A Study of LY2963016 Compared to LANTUS® in Adult Participants With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety and efficacy of the study drug known as LY2963016 as compared to LANTUS® in adults with type 2 diabetes mellitus who are on 2 or more oral antihyperglycemic medications (OAMs).

Official Title
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A Prospective, Randomized, Open-Label Comparison of a Long-Acting Basal Insulin Analog LY2963016 to LANTUS® in Adult Patients With Type 2 Diabetes Mellitus: The ELEMENT 5 Study

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: LY2963016
* Drug: LANTUS®
* Drug: Oral Antihyperglycemic Medication


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have type 2 diabetes mellitus (T2DM). Have been receiving 2 or more OAMs at stable doses for the 12 weeks prior to screening, with or without basal insulin. If currently on basal insulin, must be taking LANTUS® QD or NPH or insulin detemir either QD or twice a day for at least 90 days prior to study entry. Have an HbA1c ≥7.0% and ≤11.0% if insulin naïve; if previously on basal insulin, then HbA1c ≤11.0%. Body mass index (BMI) ≤45 kilograms per meter squared (kg/m^2). As determined by the investigator, are capable and willing to do the following: perform self monitored blood glucose (SMBG) complete participant diaries as instructed are receptive to diabetes education comply with required study treatment and study visits Exclusion Criteria: Have been on LANTUS® more than once daily within the previous 30 days. Have used any other insulin except the entry insulin [LANTUS®, insulin detemir, or NPH] including commercial (includes any premixed insulins) and investigational insulins within the previous 30 days. Have been exposed to a biosimilar insulin glargine within the previous 90 days. Have participated in a LY2963016 study. Have taken basal plus mealtime insulin (basal bolus therapy) within the last year for greater than 4 continuous weeks. Have used any glucagon like peptide (GLP-1) receptor agonists within the previous 90 days. Have used pramlintide within the previous 30 days. Have excessive insulin resistance at study entry (total insulin dose ≥1.5 units/kg). Have more than 1 episode of severe hypoglycemia within 6 months prior to screening. Have had 2 or more emergency room visits or hospitalizations due to poor glucose control in the 6 months prior to screening. Have known hypersensitivity or allergy to LANTUS® or its excipients. Are receiving chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy or have received such therapy within 4 weeks immediately preceding screening. Have obvious signs or symptoms, or laboratory evidence, of liver disease. Have one of the following concomitant diseases: significant cardiac (e.g., congestive heart failure Class III or IV) or gastrointestinal disease (e.g., significant gastroparesis). Have a history of renal transplantation or are currently receiving renal dialysis. Have a serum creatinine greater than 2.0 milligrams/deciliter (177 micromoles/liter). 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. Participants with active cancer or personal history of cancer within the previous 5 years (with the exception of basal cell carcinoma or carcinoma in situ). Have a history or diagnosis of Human Immunodeficiency Virus (HIV) infection. Have any other condition (including known drug or alcohol abuse or psychiatric disorder including dementia) that precludes the participant from following and completing the protocol. Are pregnant or intend to become pregnant during the course of the study. Women who are breastfeeding. Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device other than LY2963016, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

