A Study for Patients With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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A multicenter, multinational, randomized,double-blind, placebo-controlled study in patients with Type 2 Diabetes Mellitus (T2DM). Patients with inadequate glycemic control using diet and exercise alone, or in combination with metformin, will be enrolled. The primary objective of this study is to test the hypothesis that LY2428757 given to patients with T2DM inadequately controlled with diet and exercise alone, or metformin monotherapy, produces a significant decrease in the mean hemoglobin A1c (HbA1c) from baseline to endpoint at 12 weeks as compared to placebo. Trial consists of 12 weeks of double-blind treatment and 4-week safety follow-up.

Official Title
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A 12-Week,Double-Blind, Placebo-Controlled Trial of LY2428757 in Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: LY2428757
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have type 2 diabetes mellitus for at least 6 months prior to entering the trial. Treated with diet and exercise alone or in combination with at least 1000 milligrams (mg)/day of metformin for at least 2 months prior to screening. Have a glycosylated fraction of hemoglobin A (HbA1c) value of 7.0% - 10.0% at screening Women of child-bearing potential must test negative for pregnancy at screening and agree to abstain from heterosexual intercourse for the duration of the study, or use 2 effective forms of birth control during the study. Have a body mass index (BMI) between 25 and 40 kilograms per square meters kg/m^2) at screening Stable weight during the 3 months prior to screening. Exclusion Criteria: Use any antidiabetic agent other than metformin during the 2 months prior to screening. Have a gastrointestinal disease that significantly impacts gastric emptying or motility or have undergone bariatric surgery. Are currently taking prescription or over-the counter medications to promote weight loss. Have been previously diagnosed with pancreatitis Women who are breastfeeding. Have a history of myocardial infarction, unstable angina, coronary artery bypass graft (CABG), percutaneous coronary intervention, transient ischemic attack, stroke or decompensated congestive heart failure in the past 6 months. Have poorly controlled hypertension

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.5 mg LY2428757<br>Once weekly, subcutaneous injection of 0.5 milligram (mg) LY2428757 for 12 weeks. All injections were administered by study site personnel who were blinded to treatment assignment. | Drug: LY2428757<br>* Once weekly for 12 weeks as a subcutaneous injection.<br>|
| Experimental: 2.0 mg LY2428757<br>Once weekly, subcutaneous injection of 2.0 mg LY2428757 for 12 weeks. All injections were administered by study site personnel who were blinded to treatment assignment. | Drug: LY2428757<br>* Once weekly for 12 weeks as a subcutaneous injection.<br>|
| Experimental: 6.2 mg LY2428757<br>Once weekly, subcutaneous injection of 6.2 mg LY2428757 for 12 weeks. All injections were administered by study site personnel who were blinded to treatment assignment. | Drug: LY2428757<br>* Once weekly for 12 weeks as a subcutaneous injection.<br>|
| Experimental: 12.0 mg LY2428757<br>Once weekly, subcutaneous injection of 12.0 mg LY2428757 for 12 weeks. All injections were administered by study site personnel who were blinded to treatment assignment. | Drug: LY2428757<br>* Once weekly for 12 weeks as a subcutaneous injection.<br>|
| Experimental: 17.6 mg LY2428757<br>Once weekly, subcutaneous injection of 17.6 mg LY2428757 for 12 weeks. All injections were administered by study site personnel who were blinded to treatment assignment. | Drug: LY2428757<br>* Once weekly for 12 weeks as a subcutaneous injection.<br>|
| Placebo Comparator: Placebo<br>Once weekly, subcutaneous injection of placebo for 12 weeks. All injections were administered by study site personnel who were blinded to treatment assignment. | Drug: Placebo<br>* 1 of 5 volumes of placebo given once weekly for 12 weeks as a subcutaneous injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hemoglobin A1C (HbA1c) From Baseline to Week 12 Endpoint | LSMean adjusted for baseline HbA1c, metformin use, treatment, visit, treatment-by-visit interaction. | baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Visual Analogue Scales (VAS) For Appetite and Satiety From Baseline to Week 12 Endpoint | The VAS scales for appetite (hunger) and satiety (how full) were recorded on a scale with range of possible scores from 0 to 100 represented in millimeters on a 10 centimeter line. For appetite, participant chooses where they think their appetite lies on a 10 centimeter line between two anchors (0 - not at all hungry and 10 - extremely hungry). For satiety, participant chooses where they think their satiety lies on a 10 centimeter line between two anchors (0 - not at all full and 10 - extremely full). LSMean adjusted for baseline, treatment, visit, treatment-by-visit interaction. | baseline, 12 weeks | 
| Number of Participants With Detectable Antibodies To LY2428757 At Any Time During The Study | Blood samples were collected from all randomized participants to test for the development of antibodies binding to LY2428757. If a participant developed a positive anti-LY2428757 antibody titer, appropriate medical management was to be utilized at the discretion of the sponsor and investigator, if deemed necessary. | baseline through 16 weeks | 
