Effects of LY2189265 on Glycemic Control in Participants With Type 2 Diabetes

Study Overview
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Brief Summary
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This is a study to demonstrate that different doses of once-weekly LY2189265 injected subcutaneously will have dose proportional effect on hemoglobin A1c (HbA1c) at 12 weeks in participants with type 2 diabetes mellitus.

Detailed Description
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Participants in the trial will be randomized to one of the LY2189265 doses (4 doses are planned, range 0.1-1.5 milligram [mg]) or placebo. The main purpose is to assess dose-dependent effect of this new compound on blood glucose over a period of 12 weeks. Therefore, glycosylated hemoglobin (HbA1c) is chosen as the primary efficacy measure. Several other attributes of glycemic control and endocrine function of pancreas will be assessed as secondary objectives. These secondary objectives will be used to compare the effect of the experimental compound and placebo. Since LY2189265 is in early phase of development, comprehensive safety assessment is planned to learn more about possible side-effects and to establish benefit/risk profile of individual doses of the drug. The trial is organized in four phases: screening, lead-in period to establish baseline status of participants in each group, treatment period during which participants will be randomized into 1 of 5 groups (4 will receive one of the LY2189265 doses, 1 group will receive placebo), and safety follow up. Maximum of 9 study visits are planned. Study drug (LY2189265 or placebo) will be administered once weekly via subcutaneous (SC) injections. Rescue intervention was allowed after randomization for those participants whose hyperglycemia reached pre-defined unacceptable high values. Participants on rescue therapy remained in the study and continued to receive study drug. Participants who received rescue therapy were included in the analysis population, but only measurements obtained prior to the beginning of rescue therapy were included in specified efficacy analyses. A 3-mg LY2189265 dose was discontinued and replaced with the 1.5 mg dose based on dose finding Study H9X-MC-GBCF; NCT00734474. Except where noted, data summaries from the 3 discontinued 3-mg LY2189265 participants (n=3) are not included due to the small number of participants and the short treatment duration.

Official Title
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Assessment of Dose-Dependent Effects of LY2189265 on Glycemic Control in Patients With Type 2 Diabetes Treated Only With Lifestyle Interventions

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: LY2189265 and Lifestyle Measures
* Drug: Placebo solution and Lifestyle Measures


