A Study Comparing Insulin Peglispro With Insulin Glargine as Basal Insulin Treatment

Study Overview
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Brief Summary
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The purpose of this study is to compare insulin peglispro (LY2605541) to insulin glargine in Asian insulin naïve participants who have been treated with oral anti hyperglycemia medications. Participants will receive 26 weeks of treatment.

Official Title
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A Phase 3, Open Label, Randomized, Parallel, 26 Week Treatment Study Comparing LY2605541 With Insulin Glargine as Basal Insulin Treatment in Combination With Oral Anti Hyperglycemia Medications in Asian Insulin Naïve Patients With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Insulin Peglispro
* Drug: Insulin Glargine
* Drug: Oral Antihyperglycemic Medications (OAMs)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have Type 2 Diabetes Mellitus (T2DM) for at least 1 year not treated with insulin Have been receiving at least two oral antihyperglycemic medications (OAMs) for at least 3 months prior to screening Have Hemoglobin A1c (HbA1c) of 7.0% to 11.0%, inclusive, according to central laboratory at screening Body mass index (BMI) ≤35.0 kilogram per square meter (kg/m^2) Inject insulin with a pre-filled insulin pen and perform Self-Monitored Blood Glucose (SMBG) Record keeping as required by this protocol Women of childbearing potential are not breastfeeding, have a negative pregnancy test at screening, do not plan to become pregnant during the study, have practiced reliable birth control during the study and 2 weeks following the last dose of investigational product Exclusion Criteria: Have used insulin therapy (outside of pregnancy) anytime in the past 2 years, except for short term treatment of acute conditions Have been treated with rosiglitazone, pramlintide, glucagon-like peptide-1 (GLP-1) receptor agonist within 3 months prior to screening 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 Local OAM restrictions: have any restrictions for cardiac, renal, and hepatic diseases in the local product regulations Are taking, or have taken within 3 months 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 had 1 or more episodes of ketoacidosis or hyperosmolar state/coma in the past 6 months 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 ≥2.0 milligram per deciliter (mg/dL) (177 micromole per liter [μmol/L]). Participants taking metformin should not exceed the creatinine level specified in the local label Have obvious clinical signs or symptoms of liver disease (excluding non-alcoholic fatty liver disease [NAFLD]), acute or any chronic hepatitis, non alcoholic 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 Have known hypersensitivity or allergy to any of LY2605541 and insulin glargine or their excipients Have pre proliferative and proliferative retinopathy, maculopathy requiring treatment or not clinically stable in the last 6 months, or participants with active changes in subjective eye symptoms as determined by the investigator if an eye exam has not been performed in the last 6 months 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 as determined by the central laboratory Have an irregular sleep/wake cycle (for example, participants who sleep during the day and work during the night) in the investigator's opinion

