A Study for Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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Comparison of fasting blood glucose levels in patients with Type 2 diabetes after 12 weeks of treatment with a new basal insulin analog or with insulin glargine.

Detailed Description
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Patients in this study will continue to use their stable prestudy dose of metformin and/or a sulfonylurea. Prestudy therapy also includes once daily insulin glargine or neutral protamine Hagedorn (NPH) insulin. The 12-week active treatment phase will be followed by a 4-week follow-up period, during which patients will return to the basal insulin recommended by the investigator.

Official Title
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A Phase 2 Study of LY2605541 Compared With Insulin Glargine in the Treatment of Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: LY2605541
* Drug: insulin glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus (T2DM) for at least 1 year At least 18 years of age Using metformin and/or sulfonylurea(s) with once daily glargine or NPH for at least 3 months prior to the study. Prestudy dose requirements: insulin dose maximum 1.0 unit/kilogram/day (U/kg/day). Oral antihyperglycemic medications (OAMs): Metformin dose at least 1500 milligram/day (mg/day) and/or sulfonylurea dose at least half the maximum daily dose specified in the local package insert. OAM doses stable for 6 weeks prior to the study. Hemoglobin A1c (HbA1c) less than or equal to 10.5% before randomization Body Mass Index (BMI) 19 to 45 kilogram/square meter (kg/m²) Capable and willing to prepare and inject insulin with a syringe while continuing to use the prestudy OAMs, monitor own blood glucose; complete the study diary; be receptive to diabetes education; comply with study visits and receive telephone calls between visits Women of childbearing potential must test negative for pregnancy before receiving treatment and agree to use reliable birth control until completing the follow-up visit Exclusion Criteria: Long-term use of short- or rapid-acting or premixed insulin within the 6 months before the study. Short-term insulin therapy or occasional use are permitted Use of any glucose-lowering medications not allowed by the inclusion criteria in the 3 months before entry into the study Use of prescription or over-the-counter medications to promote weight loss within 3 months before entry into the study Current participation in a weight loss program, or plans to do so during the study Treatment with any antibody-based therapy within 6 months prior to the study Use of chronic (>14 consecutive days) systemic glucocorticoid therapy currently or within 4 weeks prior to the study More than 1 episode of severe hypoglycemia within 6 months prior to the study, or currently diagnosed with hypoglycemia unawareness 2 or more emergency room visits or hospitalizations due to poor glucose control in the 6 months preceding the study Liver disease History of renal transplantation, current renal dialysis, or creatinine >2.0 milligram/deciliter (mg/dL) (177 micromole/Liter [μmol]/L) Cardiac disease with a marked impact on physical functioning Clinically significant electrocardiogram (ECG) abnormalities at screening Malignancy other than basal cell or squamous cell skin cancer Fasting triglycerides >500 mg/dL Known diabetic autonomic neuropathy Known hypersensitivity or allergy to study insulin or its excipients Blood transfusion or severe blood loss within 3 months prior to entry into the study or known hemoglobinopathy, hemolytic anemia, or sickle cell anemia, or any other traits of hemoglobin abnormalities known to interfere with the HbA1c methodology Irregular sleep/wake cycle Women who are breastfeeding

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2605541 Dosing Algorithm 1<br>Participants took both LY2605541 and their pre-study insulin for first several days | Drug: LY2605541<br>* subcutaneous injection of LY2605541 every morning with dose titration based on blood glucose measures for 12 weeks<br>|
| Experimental: LY2605541 Dosing Algorithm 2<br>Participants took only LY2605541 with first dose doubled | Drug: LY2605541<br>* subcutaneous injection of LY2605541 every morning with dose titration based on blood glucose measures for 12 weeks<br>|
