A Study of LY2409021 in Participants With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The intent of this study is to assess the safety of LY2409021 in participants with Type 2 diabetes mellitus taking metformin and sulfonylurea as prescribed by their personal physician. The study treatment is expected to last 12 months (52 weeks).

Official Title
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A Phase 2, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of LY2409021 Compared to Sitagliptin in Subjects With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: LY2409021
* Drug: Sitagliptin
* Drug: Placebo
* Drug: Metformin
* Drug: Sulfonylurea


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have been treated with a stable dose of metformin for at least 3 months and have been treated with an optimally effective and stable dose of an sulfonylurea for at least 6 months prior to screening. HbA1c value between 7.0% and 10.0%, inclusive. Body mass index (BMI) between 20 and 45 kilograms/square meter (kg/m^2), inclusive. Exclusion Criteria: Known type 1 diabetes mellitus. More than 1 episode of severe hypoglycemia within 6 months prior to screening. Two or more emergency room visits or hospitalizations due to poor glucose control in the 6 months prior to screening. Severe gastrointestinal disease that may significantly impact gastric emptying or motility or having undergone gastric bypass or gastric banding surgery. Previous history or active diagnosis of pancreatitis. Positive hepatitis B surface antigen or hepatitis C antibody. Clinical signs or symptoms of liver disease, or hepatic aminotransferases (aminotransferase or alanine aminotransferase) greater than 2.0× upper limit of normal (ULN) or elevated alkaline phosphatase (greater than ULN) unrelated to bone metabolic disease. Elevated total bilirubin level (greater than ULN), clinically suspicious signs/symptoms of cirrhosis or history of cirrhosis. Current diagnosis, personal history of neuroendocrine tumors, family history of any type of multiple endocrine neoplasia (MEN), or Von Hippel-Lindau. Contraindications for magnetic resonance imaging.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2409021<br>20 milligrams (mg) LY2409021 given orally once daily in the morning for 12 months (52 weeks). Participants remain on stable doses of metformin and sulfonylurea, as prescribed by their personal physician. | Drug: LY2409021<br>* Administered orally<br>Drug: Metformin<br>* Administered orally<br>Drug: Sulfonylurea<br>* Administered orally<br>|
| Active Comparator: Sitagliptin<br>100 mg sitagliptin given orally once daily in the morning for 12 months (52 weeks). Participants remain on stable doses of metformin and sulfonylurea, as prescribed by their personal physician. | Drug: Sitagliptin<br>* Administered orally<br>Drug: Metformin<br>* Administered orally<br>Drug: Sulfonylurea<br>* Administered orally<br>|
| Placebo Comparator: Placebo<br>Placebo matching LY2409021 and sitagliptin given orally once daily in the morning for 12 months (52 weeks). Participants remain on stable doses of metformin and sulfonylurea, as prescribed by their personal physician. | Drug: Placebo<br>* Administered orally<br>Drug: Metformin<br>* Administered orally<br>Drug: Sulfonylurea<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 6 Months in Hepatic Fat Fraction | The hepatic fat fraction (HFF) was calculated by a core imaging laboratory from noncontrast magnetic resonance imaging (MRI) of the liver. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit. | Baseline, 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 6 Months in Alanine Aminotransferase Levels | Alanine aminotransferase (ALT) assessed by a central laboratory. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit. | Baseline, 6 months | 
| Number of Participants With Hepatobiliary Adverse Events of Special Interest (AESI) | Number of participants with ALT or AST greater than 3 times the upper limit of normal at a post-baseline visit. A summary of other non-serious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. | Baseline, 6 months | 
| Change From Baseline to 6 Months in Fasting Lipids Levels | Lipid values (cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides) assessed by a central laboratory. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit. | Baseline, 6 months | 
| Change From Baseline to 6 Months in Fasting Blood Glucagon | Glucagon values assessed by a central laboratory. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit. | Baseline, 6 months | 
| Change From Baseline to 6 Months in Body Weight | Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit. | Baseline, 6 months | 
| Change From Baseline to 6 Months in Hemoglobin A1c (HbA1c) | HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, visit, baseline score, and treatment-by-visit. | Baseline, 6 months | 
| Change From Baseline to 6 Months in Fasting Plasma Glucose | Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit. | Baseline, 6 months | 
| Change From Baseline to 6 Months in Blood Pressure | Seated systolic blood pressure (SBP) and seated diastolic blood pressure (DBP) were measured in triplicate throughout the study. At each visit, all available blood pressure measurements for a subject were averaged to provide the blood pressure for that visit. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit. | Baseline, 6 months | 
| Change From Baseline to 6 Months in Pulse Rate | Seated pulse rate was measured in triplicate throughout the study. At each visit, all available pulse measurements for a subject were averaged to provide the pulse for that visit. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) adjusting for treatment, country, baseline HbA1c stratum (<=8.0%, >8.0%), visit, baseline score, and treatment-by-visit. | Baseline, 6 months | 
| Change From Baseline to 6 Months in 7-Point Self-Monitoring of Blood Glucose (SMBG) | 7-point profile consists of pre-meal and 2-hour postprandial SMBG measurements for the morning, midday, and evening meals in 1 day and at 3 AM (nocturnal blood glucose measurement). Pre-meal measurements were taken before the subject began eating the meal. Participants recorded their glucose measurements in their study diaries. | Baseline, 6 months | 
| Population Pharmacokinetics: Apparent Clearance of LY2409021 | Reported as a Population Estimate with % Standard Errors of Estimation (SEE), 5th-95th confidence interval. | Day 1 Month 1, 3, 6, 9, predose, 1 hour postdose, | 
| Population Pharmacokinetics: Apparent Volume of Distribution of LY2409021 |  | Day 1 Month 1, 3, 6, 9, predose, 1 hour postdose, | 
| Rate of Hypoglycemic Events Adjusted Per 30 Days | Documented symptomatic hypoglycemia, an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration <=70 mg/dL (<=39 mmol/L),is presented. Rate: (30 days) is calculated as: (number of episodes during the time period divided by the number of days during the time period) multiplied by 30. | Baseline through 6 months | 
| Number of Participants With Hypoglycemic Events | Documented symptomatic hypoglycemia, an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration <=70 mg/dL (<=39 mmol/L), is presented. The number of subjects with an event are subjects who had at least one episode of documented symptomatic hypoglycemia during the time period. | Baseline through 6 months |