A Study to Compare the Effect of a Double Dose of Two Long-acting Insulin Therapies in Participants With Type 2 Diabetes

Study Overview
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Brief Summary
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The primary purpose of this study is to compare the effect of a double dose of a study drug known as insulin peglispro to a double dose of insulin glargine in participants who have type 2 diabetes. Participants will be treated with study insulin daily, in two 4-week study periods. Each participant will receive insulin peglispro during one treatment period and insulin glargine during the other treatment period.

Official Title
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A Comparison of Pharmacodynamics When Receiving a Double Dose of Insulin Peglispro or Insulin Glargine in Patients With Type 2 Diabetes Mellitus: A Double-Blind, Crossover Design Study

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Insulin Peglispro
* Drug: Insulin Glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have type 2 diabetes mellitus (T2DM), based on the World Health Organization (WHO) classification, for ≥1 year. Use any type of basal insulin (except degludec), including once-or twice-daily human insulin neutral protamine Hagedom (NPH), insulin detemir, or insulin glargine. Have hemoglobin A1c (HbA1c) levels ≤9.0% according to local laboratory testing at screening. Have body mass index (BMI) ≤40.0 kilograms/square meter (kg/m^2). Have been treated with stable doses of insulin for at least 30 days before screening with: Basal insulin with daily doses ±30% of mean during the last 4 weeks. Doses of a basal insulin must be between 0.3 unit/kg/day and 1 unit/kg/day. If on metformin, thiazolidinediones (TZDs), sodium glucose co-transporter 2 (SGLT-2) inhibitors, or dipeptidyl peptidase (DPP4) inhibitors, must be on stable doses for the last 30 days. Exclusion Criteria: Are using prandial, self-mixed, or premixed insulin. Participants using prandial insulin may be switched to everyday (qd) glargine if investigator judges that the participant will still meet fasting glucose requirements for randomization. Are using insulin pump therapy. Have excessive insulin resistance: Defined as >1.0 unit/kg/day as baseline treatment. If being treated with sulfonylureas (SUs) before screening, then must have SUs washed out between screening and randomization. Use any of these concomitant medications: morphine, codeine, antidiuretics, glucagon-like peptide-1 (GLP-1) receptor agonists (for example, exenatide, exenatide once weekly, lixisenatide or liraglutide), or pramlintide, used concurrently or within 90 days before screening. Have hypoglycemia unawareness, defined as confirmed by laboratory test results or by historical episodes of hypoglycemia <54 mg/dL (3.0 mmol/L) without symptoms. Have fasting hypertriglyceridemia >400 mg/dL (>4.5 mmol/L) at screening, as determined by the local laboratory. Have had any episode of severe hypoglycemia (defined by requiring assistance due to neurologically disabling hypoglycemia) within 6 months before entry into the study. Have had 2 or more emergency room visits or hospitalizations due to poor glucose control in the past 6 months. Have had a previous clinically significant episode of ketoacidosis as determined by the investigator (ketone bodies at fasting and without acidosis is acceptable) in the past 6 months. Have history of renal transplantation, are currently receiving renal dialysis, or have estimated Glomerular Filtration Rate (eGFR) <60 milliliters/minute. Have obvious clinical signs or symptoms of liver disease (excluding nonalcoholic fatty liver disease), acute or chronic hepatitis, nonalcoholic steatohepatitis, or elevated liver enzyme measurements. Have active or untreated malignancy, have been in remission from clinically significant malignancy (other than basal cell or squamous cell skin cancer) for less than 5 years, or are at increased risk for developing cancer or a recurrence of cancer in the opinion of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Insulin Peglispro<br>Standard dose of insulin peglispro administered subcutaneously (SQ) once daily for 4 weeks in one of two study periods. Double dose of insulin peglispro administered once, SQ on day 3 of the inpatient stay. | Drug: Insulin Peglispro<br>* Administered SQ<br>* Other names: LY2605541;|
| Experimental: Insulin Glargine<br>Standard dose of insulin glargine administered subcutaneously (SQ) once daily for 4 weeks in one of two study periods. Double dose of insulin glargine administered once, SQ on day 3 of the inpatient stay. | Drug: Insulin Glargine<br>* Administered SQ<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinically Significant Hypoglycemia | The percentage was calculated by dividing the number of participants with clinically significant hypoglycemia events defined as blood glucose <54 milligrams per deciliter (mg/dL) (3.0 millimole per liter [mmol/L]) or symptoms of severe hypoglycemia by the total number of participants analyzed, multiplied by 100. | Predose to 84 Hours Post Double Dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinically Significant Hypoglycemia 12 Hours Post Double Dose | The percentage was calculated by dividing the number of participants with clinically significant hypoglycemia events defined as blood glucose <54 mg/dL (3.0 mmol/L) or symptoms of severe hypoglycemia by the total number of participants analyzed, multiplied by 100. | Predose to 12 Hours Post Double Dose | 
| Percentage of Participants With Hypoglycemia | The percentage was calculated by dividing the number of participants with hypoglycemia events defined as blood glucose ≤70 mg/dL (3.9 mmol/L) by the total number of participants analyzed, multiplied by 100. | Predose to 12 Hours Post Double Dose and 84 Hours Post Double Dose | 
| Nadir Glucose | Nadir glucose was defined as the lowest blood glucose for a participant with blood glucose ≤70 mg/dL (3.9 mmol/L). Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor. | Predose to 84 Hours Post Double Dose | 
| Time to the Nadir Glucose | Nadir glucose was defined as the lowest blood glucose for a participant with blood glucose ≤70 mg/dL (3.9 mmol/L). The average time was calculated by dividing the sum of time from double dose to the nadir glucose for participants with blood glucose ≤70 mg/dL (3.9 mmol/L) by the number of participants with blood glucose ≤70 mg/dL (3.9 mmol/L) during the first 84 hours after the double dose. | Predose to 84 Hours Post Double Dose | 
| Duration of Glucose ≤70 mg/dL | The duration in minutes of each hypoglycemia episode with glucose ≤70 mg/dL (3.9 mmol/L) was calculated from start time to end time. The duration for a participant was the sum of the durations over the multiple hypoglycemia episodes. LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor. | Predose to 84 Hours Post Double Dose | 
| Fasting Blood Glucose | Fasting blood glucose (FBG) was measured by self-monitored blood glucose. LS means were calculated by MMRM analysis with fixed effects of treatment, dosing day, sequence, period, interaction of treatment and dosing day, baseline basal insulin dose stratification factor, and baseline FBG. | Day 1, Day 2, and Day 3 Following Double Dose | 
| Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) | Glucose AUC within 3 hours after each meal assessed by the AUC of glucose from preprandial to 3 hours postprandial. LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor. | Preprandial to 3 Hours Postprandial during the day following the standard dose | 
| Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) Excursion | Glucose AUC excursion within 3 hours after each meal assessed by the AUC of adjusted glucose (= observed glucose - preprandial glucose) from preprandial to 3 hours postprandial. LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor. | Preprandial to 3 Hours Postprandial during the day following the standard dose | 
| Beta Cell Function | Beta cell function assessed by the change between pre meal tolerance test and 30 minutes post meal tolerance test in C-peptide corrected insulin/Glucose (ΔC-peptide corrected insulin/ΔGlucose). LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor. | 0-30 minutes during the meal tolerance test on the day following the standard dose |