| Active Comparator: Insulin glargine<br> | Drug: insulin glargine<br>* subcutaneous injection of insulin glargine every morning with dose titration based on blood glucose measures for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fasting Blood Glucose (FBG) Level at Week 12 Endpoint as Measured by the 8-Point Self-Monitored Blood Glucose (SMBG) Profiles | 8-point SMBG profiles are measured at morning FBG, midday and evening pre-meal blood glucose (BG), 2-hour postprandial BG after each of the 3 main meals, bedtime BG, 0300 hours BG. Least squares (LS) mean of the FBG is from mixed-model repeated measures (MMRM) approach, which includes fixed effects of treatment (LY2605541 algorithm 1 and 2, glargine); dose conversion (pre-interim analysis [IA], post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline hemoglobin A1c [HbA1c] group); visit; visit and treatment interaction; random effect for participant. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Blood Glucose (FBG) at Week 12 Endpoint | FBG is measured by 8-point SMBG profiles, which are measured at morning FBG, midday pre-meal BG, evening pre-meal BG, 2-hour postprandial BG after each of the 3 main meals, bedtime BG, 0300 hours BG. LS mean of the change from baseline to 12 weeks is from MMRM approach, which includes fixed effects of treatment (LY2605541 algorithm 1 and 2, glargine); dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; visit and treatment interaction; and random effect for participant. | Baseline, Week 12 | 
| Change From Baseline in Hemoglobin A1c (HbA1c) at Week 12 Endpoint | HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. LS mean of the change from baseline is from MMRM approach. MMRM model includes fixed effects of treatment (LY2605541 dose algorithm 1 and 2, glargine); dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group); baseline HbA1c; visit; visit and treatment interaction; and a random effect for participant. | Baseline, Week 12 | 
| Percentage of Participants With HbA1c <7.0% and ≤6.5% at Week 12 Endpoint | HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. | Week 12 | 
| Percentage of Participants With HbA1c <7.0% and HbA1c ≤6.5% at Week 12 Endpoint Who Did Not Experience a Hypoglycemic Episode During Treatment | HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 millimole/Liter (mmol/L) (≤70 milligram/deciliter [mg/dL]) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]). | Week 12 | 
| 8-Point Self-Monitored Blood Glucose (SMBG) Measures at Week 12 Endpoint | 8-point SMBG profiles are measured at morning FBG, midday pre-meal BG, evening pre-meal BG, 2-hour postprandial BG after each of the 3 main meals, bedtime BG, 0300 hours BG. LS mean is obtained using MMRM approach, which includes fixed effects of treatment (LY2605541 algorithm 1 and 2, glargine); dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; visit and treatment interaction; and a random effect for participant. | Week 12 | 
| Daily Basal Insulin Dose at Week 2 and Week 12 | LS mean is obtained using MMRM approach, which includes fixed effects of treatment (LY2605541 algorithm 1 and 2, glargine); dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; visit and treatment interaction; and a random effect for participant. | Week 2 and Week 12 | 
| Percentage of Participants With Hypoglycemia From Baseline Through Week 12 | Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 mmol/L (≤70 mg/dL) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]). | Baseline through Week 12 | 
| Rate of Hypoglycemia Per 30 Days From Baseline Through Week 12 | Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 mmol/L (≤70 mg/dL) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]). Hypoglycemia rate per 30 days is calculated as the number of hypoglycemia/number of days at risk*30. | Baseline through Week 12 | 
| Percentage of Participants With Antibody Status Change From Baseline to Week 12 and Week 16 | Negative is defined as either 'negative' from lab or percent binding <1.16%. Positive is defined as the percent binding is ≥1.16%. The antibody status change is from negative to positive or positive to negative. | Week 12 and Week 16 | 
| Glycemic Variability in Fasting Blood Glucose at Baseline and Week 12 | Within-patient glycemic variability was assessed as the standard deviation of fasting blood glucose each day at baseline, and each day between Week 10 and Week 12. LS mean is obtained using MMRM approach, which includes fixed effects of treatment (LY2605541 algorithm 1 and 2, glargine); dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; visit and treatment interaction; and a random effect for participant. | Baseline and Week12 | 
