, with a 7-day washout between each period. | Drug: Placebo<br>* Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 2 mg<br>* One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 4 mg<br>* Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Procedure: Hypoglycemic Clamp<br>* 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.<br>|
| Experimental: Glimepiride 4 mg → Placebo → Glimepiride 2 mg<br>Participants received 4 mg glimepiride in the first period, placebo in the second period and 2 mg glimepiride in the third period, with a 7-day washout between each period. | Drug: Placebo<br>* Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 2 mg<br>* One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 4 mg<br>* Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Procedure: Hypoglycemic Clamp<br>* 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.<br>|
| Experimental: Placebo → Glimepiride 4 mg → Glimepiride 2 mg<br>Participants received placebo in the first period, 4 mg glimepiride in the second period and 2 mg glimepiride in the third period, with a 7-day washout between each period. | Drug: Placebo<br>* Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 2 mg<br>* One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 4 mg<br>* Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Procedure: Hypoglycemic Clamp<br>* 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.<br>|
| Experimental: Glimepiride 2 mg → Placebo → Glimepiride 4 mg<br>Participants received 2 mg glimepiride in the first period, placebo in the second period and 4 mg glimepiride in the third period, with a 7-day washout between each period. | Drug: Placebo<br>* Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 2 mg<br>* One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 4 mg<br>* Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Procedure: Hypoglycemic Clamp<br>* 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.<br>|
| Experimental: Glimepiride 4 mg → Glimepiride 2 mg → Placebo<br>Participants received 4 mg glimepiride in the first period, 2 mg glimepiride in the second period and placebo in the third period, with a 7-day washout between each period. | Drug: Placebo<br>* Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 2 mg<br>* One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.<br>Drug: Glimepiride 4 mg<br>* Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.<br>Procedure: Hypoglycemic Clamp<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From 1 to 180 minutes post hypoglycemic clamp | 
| 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. | From 1 to 180 minutes post hypoglycemic clamp | 
| 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. | From 1 to 180 minutes post hypoglycemic clamp |