A Study to Compare a New Long-Acting Insulin (LY2605541) and Human Insulin NPH in Participants With Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to compare LY2605541 and human insulin isophane suspension (NPH) using the following measures for participants treated for up to 26 weeks: Change in participants' overall blood sugar control The rate of night time low blood sugar episodes The number of participants that reach blood sugar targets without low night time blood sugar episodes The total number of low blood sugar episodes reported

Official Title
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A Comparison of LY2605541 Versus Human Insulin NPH as Basal Insulin Treatment in Insulin-Naïve Patients With Type 2 Diabetes Mellitus Not Adequately Controlled With 2 or More Oral Antihyperglycemic Medications: An Open-Label, Randomized Study

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: LY2605541
* Drug: Human Insulin NPH
* Drug: Oral Antihyperglycemic Medications (OAM)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have had type 2 diabetes mellitus for at least 1 year, not treated with insulin Have been receiving 2 or more OAMs for at least 3 months prior to the study Have a hemoglobin A1c (HbA1c) of 7.0% to 11.0%, inclusive, at screening Have a body mass index (BMI) less than or equal to 45.0 kilograms per square meter (kg/m^2) Women of childbearing potential are not breastfeeding, have a negative pregnancy test at screening and randomization, do not plan to become pregnant during the study, have practiced reliable birth control for at least 6 weeks prior to screening and will continue to do so during the study and until 2 weeks after the last dose of study drug Exclusion Criteria: Have used insulin therapy in the past 2 years (except for use during pregnancy or for short term use for acute conditions) Have been treated with glucagon-like peptide-1 (GLP-1) receptor agonist, rosiglitazone, pramlintide, or weight-loss medication within 3 months before screening For participants on OAMs: have any restrictions for cardiac, renal, and hepatic diseases in the local product regulations Are taking, or have taken within the 90 days before screening, prescription or over-the-counter medications to promote weight loss Have had any episodes of severe hypoglycemia, diabetic ketoacidosis, or hyperosmolar state/coma within 6 months prior to screening Have cardiac disease with functional status that is New York Heart Association Class III or IV Have a history of renal transplantation, or are currently receiving renal dialysis or have serum creatinine greater than or equal to 2 milligrams per deciliter (mg/dL) [177 millimoles per liter (mmol/L)] Have obvious clinical signs or symptoms of liver disease [excluding nonalcoholic fatty liver disease (NAFLD)], acute or chronic hepatitis, nonalcoholic steatohepatitis (NASH), or elevated liver enzyme measurements Have had a blood transfusion or severe blood loss within 3 months prior to screening or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia, or any other traits of hemoglobin abnormalities known to interfere with the measurement of HbA1c Have active or untreated cancer, have been in remission from clinically significant cancer(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 Are receiving chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy (excluding topical, intranasal, intraocular, and inhaled preparations) or have received such therapy within the 8 weeks immediately preceding screening Have fasting triglycerides greater than 400 mg/dL (4.5 mmol/L) at screening Have an irregular sleep/wake cycle (for example, participants who sleep during the day and work during the night) in the investigator's opinion Are using or have used any of the following lipid-lowering medications: niacin preparations as a lipid-lowering medication and/or bile acid sequestrants within 90 days prior to screening

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<br>Administered by subcutaneous (SC) injection once daily in the morning or at bedtime. Initial dose is 10 units (or less for some of the participants in Korea) and is adjusted weekly based on Fasting Blood Glucose (FBG). LY2605541 will be given alone or in combination with up to 3 pre-study oral antihyperglycemic medications [OAM(s)] whose use is not excluded in combination with insulin. Treatment may last up to 26 weeks. | Drug: LY2605541<br> <br> Drug: Oral Antihyperglycemic Medications (OAM)<br> <br> |
| Active Comparator: Human Insulin NPH<br>Administered by SC injection once daily at bedtime. Initial dose is 10 units (or less for some of the participants in Korea) and is adjusted weekly based on FBG. Human insulin NPH will be used alone or in combination with up to 3 pre-study OAM(s) whose use is not excluded in combination with insulin. Treatment may last up to 26 weeks. Some participants who are unable to achieve glycemic control after at least 12 weeks of treatment with a single injection of NPH may be asked to add a second injection prior to the morning meal. | Drug: Human Insulin NPH<br> <br> Drug: Oral Antihyperglycemic Medications (OAM)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 26 Weeks in Hemoglobin A1c (HbA1c) | Glycosylated hemoglobin A1 (HbA1c) is a test that measures a participant's average blood glucose level over a 2 to 3 month timeframe. Least Squares (LS) means were calculated by mixed model repeated measures (MMRM) using treatment, stratification factors (country, sulfonylureas/meglitinide use [Yes/No]), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects. | Baseline, 26 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events | Hypoglycemic episodes are defined as an event which is associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of <=70 milligram per deciliter (mg/dL) (3.9 millimoles per liter [mmol/L]). A nocturnal hypoglycemic event is defined as any total hypoglycemia event that occurred between bedtime and waking. Group mean rates of total and nocturnal hypoglycemia (per 30 days) are presented and were calculated from negative binomial regression models with treatment, baseline sulfonylurea/meglitinide use, baseline event rate of the corresponding hypoglycemia as covariates, log (exposure/30 days) as the offset in the model. Group Mean is estimated by taking the inverse link function on individual participant covariates first and then averages over all participants. | Baseline through 26 Weeks | 