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: LY2963016<br>Insulin naive participants started on 10 units (U) LY2963016 given subcutaneously (SC) once a day (QD) for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or neutral protamine hagedorn (NPH) QD will begin the study at their current dose SC. Participants will self titrate LY2963016 based on fasting blood glucose (FBG). Participants entering on insulin detemir or NPH twice a day will be started at 80% of the total daily dose SC. Participants will continue oral antihyperglycemic medication (OAM). | Drug: LY2963016<br>* Administered SC<br>Drug: Oral Antihyperglycemic Medication<br>* Administered as per standard-of-care.<br>|
| Active Comparator: LANTUS®<br>Insulin naive participants started on 10 U LANTUS® given SC QD for 24 weeks. Participants entering the study on LANTUS®, insulin detemir or NPH QD will be started at the same dose SC. Participants entering on insulin detemir or NPH twice a day will be started at 80% of the total daily dose SC. Participants will self titrate LANTUS® based on FBG. Participants will continue OAM. | Drug: LANTUS®<br>* Administered SC<br>Drug: Oral Antihyperglycemic Medication<br>* Administered as per standard-of-care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 24 Weeks in Hemoglobin A1c (HbA1c) | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline of response, treatment (LY2963016, LANTUS), pooled country, basal insulin at entry (yes/no), sulfonylurea (SU) use (yes/no), visit, treatment and visit*treatment in the model. | Baseline, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HbA1c <7% and ≤6.5% | Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. | Endpoint [up to 24 weeks] | 
| Change From Baseline in 7-point Self-Monitored Blood Glucose (SMBG) Values | Seven-point SMBG are completed at the following timepoints: Before Morning Meal, 2 Hours After Morning Meal, Before Mid-Day Meal, 2 Hours After Mid-Day Meal, Before Evening Meal, Bed Time and 03:00 AM hours. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit*treatment in the model. | Baseline, Week 24 | 
| Intra-Participant Variability in Fasting Blood Glucose (FBG) | Fasting blood glucose (FBG) is a test to determine how much glucose (sugar) is in a blood sample after an overnight fast. Intra-Participant FBG variability was calculated based on the standard deviation (SD) of the morning pre-meal BG value. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit*treatment in the model. | Week 24 | 
| Basal Insulin Dose Units Per Day | Units of Basal Insulin dose taken per day (U/day). Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit*treatment in the model. | Week 24 | 
| Basal Insulin Dose Per Body Weight (U/kg/Day) | Basal Insulin dose in units (U) per body weight in kilograms (kg) per day. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit*treatment in the model. | Week 24 | 
| Change From Baseline to 24 Weeks in Body Weight | Change from baseline in body weight. Least Squares (LS) means was determined by mixed model repeated measures (MMRM) methodology with baseline of response, baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit*treatment in the model. | Baseline, 24 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. Items divided into 5 domains of satisfaction: Inconvenience of Regimen [(IR) 5 items: domain scores range (DSR) 5-35], Lifestyle Flexibility [(LF) 3 items: DSR 3-21], Glycemic Control [(GC) 3 items: DSR 3-21], Hypoglycemic Control [(HC) 5 items: DSR 5-35], Insulin Delivery Device [(IDD) 6 items: DSR 6-42]. All items measured on a 7-point scale: 1 (no bother at all) to 7 (a tremendous bother), with lower scores reflecting better outcomes. ITSQ Total Overall Raw Scores range from 22-154. Both raw domain and overall scores are transformed on a scale of 0-100, where transformed score=100*[(7-mean raw score)/6]. Higher scores indicate better treatment satisfaction. LS means was determined by MMRM with baseline of response, baseline HbA1c, country, sulfonylurea use, basal insulin status at study entry, visit, treatment and visit*treatment in the model. | Week 4 and Week 24 | 
| Percentage of Participants With Detectable Anti-Drug Antibodies to LY2963016 or LANTUS® | The percentage of participants with detected insulin antibodies were summarized as counts and percentages at baseline, at each visit, at the 24-week endpoint (LOCF), and overall for the 24-week treatment period. | Endpoint [up to 24 weeks] | 
| Rate of Hypoglycemic Events Adjusted Per 1 Year | The rate of hypoglycemic events were analyzed at baseline, titration, maintenance, and overall study periods and at endpoint using the Wilcoxon test. In addition, a negative binomial model was used as a sensitivity analysis. A hypoglycemic event is defined as any time a participant has a blood glucose (BG) level of ≤70 milligrams per deciliter (mg/dL) even if the event was not associated with signs, symptoms, or treatment consistent with current guidelines (American Diabetes Association 2005). Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between bedtime and waking. Severe hypoglycemia is defined as a hypoglycemic event requiring assistance of another person to actively administer carbohydrates, glucagons, or other resuscitative actions. Severe Hypoglycemic events may or may not have a reported BG ≤70 mg/dL. These events may be associated with sufficient neuroglycopenia to induce seizure or coma. | Baseline through Endpoint [up to 24 weeks] | 
| Percentage of Participants With Hypoglycemic Events | The percentage of participants (with at least 1 hypoglycemic event (total, severe, nocturnal, and others) or incidence during the study was analyzed using Fisher's exact test. A hypoglycemic event is defined as any time a participant has a blood glucose (BG) level of ≤70 milligrams per deciliter (mg/dL) even if the event was not associated with signs, symptoms, or treatment consistent with current guidelines (American Diabetes Association 2005). Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between bedtime and waking. Severe hypoglycemia is defined as a hypoglycemic event requiring assistance of another person to actively administer carbohydrates, glucagons, or other resuscitative actions. Severe Hypoglycemic events may or may not have a reported BG ≤70 mg/dL. These events may be associated with sufficient neuroglycopenia to induce seizure or coma. | Endpoint [up to 24 weeks] |