| Total Average Concentration (Cavg) of LY2428757 | Average concentration (Cavg) is calculated as the AUC0-168 (area under the plasma concentration vs. time curve during one dosing interval of 168 hours) divided by 168 hours. The numbers presented reflect the average LY2428757 drug concentration circulating in the body over 168 hours (one dosing interval). | 4 weeks, 6 weeks, 8 weeks, 10 weeks | 
| Change in 7-Point Self-Monitored Glucose From Baseline to Week 12 Endpoint | Self-monitored glucose levels measured at 7 timepoints during the day. Timepoints include: fasting pre-breakfast, 2 hours post breakfast, prior to lunch, 2 hours post lunch, prior to dinner, 2 hours post dinner, and prior to bed. LSMean adjusted for baseline, treatment, visit, treatment-by-visit interaction. | baseline, 12 weeks | 
| Change in Total Glucose Area Under the Curve (AUC) From Baseline to Week 12 Endpoint | An oral glucose tolerance test (OGTT) was used to assess changes in glucose tolerance. The area under the plasma glucose concentration versus time curve was calculated using the linear-trapezoidal method. Area under the curve (AUC) for glucose represents the area that is under the curve of glucose values when they are plotted over time. Larger AUC values represent a greater average glucose value over time. LSMean adjusted for baseline, treatment, visit, treatment-by-visit interaction. | baseline, 12 weeks | 
| Change in Insulin Total Area Under the Curve (AUC) From Baseline to Week 12 Endpoint | An oral glucose tolerance test (OGTT) was used to assess changes in insulin secretory response. The area under the insulin concentration versus time curve was calculated using the linear-trapezoidal method. Area under the curve (AUC) for insulin represents the area that is under the curve of insulin values when they are plotted over time. Larger AUC values represent a greater average insulin value over time. LSMean adjusted for baseline, treatment, visit, treatment-by-visit interaction. | baseline, 12 weeks | 
| Change in C-peptide Area Under the Curve (AUC) From Baseline to Week 12 Endpoint | An oral glucose tolerance test (OGTT) was used to assess changes in insulin secretory response. The area under the C-peptide concentration versus time curve was calculated using the linear-trapezoidal method. Area under the curve (AUC) for C-peptide represents the area that is under the curve of C-peptide values when they are plotted over time. Larger AUC values represent a greater average C-peptide value over time. LSMean adjusted for baseline, treatment, visit, treatment-by-visit interaction. | baseline, 12 weeks | 
| Change in Fasting Lipids From Baseline to Week 12 Endpoint | Fasting lipids were measured after overnight fasting of at least 8 hours. Lipids analyzed include triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total-cholesterol. LSMean adjusted for baseline and treatment. | baseline, 12 weeks | 
| Change in Fasting Weight From Baseline to Week 12 Endpoint | LSMean adjusted for baseline, treatment, visit, treatment-by-visit interaction. | baseline, 12 weeks | 
| Change in Impact of Weight on Quality of Life - Lite (IWQoL-Lite) Average Score From Baseline to Week 12 Endpoint | Impact of Weight on Quality of Life (IWQoL) - Lite Version consists of 31 items from 5 subscales: physical functioning, self-esteem, sexual life, public distress, and work as well as a total score. Individual item scoring ranges from 0 (never true) to 4 (always true) with total score range from 0 to 124. Higher scores on the subscales and total score correspond with lower levels of functioning or greater negative effect. LSMean adjusted for baseline, baseline HbA1c (less than 8.5% versus greater than or equal to 8.5%), metformin use, treatment. | baseline, 12 weeks | 
| Change in Diabetes Symptom Checklist-Revised (DSC-R) Average Score From Baseline to Week 12 Endpoint | DSC-R assesses the presence and perceived burden of diabetes-related symptoms using the following subscales: hypoglycemic, hyperglycemic, psychological, cardiovascular, neurological, ophthalmological. Participants evaluate symptoms based on a 5-point Likert-type scale, ranging from 1=not at all troublesome to 5=extremely troublesome. Higher scores indicated greater severity of symptoms within a domain, or poorer perceived health, respectively. LSMean adjusted for baseline, baseline HbA1c (less than 8.5% versus greater than or equal to 8.5%), metformin use, treatment. | baseline, 12 weeks | 
| Change in European Quality of Life (EuroQol)- Visual Analog Scale From Baseline to Week 12 Endpoint | Participant chooses where they think their current health state lies on a 10 centimeter line between two anchors (0 - worst imaginable health state and 10 - best imaginable health state). The possible range of scores is 0 to 100 and represents millimeters on the 10 centimeter line. A higher score is associated with better health state. LSMean adjusted for baseline, baseline HbA1c (less than 8.5% versus greater than or equal to 8.5%), metformin use, treatment. | baseline, 12 weeks | 
| Percent of Participants Domain Scores Indicating No Problems on European Quality of Life (EuroQol) at Baseline and Week 12 Endpoint | The EuroQoL Questionnaire - 5 Dimension (EQ-5D) 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 mood. A single score between 1 and 3 is generated for each domain. For each participant, the outcome rating on the 5 domains will be mapped to a single index through an algorithm. The index ranges between 0 and 1, with the higher score indicating a better health state perceived by the participant. | Baseline, 12 Weeks |