A Study of the Safety and Effectiveness of LY3053102 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 investigate the safety and effectiveness of the study drug known as LY3053102 in participants with Type 2 diabetes mellitus. The study drug will be given in different doses as an injection under the skin. The study is expected to last up to 6 months for each participant. Participants may remain on stable-dose metformin as prescribed by their personal physician.

Official Title
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Safety, Tolerability, Pharmacokinetics, and Efficacy of LY3053102 With 12 Weeks of Treatment in Patients With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: LY3053102
* Drug: Exenatide ER
* Drug: Placebo
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Participants with type 2 diabetes mellitus for at least 6 months before entering the trial based on the disease diagnostic criteria (World Health Organization [WHO]) classification managed with diet or exercise alone or with a stable dose of metformin of at least 1000 mg/day for at least 60 days before screening or on metformin and an eligible second oral anti-hyperglycemic medication after a 60-day washout of the second oral anti-hyperglycemic medication Women not of childbearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause Have a hemoglobin A1c value of ≥7.0% and ≤10.5%, if on diet and exercise or diet, exercise, and metformin (stable dose of at least 1000 mg/day for at least 60 days), or have a hemoglobin A1c value of ≥7.0% and ≤9.5%, and are on an appropriate diet and exercise regimen, a stable dose of metformin and willing to discontinue a second oral anti-hyperglycemic medication Have a body mass index ≥23 and ≤45 kilograms per square meter (kg/m^2) Exclusion Criteria Have used insulin for diabetic control for more than 6 consecutive days within 1 year prior to screening Have used thiazolidinediones within 3 months, or any other drugs for treatment of hyperglycemia (except metformin) within 2 months, prior to the first week of the study Have hepatitis B and/or positive hepatitis B surface antigen. hepatitis C or human immunodeficiency virus (HIV) and/or positive HIV antibodies Have known or suspected cardiac autonomic neuropathy (for example, resting tachycardia or orthostatic hypotension), based on clinical signs, symptoms, or appropriate diagnostic testing Have cardiac disease with functional status that is New York Heart Association Class II, III, or IV or in the last 6 months have had any of the following: a history of myocardial infarction , unstable angina, coronary artery bypass graft, percutaneous coronary intervention (diagnostic angiograms are permitted), transient ischemic attack, or cerebrovascular accident (for example, stroke) Have poorly controlled hypertension, malignant hypertension, renal artery stenosis, and/or evidence of labile blood pressure including symptomatic postural hypotension. Doses of antihypertensive medications must be stable for 30 days prior to the first week of the study Have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or an alanine transaminase or aspartate aminotransferase levels >2 times the upper limit of the reference range Have evidence of hypothyroidism or hyperthyroidism based on clinical evaluation and/or an abnormal thyroid-stimulating hormone which, in the opinion of the investigator, would pose a risk to participant safety. Participants on a stable dose of thyroid replacement therapy may be eligible if they meet the other criteria Have clinically significant peripheral vascular disease, or clinical evidence of active diabetic proliferative retinopathy, (known significant autonomic neuropathy) as evidenced by urinary retention, orthostatic hypotension, diabetic diarrhea or gastroparesis Have an active or untreated malignancy or have been in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years Have impaired renal function Have fasting triglycerides >500 milligrams per deciliter (mg/dL) at screening Have experienced a keto-acidotic episode requiring hospitalization in the last 6 months Have an electrocardiogram (ECG) considered to be indicative of cardiac disease Have personal or family history of long QT syndrome, family history of sudden death in a first-degree relative before age 40, or personal history of unexplained syncope within the last year. Use of prescription or over-the-counter medications known to prolong the QT or QTc interval Have a history of bone disease (including osteoporosis or unhealed fractures), evidence of osteoporosis (femoral neck or lumbar spine T-score <-2.5) determined by dual X-ray absorptometry (DXA) scan at screening, evidence of osteopenia (T-score between -1.0 and -2.5 at the femoral neck or lumbar spine) with a high risk of fracture based on risk factors or current active treatment of periodontal disease

Ages Eligible for Study
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Minimum Age: 21 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY3053102<br>Stage 1: Escalating dose (7 milligrams [mg] up to 200 mg) of LY3053102 administered once a week by subcutaneous (SC) injection for 12 weeks. Stage 2: LY3053102 administered once a week by SC injection for 12 weeks | Drug: LY3053102<br>* Administered SC<br>Drug: Metformin<br>* Administered orally (PO)<br>|