| Percentage of Participants With HbA1c ≤6.5% and <7.0% | Percentage of participants was calculated by dividing the number of participants reaching target HbA1c by the total number of participants analyzed, multiplied by 100. | 26 Weeks | 
| Fasting Serum Glucose (FSG) (by Laboratory) | LS means were calculated from MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use [Yes/No]), baseline HbA1c strata [≤8.5% or >8.5%]), visit, treatment-by-visit interaction, and baseline value of the response variable as the fixed effects. | 26 Weeks | 
| Fasting Blood Glucose (FBG) (by Self Monitoring) | LS means were calculated from MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use [Yes/No]), baseline HbA1c strata [≤8.5% or >8.5%]), visit, treatment-by-visit interaction, and baseline value of the response variable as the fixed effects. | 26 Weeks | 
| 6-Point Self-Monitored Blood Glucose (SMBG) | 6-point SMBG profiles were obtained on 3 nonconsecutive days in the week prior to Weeks 0, 4, 8, 12, 16, and 26. The SMBG measurements were performed while fasting (prior to the morning meal [breakfast]), prior to the midday meal (lunch), prior to the evening meal (dinner), at bedtime, at approximately 0300 hours, and the next day fasting (prior to the morning meal). LS means were calculated by MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use [Yes/No]), ], baseline HbA1c strata [≤8.5% or >8.5%]), visit, treatment-by-visit interaction, and baseline SMBG at the same time point of the response variable as the fixed effects. | 26 Weeks | 
| Change From Baseline to 26 Weeks in Body Weight | LS means were calculated by MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use [Yes/No]), baseline HbA1c strata [≤8.5% or >8.5%]), visit, treatment-by-visit interaction, and baseline weight as the fixed effects. | Baseline, 26 Weeks | 
| HbA1c | HbA1c is a test that measures a participant's average blood glucose level over a 2 to 3 month timeframe. LS means were calculated by MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use [Yes/No]), visit, treatment-by-visit interaction, and baseline HbA1c as the fixed effects. | 26 Weeks | 
| Insulin Dose Per Kilogram (kg) of Body Weight | LS means were calculated by MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use [Yes/No]), baseline HbA1c strata [≤8.5% or >8.5%]), visit, and treatment-by-visit interaction as the fixed effects. | 26 Weeks | 
| Time to Steady-State (Stable Maximum Dose) | Steady-state was defined as the first local maximum dose (peak dose value) of LY2605541 or human insulin NPH within the window of -2 to +2 weeks. The median time to steady-state of basal insulin dose estimated from Kaplan-Meier analysis was summarized by treatment. | Baseline through 26 Weeks | 
| Change From Baseline to 26 Weeks in European Quality of Life - 5 Dimension 3 Levels (EQ-5D-3L) Index | The EQ-5D-3L is a generic, multidimensional, health-related, quality-of-life instrument. The profile allows participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a three level scale 1-3 (no problem, some problems, and extreme problems). These combinations of attributes were converted into a weighted health-state Index Score according to the United States (US) population-based algorithm. The EQ-5D-3L US based index scores ranged from -0.11 to 1.0 where a score of 1.0 indicates perfect health. LS means were calculated from ANCOVA using treatment, stratification factor (country, baseline sulfonylurea sulfonylureas/meglitinide use [Yes/No], baseline HbA1c strata [≤8.5% or >8.5%]) and baseline value of EQ-5D-3Las covariates. | Baseline, 26 Weeks | 
| Insulin Treatment Satisfaction Questionnaire (ITSQ) Score | ITSQ is a validated instrument containing 22 items that assess treatment satisfaction for participants with diabetes and on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, Insulin Delivery Device. Data presented are the transformed score on a scale of 0-100, higher scores indicate better treatment satisfaction. LS means were calculated using analysis of variance (ANOVA) adjusting for treatment and stratification factors (country, baseline sulfonylureas/meglitinide use [Yes/No], baseline HbA1c [≤8.5% or >8.5%]). | 26 Weeks | 
| Change From Baseline to 26 Weeks in Adult Low Blood Sugar Survey (LBSS) Scores | Adult LBSS (also referenced as Hypoglycemia Fear Survey - II [HFS-II]) contains 33 items, with each item scored on a 5-point response scale: 0 (never) to 4 (always). Items are categorized in 2 domains: Behavior (or avoidance) with 15 items and Worry (or affect) with 18 items. Sum all the items to obtain a total score (range 0-132). Higher total scores reflect greater fear of hypoglycemia. LS means were calculated using analysis of covariance (ANCOVA) adjusting for treatment, stratification factor (country, baseline sulfonylureas/meglitinide use [Yes/No]), baseline HbA1c (≤8.5% or >8.5%), and baseline value of LBSS. | Baseline, 26 Weeks | 