| Pharmacokinetics - Drug (LY2605541) Concentration at Steady State (Css) at Week 12 Endpoint | The drug (LY2605541) concentration at steady state (Css) is calculated from the clearance (Liter/hour) and the final dose of the participants. Clearance was estimated using population-based approaches. | Week 12 | 
| Change From Baseline in Fasting Blood Glucose (FBG) at Week 12 Endpoint - Subgroup Analysis of LY2605541 Dosing Algorithms | FBG is measured by 8-point SMBG profiles, which are measured at morning FBG, midday pre-meal BG, evening pre-meal BG, 2-hour postprandial BG after each of the 3 main meals, bedtime BG, 0300 hours BG. LS mean of the change from baseline to 12 weeks is from MMRM approach. MMRM model includes fixed effects of treatment (LY2605541 algorithm 1, LY2605541 algorithm 2, glargine); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; visit and treatment interaction; and a random effect for participant. | Baseline, Week 12 | 
| Change From Baseline in HbA1c at Week 12 Endpoint - Subgroup Analysis of LY2605541 Dosing Algorithms | HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. LS mean of the change from baseline is from MMRM approach. MMRM model includes fixed effects of treatment (LY2605541 algorithm 1, LY2605541 algorithm 2, glargine); stratification variables (country, baseline daily basal insulin dose group); baseline HbA1c; visit; visit and treatment interaction; and a random effect for participant. | Baseline, Week 12 | 
| Percentage of Participants With HbA1c <7.0% and ≤6.5% at Week 12 Endpoint - Subgroup Analysis of LY2605541 Dosing Algorithms | HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. | Week 12 | 
| Percentage of Participants Who Did Not Experience a Hypoglycemic Episode During Treatment With HbA1c <7.0% and HbA1c ≤6.5% at Week 12 Endpoint - Subgroup Analysis of LY2605541 Dosing Algorithms | HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 mmol/L (≤70 mg/dL) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]). | Week 12 | 
| 8-Point Self-Monitored Blood Glucose (SMBG) Measures at Week 12 Endpoint - Subgroup Analysis of LY2605541 Dosing Algorithms | 8-point SMBG profiles are measured at morning FBG, midday pre-meal BG, evening pre-meal BG, 2-hour postprandial BG after each of the 3 main meals, bedtime BG, 0300 hours BG. LS mean is obtained using MMRM approach, which includes fixed effects of treatment (LY2605541 algorithm 1, LY2605541 algorithm 2, glargine); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; visit and treatment interaction; and a random effect for participant. | Week 12 | 
| Daily Basal Insulin Dose at Week 2 and Week 12 - Subgroup Analysis of LY2605541 Dosing Algorithms | LS mean is obtained using MMRM approach, which includes fixed effects of treatment (LY2605541 algorithm 1, LY2605541 algorithm 2, glargine); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; visit and treatment interaction; and a random effect for participant. | Week 2 and Week 12 | 
| Percentage of Participants With Hypoglycemia From Baseline Through Week 12 - Subgroup Analysis of LY2605541 Dosing Algorithms | Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 mmol/L (≤70 mg/dL) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]). | Baseline through Week 12 | 
| Rate of Hypoglycemia Per 30 Days From Baseline Through Week 12 - Subgroup Analysis of LY2605541 Dosing Algorithms | Hypoglycemia episode is defined as any time a participant feels that he/she is experiencing a sign or symptom that is associated with hypoglycemia or has a BG level of ≤3.9 mmol/L (≤70 mg/dL) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]). Hypoglycemia rate per 30 days is calculated as the number of hypoglycemia/number of days at risk*30. | Baseline through Week 12 | 
| Glycemic Variability in Fasting Blood Glucose at Baseline and Week 12 - Subgroup Analysis of LY2605541 Dosing Algorithms | Within-patient glycemic variability was assessed as the standard deviation of fasting blood glucose each day at baseline, and each day between Week 10 and Week 12. LS mean is obtained using MMRM approach, which includes fixed effects of treatment (LY2605541 algorithm 1, LY2605541 algorithm 2, glargine); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; interaction between visit and treatment; and a random effect for participant. | Baseline and Week 12 |