| Placebo Comparator: Placebo<br>Stage 1 and Stage 2: Placebo to match LY3053102 administered by SC injection once a week for 12 weeks | Drug: Placebo<br>* Administered SC<br>Drug: Metformin<br>* Administered orally (PO)<br>|
| Active Comparator: Exenatide Extended-Release (ER)<br>Stage 1 and Stage 2: Exenatide ER 2 mg given by SC injection once a week for 12 weeks | Drug: Exenatide ER<br>* Administered SC<br>Drug: Metformin<br>* Administered orally (PO)<br>|
| Experimental: LY3053102 + Exenatide ER<br>Stage 2: LY3053102 administered by SC injection once a week for 12 weeks and exenatide ER 2 mg administered by SC injection once a week for 12 weeks | Drug: LY3053102<br>* Administered SC<br>Drug: Exenatide ER<br>* Administered SC<br>Drug: Metformin<br>* Administered orally (PO)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (HbA1c) at 12-Week Endpoint | 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) analysis adjusting for metformin use, washout of second oral anti-hyperglycemic medication (OAM), treatment, visit, and treatment-by-visit interaction as fixed effects, baseline as a covariate, and participant as a random effect. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving HbA1c <7.0% or HbA1c ≤6.5% at 12-Week Endpoint | HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. | Week 12 | 
| Percentage of Participants That Require Rescue Therapy | Percentage of participants that required >=1 rescue (blood glucose lowering) medications. | Baseline through Week 12 | 
| Change From Baseline in Body Weight at 12-Week Endpoint | LS means were calculated using MMRM analysis adjusting for baseline HbA1c category, metformin use, washout of second OAM, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline as a covariate, and participant as a random effect (excludes data after rescue therapy). | Baseline, Week 12 | 
| Change From Baseline in 7-Point Blood Glucose Profile at 12-Week Endpoint | 7-Point Self-Monitored Blood Glucose profiles are measures of blood glucose concentration taken 7 times a day at morning pre-prandial, morning 2 hours postprandial, midday pre-prandial, midday 2 hours postprandial, evening pre-prandial, evening 2 hour postprandial, and bedtime. LS means were calculated using MMRM analysis adjusting for baseline HbA1c category, metformin use, washout of second OAM, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline as a covariate, and participant as a random effect (excludes data after rescue therapy). | Baseline, Week 12 | 
| Change From Baseline in Lipids at 12-Week Endpoint | Lipids includes: High Density Lipoprotein-Cholesterol (HDL-C), Low Density Lipoprotein-Cholesterol (LDL-C), Triglycerides, and Cholesterol. LS means were calculated using MMRM analysis adjusting for metformin use, washout of second OAM, baseline HbA1c category, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline as a covariate, and participant as a random effect (excludes data after rescue therapy). | Baseline, Week 12 | 
| Percentage of Participants With Anti-Drug Antibodies to LY3053102 | Percentage of participants with anti-LY3053102 antibody titre changes from baseline to the maximum postbaseline value. | Baseline through Study Completion (Up to 6 Months) | 
| Percentage of Participants With Hypoglycemia | Hypoglycemia was defined as any event meeting the criteria for documented symptomatic hypoglycemia, asymptomatic hypoglycemia, or probable symptomatic hypoglycemia. | Baseline through Week 12 | 
| Change From Baseline in Bone Metabolism at 12-Week Endpoint (Osteocalcin and Bone-Specific Alkaline Phosphatase [Bone-Specific ALP]) | LS means were calculated using MMRM analysis adjusting for metformin use, washout of second OAM, baseline HbA1c category, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline as a covariate, and participant as a random effect (excludes data after rescue therapy). | Baseline, Week 12 | 
| Change From Baseline in Bone Metabolism at 12-Week Endpoint (Beta-Crosslaps and Procollagen 1 N-Terminal Propeptide [P1NP]) | LS means were calculated using MMRM analysis adjusting for metformin use, washout of second OAM, baseline HbA1c category, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline as a covariate, and participant as a random effect (excludes data after rescue therapy). | Baseline, Week 12 | 
| Change From Baseline in Bone Mineral Density Markers at 12-Week Endpoint | LS means were calculated using MMRM analysis adjusting for metformin use, washout of second OAM, baseline HbA1c category, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline as a covariate, and participant as a random effect (excludes data after rescue therapy). | Baseline, Week 12 | 
| Pharmacokinetics: Area Under the Concentration Versus Time Curve During One Dosing Interval at Steady State (AUC [τ,ss]) of LY3053102 | AUC (τ,ss) = area under the concentration versus time curve during one dosing interval at steady state, where the dosing interval (τ) = 168 hours. | Predose, 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 168 hours post-dose |