Ages Eligible for Study
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Minimum Age: 20 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: Insulin Peglispro<br>Insulin Peglispro administered subcutaneously (SC) once daily for 26 weeks in combination with Oral Antihyperglycemic Medications (OAMs). | Drug: Insulin Peglispro<br>* Administered SC using a prefilled pen.<br>* Other names: LY2605541;Drug: Oral Antihyperglycemic Medications (OAMs)<br>* Administered orally<br>* Other names: Pioglitazone;|
| Active Comparator: Insulin Glargine<br>Insulin Glargine administered SC once daily for 26 weeks in combination with OAMs. | Drug: Insulin Glargine<br>* Administered SC using a prefilled pen<br>Drug: Oral Antihyperglycemic Medications (OAMs)<br>* Administered orally<br>* Other names: Pioglitazone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 26 in Hemoglobin A1c (HbA1c) | Hemoglobin A1c (HbA1c) is a test that measures a participant's average blood glucose level over the past 2 to 3 months. Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis adjusting for treatment, stratification factors (region, sulfonylureas/meglitinide use, baseline Low-Density Lipoprotein [LDL-C], visit, treatment-by-visit interaction, and baseline HbA1c as fixed effects and participants as the random effect. P-value is from MMRM with terms for treatment, visit, treatment-by-visit interaction, stratification, and baseline HbA1C. | Baseline, Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 30-Day Adjusted Rate of Total and Nocturnal Hypoglycemic Events | Hypoglycemia Events (HE) occurs when blood glucose level ≤ 70 milligram per deciliter (mg/dL) (<3.9 micromoles per liter [mmol/L]). Nocturnal HE includes any total HE that occurred between bedtime and waking. Group mean rates of nocturnal hypoglycemia (per 30 days) are presented and were calculated from negative binomial regression models with treatment, baseline sulfonylurea/meglitinide use, baseline total hypoglycemia event rate, 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 to Week 26 | 
| Fasting Serum Glucose (FSG) | LS means were calculated using MMRM analysis adjusting for baseline, treatment, stratification factor (region, HbA1c, LDL-C, and sulfonylurea [SU]/meglitinide use), visit, and treatment-by-visit interaction. | Weeks 0 and 26 | 
| Fasting Blood Glucose (FBG) | LS Means were calculated using MMRM analysis adjusting for baseline, treatment, stratification factor (region, HbA1c, LDL-C, and SU/meglitinide use), visit and treatment-by-visit interaction. | Weeks 0 and 26 | 
| Change From Baseline to Week 26 in Body Weight | LS Means were calculated using MMRM analysis adjusting for baseline, treatment, stratification factor (region, HbA1c, LDL-C, and SU/meglitinide use), visit and treatment-by-visit interaction. | Baseline, Week 26 | 
| 9-Point Self-Monitored Blood Glucose (SMBG) | LS means were calculated using MMRM analysis adjusting for baseline, treatment, stratification factor (region, HbA1c, LDL-C, and SU/meglitinide use), visit and treatment-by-visit interaction. The 9-point SMBG are measured at: Pre-morning meal, 2 hours(hr) post morning meal, pre-midday meal, 2 hr post midday meal, pre-evening meal, 2 hr post pre-evening meal, bedtime, 0300 hr, and pre-morning meal next day, and should be performed on 2 non-consecutive days. | Week 0 and Week 26 | 
| Percentage of Participants With HbA1c ≤6.5% | Percentage of participants with HbA1c ≤6.5% at Week 26 were made using a logistic regression model for endpoint used last observation carried forward (LOCF) method including treatment, baseline HbA1c value. | Week 26 | 
| Insulin Dose Per Kilogram (kg) of Body Weight | LS means were calculated using MMRM analysis adjusting for baseline, treatment, stratification factor (region, HbA1c, LDL-C, and SU/meglitinide), visit, and treatment-by-visit interaction. | Week 26 | 
| Percentage of Participants Achieving Steady-State of Basal Insulin Dose at 26 Weeks (Time to Steady State for Basal Insulin [Stable Maximum Dose]) |  | Week 26 | 
| Concentration of Triglycerides, Total Cholesterol, Low-Density Lipoprotein (LDL-C), and High-Density Lipoprotein Cholesterol (HDL-C) at Week 26 | LS means were calculated using MMRM analysis adjusting for baseline, treatment, stratification factor (region, HbA1c, LDL-C, and SU/meglitinide use), visit, and treatment-by-visit interaction. | Week 26 | 
| Percentage of Participants With Detectable Anti-Insulin Peglispro Antibodies at Week 26 | For participants with detectable anti-insulin peglispro antibody level, the percentage of participants with positive cross-react with endogenous insulin was summarized. | Week 26 | 
| Change From Baseline of European Quality of Life-5 Dimensions - 3 Levels (EuroQoL-5D-3L ) Index Score and Visual Analog Scale (VAS) Health State Score at Week 26 | The EuroQoL-5D-3L questionnaire 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 3-level scale of 1 to 3 (no problem, some problems, and extreme problems). These combinations of attributes are converted into a weighted health-state Index Score according to the United States population-based algorithm. Scores ranged from -0.11 to 1.0 where a score of 1.0 indicates perfect health. Overall health state score was self-reported using a VAS marked on a scale of 0 to 100 (0 indicates worst imaginable health state and 100 indicates best imaginable health state. LS means were calculated using analysis of covariance (ANCOVA) for actual measures and changes from baseline at endpoint using LOCF method: adjusting for treatment, stratification factors (region, HbA1c and SU/meglitin. | Baseline, Week 26 | 
| Insulin Treatment Satisfaction Questionnaire (ITSQ) Score | The Insulin Treatment Satisfaction Questionnaire is a validated instrument containing 22 items that assessed treatment satisfaction for participants with diabetes on insulin. The questionnaire measures satisfaction from the following 5 domains: Inconvenience of Regimen, Lifestyle Flexibility, Glycemic Control, Hypoglycemic Control, and Insulin Delivery Device. Data presented are the transformed score on a scale of 0-100, where a higher score indicate better treatment satisfaction. LS means was achieved using a MMRM model for post-baseline measures with stratification factors (country, HbA1c, and SU/meglitinide use) treatment, visit, treatment-by-visit as fixed effects. ITSQ was assessed at Week 4 (baseline) and Week 26. | Week 4 and 26 | 
| Change From Baseline to 26 Weeks in Adult Low Blood Sugar Survey (LBSS) Scores | LBSS is a validated, participant-reported 33-item questionnaire with items rated on a 5-point Likert scale, where 0 = never and 5 - always. The LBSS measures behaviors to avoid hypoglycemia and its negative consequences (15 items) and worries about hypoglycemia and its negative consequences (18 items). Total score is the sum of all items (range 0 to 132). Higher total scores reflect greater fear of hypoglycemia. Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) with country, treatment and metformin use as fixed effects and baseline score as a covariate. LBSS was assessed during screening visit (baseline) and again at Week 26. | Baseline, Week 26 | 
| Intra-Participant Variability of the Fasting Blood Glucose (FBG) | Intra-participant variability of Fasting Blood Glucose (FBG), which was measured by Self Monitored Blood Glucose (SMBG), was assessed by the standard deviation of the FBG measurement at the Week 26 visit. LS means were calculated using a MMRM with baseline fasting blood glucose measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | Week 26 | 
| Change From Baseline to 12 Weeks in Hemoglobin A1c (HbA1c) | Hemoglobin A1c (HbA1c) is a test that measures a participant's average blood glucose level over the past 2 to 3 months.LS means were calculated using a MMRM with baseline HbA1C measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | Baseline, Week 12 | 
| Percent Hemoglobin A1c at Week 26 | HbA1c is a test that measures a participant's average blood glucose level over the past 2 to 3 months. LS means were calculated using a MMRM with baseline HbA1C measurement, stratification factors (country, HbA1c, LDL-C [< 100 mg/dL and ≥ 100 mg/dL], and SU/meglitinide use), treatment, visit, and treatment-by-visit interaction as fixed effects. | Week 26 | 
| Percentage of Participants With Total and Nocturnal Hypoglycemic Events (HE) | Percentage of participants with hypoglycemic events (total or nocturnal) to Week 26 based on BG Threshold 70mg/dL. | Baseline to Week 26 |