A Study for Patients With Type 1 Diabetes

Study Overview
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Brief Summary
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Comparison of blood glucose levels in patients with Type 1 diabetes when they take a new basal insulin analog and when they take insulin glargine

Detailed Description
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Prestudy treatment for patients who enter this study will be once daily insulin glargine along with mealtime insulins. Patients will continue to use their mealtime insulins throughout the study. The study will consist of 16 weeks of treatment and 4 weeks of follow-up. The 16 weeks of treatment will consist of two 8-week periods (Periods 1 and 2) during which patients will receive insulin glargine for 8 weeks and LY2605541 for 8 weeks in a random sequence. During the 4-week follow-up period, patients will return to insulin glargine or another 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 1 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 1

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 1 diabetes mellitus (T1DM) for at least 1 year and using insulin glargine for at least 6 months with a maximum daily dose of 1 unit per kilogram (U/kg). Hemoglobin A1c (HbA1c) of no greater than 10.5% before randomization Body mass index (BMI) 19 to 45 kilogram per square meter (kg/m²) Capable and willing to prepare and inject insulin with a syringe, monitor own blood glucose, complete the study diary, be receptive to diabetes education, comply with study requirements, and receive telephone calls during treatment Women of childbearing potential must test negative for pregnancy before receiving treatment and agree to use reliable birth control until completing the follow-up Exclusion Criteria: Twice daily use of insulin glargine within 30 days prior to the study Use of any oral or injectable medication intended for the treatment of diabetes mellitus other than insulins in the 3 months prior to the study Use of an insulin pump More than 1 episode of severe hypoglycemia within 3 months prior to the study, or currently diagnosed as having hypoglycemia unawareness 2 or more emergency room visits or hospitalizations due to poor glucose control in the 6 months preceding the study Known hypersensitivity or allergy to any of the study insulins or their excipients Blood transfusion or severe blood loss within 3 months prior to 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 Pregnant or intend to become pregnant during the study Women who are breastfeeding Use of prescription or over-the-counter medications to promote weight loss within 3 months prior to the study Current participation in a weight loss program or plans to do so during the study Use of chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy currently or within 4 weeks prior to the study Cardiac disease with a marked impact on physical functioning Clinically significant electrocardiogram (ECG) abnormalities at screening Fasting triglycerides greater than 500 milligram per deciliter (mg/dL) Liver disease History of renal transplantation, current renal dialysis, or creatinine greater than 2.0 mg/dL (177 micromole per liter [μmol/L]) Malignancy other than basal cell or squamous cell skin cancer, currently or within the last 5 years Treatment with any antibody-based therapy within 6 months prior to the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2605541 First, Then Insulin Glargine<br>Participants received LY2605541 for 8 weeks, followed by insulin glargine for 8 weeks. | Drug: LY2605541<br>* Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods.<br>Drug: Insulin glargine<br>* Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods.<br>|
| Active Comparator: Insulin Glargine First, Then LY2605541<br>Participants received insulin glargine for 8 weeks, followed by LY2605541 for 8 weeks. | Drug: LY2605541<br>* Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods.<br>Drug: Insulin glargine<br>* Administered subcutaneously every morning with dose titration based on blood glucose measures for 8 weeks in each of 2 study periods.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily Average Blood Glucose (Avg. BG) at Week 8 Endpoint as Measured by the 8-Point Self-Monitored Blood Glucose (SMBG) Profiles | It is the Avg. of the 8-point SMBG profiles, BG of morning fasting, midday & evening pre-meal, 2-hour postprandial after each of the 3 main meals, bedtime, 0300 hours. Least squares (LS) mean of daily Avg. BG is from mixed-model repeated measures (MMRM), which includes fixed effects of treatment (LY2605541, Glargine); Treatment Sequence; treatment period; dose conversion (pre-interim analysis [IA], post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline Hemoglobin [HbA1c] group); visit; visit and treatment interaction; a random effect for participant. | Week 8 of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Daily Average Blood Glucose (Avg. BG) at Week 8 Endpoint as Measured by the 8-Point Self-Monitored Blood Glucose (SMBG) Profiles | It is the Avg. of the 8-point SMBG profiles, BG of morning fasting, midday & evening pre-meal, 2-hour postprandial after each of the 3 main meals, bedtime, 0300 hours. LS mean of daily Avg. BG is from MMRM, which includes fixed effects of treatment (LY2605541, Glargine); Treatment Sequence; treatment period; dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group, and baseline HbA1c group); visit; visit and treatment interaction; a random effect for participant. | Baseline, Week 8 of each treatment period | 
| Change From Baseline in Hemoglobin (HbA1c) at Week 8 Endpoint of Period I | 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 to 8-week at Period I is from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); dose conversion (pre-IA, post-IA); stratification variables (country, baseline daily basal insulin dose group); baseline HbA1c; visit; interaction between visit and treatment; and a random effect for participant. | Baseline, Week 8 (Period I) | 
| Percentage of Participants With HbA1c <7.0% and HbA1c ≤6.5% at Week 8 Endpoint of Period I | HbA1c is a form of hemoglobin which is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. | Week 8 (Period I) | 
| Percentage of Participants With HbA1c <7.0% and HbA1c ≤6.5% at Week 8 Endpoint Who Did Not Experience a Hypoglycemic Episode During Treatment (Period I) | 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 8 (Period I) | 
| 8-Point Self-Monitored Blood Glucose (SMBG) Measures at Week 8 Endpoint | 8-point SMBG profiles are measured at morning fasting BG (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 from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); treatment sequence; treatment period; dose conversion (pre-IA, post-IA); 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. | Week 8 of each treatment period | 
| Daily Basal Insulin Dose at Week 2 and Week 8 Endpoint | LS mean is obtained from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); treatment sequence; treatment period; dose conversion (pre-IA, post-IA); 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. | Week 2 and Week 8 of each treatment period | 
| Pharmacokinetics - Drug (LY2605541) Concentration at Steady State (Css) at Week 8 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 8 of each treatment period | 
| Percentage of Participants With Antibody Status Change From Baseline to Week 8, Week 16 and Week 20 | 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 8, Week 16 and Week 20 | 
| Percentage of Participants With Hypoglycemia Baseline Through Week 8 | 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 per Liter (mmol/L) (≤70 milligram per deciliter [mg/dL]) even if it was not associated with signs, symptoms, or treatment (consistent with current guidelines [ADA 2005]. | Baseline through Week 8 of each treatment period | 
| Rate of Hypoglycemia Per 30 Days Baseline Through Week 8 | 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 8 of each treatment period | 
| Glycemic Variability in Fasting Blood Glucose (FBG) at Week 8 Endpoint | Within-patient glycemic variability was assessed as the standard deviation of fasting blood glucose each day between Week 6 and Week 8. LS mean is obtained from MMRM approach, which includes fixed effects of treatment (LY2605541, Glargine); treatment sequence; treatment period; dose conversion (pre-IA, post-IA); 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. | Week 8 of each treatment period |