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

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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo; Drug: Glimepiride 2 mg; Drug: Glimepiride 4 mg; Procedure: Hypoglycemic Clamp

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo → Glimepiride 2 mg → Glimepiride 4 mg; 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; Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 2 mg; One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 4 mg; Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.; Procedure: Hypoglycemic 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.
Experimental: Glimepiride 2 mg → Glimepiride 4 mg → Placebo; 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; Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 2 mg; One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 4 mg; Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.; Procedure: Hypoglycemic 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.
Experimental: Glimepiride 4 mg → Placebo → Glimepiride 2 mg; 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; Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 2 mg; One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 4 mg; Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.; Procedure: Hypoglycemic 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.
Experimental: Placebo → Glimepiride 4 mg → Glimepiride 2 mg; 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; Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 2 mg; One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 4 mg; Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.; Procedure: Hypoglycemic 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.
Experimental: Glimepiride 2 mg → Placebo → Glimepiride 4 mg; 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; Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 2 mg; One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 4 mg; Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.; Procedure: Hypoglycemic 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.
Experimental: Glimepiride 4 mg → Glimepiride 2 mg → Placebo; 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; Two gross-matched glimepiride placebo tablets taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 2 mg; One placebo tablet and one 2-mg glimepiride tablet taken on Day -1 and Day 1 of the three treatment periods.; Drug: Glimepiride 4 mg; Two 2-mg glimepiride tablets taken on Day -1 and Day 1 of the three treatment periods.; Procedure: Hypoglycemic 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): July 18, 2012
• Primary Completion (Actual): January 9, 2013
• Study Completion (Actual): January 23, 2013

Study Registration Dates

• First Submitted: June 6, 2012
• First Submitted That Met QC Criteria: June 7, 2012
• First Posted (Estimate): June 8, 2012

Study Record Updates

• Last Update Posted (Actual): August 16, 2018
• Last Update Submitted That Met QC Criteria: July 19, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemia; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Immunosuppressive Agents; Immunologic Factors; Hypoglycemic Agents; Glimepiride
• Other Study ID Numbers: 0000-253

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Study Data/Documents

1. CSR Snyposis Link