| Change From Baseline to 26 Weeks in Lipid Profile | Lipid profile includes total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides. LS means for post-baseline measures were calculated using MMRM with the fixed effects of stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, sulfonylureas/meglitinide use, and LDL-C [<100 mg/dL and ≥100 mg/dL], except for the LDL-C outcome variable), visit, treatment, visit-by-treatment interaction, and baseline value of corresponding lipid outcome variable. LS means for End Of Study measures were calculated using ANCOVA adjusting for stratification factors (baseline HbA1c [≤8.5% and >8.5%], country, sulfonylureas/meglitinide use, and LDL-C [<100 mg/dL and ≥100 mg/dL]except for the LDL-C outcome variable), treatment, and baseline value of corresponding lipid outcome variable. | Baseline, 26 Weeks; Baseline, End Of Study (EOS) (Up to 30 Weeks) | 
| Percentage of Participants With Insulin Antibodies | The percentage of participants with a positive treatment-emergent anti-LY2605541 antibody response (TEAR) is summarized. TEAR was defined as change from baseline to postbaseline in the anti-LY2605541 antibody level either (1) from undetectable to detectable or (2) from detectable to the value with at least 130% relative increase from baseline. Percentage of participants was calculated by dividing the number of participants with TEAR anytime during the treatment period by the total number of participants analyzed, multiplied by 100. | Baseline to 26 Weeks | 
| Intra-Participant Variability in FBG by Standard Deviation | Glucose variability was assessed by between-day variability as measured by the standard deviation or the coefficient of variation of the FBG of the last 7 days prior to the visit using SMBG. LS means were calculated by MMRM using treatment, stratification factors (country, sulfonylureas/meglitinide use [Yes/No], baseline HbA1c strata [≤8.5% or >8.5%]), visit, treatment-by-visit interaction, and baseline FBG variability as the fixed effects. | 26 Weeks | 
| Intra-Participant Variability in FBG by the Coefficient of Variation | Glucose variability was assessed by between-day variability as measured by the standard deviation or the coefficient of variation of the FBG of the last 7 days prior to the visit using SMBG. | 26 Weeks | 
| Percentage of Participants With Total and Nocturnal Hypoglycemic Events | Hypoglycemic episodes are defined as an event which is associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of <=70 milligram per deciliter (mg/dL) (3.9 millimoles per liter [mmol/L]). A nocturnal hypoglycemic event is defined as any total hypoglycemia event that occurred between bedtime and waking. Percentage of participants was calculated by the number of participants with at least one hypoglycemia divided by the total number of participants analyzed, multiplied by 100. | Baseline through 26 Weeks | 
| Percentage of Participants With HbA1c <7.0% and Without Nocturnal Hypoglycemia | Hypoglycemic episodes are defined as an event which is associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of <=70 milligram per deciliter (mg/dL) (3.9 millimoles per liter [mmol/L]). A nocturnal hypoglycemic event is defined as any total hypoglycemia event that occurred between bedtime and waking. Percentage of participants was calculated by the number of participants reaching target HbA1c without nocturnal hypoglycemia divided by the total number of participants analyzed, multiplied by 100. | 26 Weeks | 
| Percentage of Participants With Injection Site Reactions | The percentage of participants with at least one treatment-emergent injection site reaction is presented. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 26 Weeks | 
| Rate of Severe Hypoglycemic Events | Hypoglycemic event are defined as an event which is associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of <=70 milligram per deciliter (mg/dL) (3.9 millimoles per liter [mmol/L]). A severe hypoglycemic event was defined as a hypoglycemic episode requiring assistance of another person to actively administer carbohydrates, glucagon, or other resuscitative actions. The hypoglycemia rate per 100 years during a defined period was calculated by the number of hypoglycemia events within the period divided by the number of days participant at risk within the period*36525 days. | Baseline through 26 Weeks | 
| Percentage of Participants With Severe Hypoglycemic Events | Hypoglycemic event are defined as an event which is associated with reported signs and symptoms of hypoglycemia, and/or a documented blood glucose (BG) concentration of <=70 milligram per deciliter (mg/dL) (3.9 millimoles per liter [mmol/L]). A severe hypoglycemic event was defined as a hypoglycemic episode requiring assistance of another person to actively administer carbohydrates, glucagon, or other resuscitative actions. The percentage of participants with at least one severe hypoglycemia is presented. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 26 Weeks | 
| Change From Baseline to 26 Weeks in European Quality of Life (EQ-5D-3L) - Visual Analog Scales (VAS) Scores | The EQ-5D-3L is a generic, multidimensional, health-related, quality-of-life instrument. Overall health state score was self-reported using a visual analogue scale (VAS) marked on a scale of 0 to 100 with 0 representing worst imaginable health state and 100 representing best imaginable health state. | Baseline, 26 Weeks |