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diabetes mellitus, type 2 Treatment regimens: diet and exercise only or are taking metformin as monotherapy and are willing to discontinue this medication Have completed at least 8 weeks of wash-out prior to randomization (if on metformin therapy at screening) Have a qualifying glycosylated hemoglobin (HbA1c) value, as determined by the central laboratory: at screening (for diet and exercise only ≥7.0% to ≤9.5%; for metformin monotherapy >6.5% to ≤9.0%) and at time of randomization for all participants ≥6.5% to ≤9.5% Females of childbearing potential must test negative for pregnancy and agree to use a reliable birth control method Have a body mass index (BMI) between 23 and 40 kilograms/meter squared (kg/m^2), inclusive, for participants who are native to, and reside in, South and/or East Asia; all other participants must have a BMI between 25 and 40 kg/m^2, inclusive. Stable weight for 3 months prior to screening Exclusion Criteria: Diabetes mellitus, type 1 Taking any glucose-lowering oral agents other than metformin within 3 months prior to screening Use of glucagon-like peptide-1 (GLP-1) analog (for example, exenatide) within 6 months prior to screening or being treated within insulin (with the exception of short-term management of acute conditions that occurred more than 3 months immediately prior to screening) Use of medications (prescription or over-the counter) to promote weight loss Chronic (>2 weeks) use of systemic glucocorticoid therapy Gastric emptying abnormality, history of bariatric surgery or chronic use of drugs that affect gastrointestinal motility Use of central nervous system (CNS) stimulant (for example, Ritalin-sustained release [SR]) Cardiovascular event within 6 months prior to screening Poorly controlled hypertension (determined by a mean seated systolic blood pressure (BP) ≥160 millimeters of mercury (mmHg) or mean seated diastolic BP ≥95 mmHg at screening or randomization) Electrocardiogram (ECG) reading considered outside the normal limits by the investigator and relevant for interpretation or indicating cardiac disease Liver disease, hepatitis, chronic hepatitis, or alanine transaminase levels >3.0 times upper limit of normal Clinical signs or symptoms of pancreatitis or history of chronic or acute pancreatitis at time of screening Amylase ≥3 times the upper limit of normal and/or lipase ≥2 times upper limit of normal which are determined by central labs at the time of screening Serum creatinine ≥1.5 milligrams per deciliter (mg/dL) for men or ≥1.4 mg/dL for women or a creatinine clearance <60 milliliter (mL)/minute which are determined by central labs at the time of screening Uncontrolled diabetes (defined as 2 or more episode of hyperosmolar state requiring hospitalization in the 6 months prior to screening) Significant active, uncontrolled endocrine or autoimmune abnormality History of a transplanted organ (corneal transplants are allowed) Active or untreated 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 any other condition, in the opinion of the investigator, that may preclude the participant from following or completing the protocol Investigator site personnel directly affiliated with this study and/or their immediate families (spouse, parent, child, or sibling, whether biological or legally adopted) Sponsor employees Received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry Participated in an interventional medical, surgical, or pharmaceutical study within 30 days prior to entry into the study Have previously completed or withdrawn from this study after providing informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: 0.1 milligram (mg) LY2189265<br>LY2189265: 0.1 milligram (mg), subcutaneous (SC), once weekly (QW) | Drug: LY2189265 and Lifestyle Measures<br>* Subcutaneous injection once-weekly for up to 12 weeks<br>* Other names: Dulaglutide;|
| Experimental: 0.5 milligram (mg) LY2189265<br>LY2189265: 0.5 milligram (mg), subcutaneous (SC), once weekly (QW) | Drug: LY2189265 and Lifestyle Measures<br>* Subcutaneous injection once-weekly for up to 12 weeks<br>* Other names: Dulaglutide;|
| Experimental: 1.0 milligram (mg) LY2189265<br>LY2189265: 1.0 milligram (mg), subcutaneous (SC), once weekly (QW) | Drug: LY2189265 and Lifestyle Measures<br>* Subcutaneous injection once-weekly for up to 12 weeks<br>* Other names: Dulaglutide;|
| Experimental: 1.5 milligram (mg) LY2189265<br>LY2189265: 1.5 milligram (mg), subcutaneous (SC), once weekly (QW) | Drug: LY2189265 and Lifestyle Measures<br>* Subcutaneous injection once-weekly for up to 12 weeks<br>* Other names: Dulaglutide;|
| Placebo Comparator: Placebo<br>Placebo: subcutaneous (SC) once weekly (QW) | Drug: Placebo solution and Lifestyle Measures<br>* Subcutaneous injection once-weekly for up to 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Least Squares (LS) means of change from baseline for glycosylated hemoglobin (HbA1c) were calculated using mixed model repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and baseline HbA1c as covariate. | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) | Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and baseline glycosylated hemoglobin (HbA1c) as covariate. | Baseline, 4 weeks, 8 weeks | 
| Change From Baseline in Fasting Blood Glucose | Fasting blood glucose is a test to determine how much glucose (sugar) is in a blood sample after an overnight fast. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and baseline fasting glucose as covariate. | Baseline, 12 weeks | 
| Percentage of Participants Who Achieve Glycosylated Hemoglobin (HbA1c) <7% or ≤6.5% | Percentages of participants who achieved glycosylated hemoglobin (HbA1c) levels of <7.0% or ≤6.5% were compared across treatment arms using the Cochran-Armitage trend test. | 12 weeks | 
| Change From Baseline in Daily Mean Blood Glucose Values From the 7-point Self Monitored Blood Glucose (SMBG) Profiles | Change from baseline in mean daily blood glucose values were measured with a 7-point self-monitored blood glucose (SMBG) profile over a 24-hour period in the 7-day period prior to each visit. The 7-point SMBG profile consisted of preprandial blood glucose measures before the morning, midday, and evening meals; blood glucose measures 2 hours after the start of the morning, midday, and evening meals; and the fasting blood glucose obtained the following morning. Mean at 12 weeks was assessed in all treatment groups. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and as covariate. | Baseline, 12 weeks | 
| Change From Baseline in Beta-cell Function (HOMA2-%B) | Change from baseline in beta (β)-cell function (HOMA2-%B) was assessed by using the homeostatic model assessment (HOMA) to quantify β-cell function. HOMA2-%B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state beta cell function (%B), as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. Least Squares (LS) means were calculated using a mixed-effects model for repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and baseline HOMA2-%B as covariate. | Baseline, 12 weeks | 
| Change From Baseline in Insulin Sensitivity (HOMA2-%S) | Change from baseline in insulin sensitivity (HOMA2-%S) was assessed by using the homeostatic model assessment (HOMA) to quantify insulin sensitivity. HOMA2-%S is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state insulin sensitivity (%S), as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. Least Squares (LS) means were calculated using a mixed-effects model for repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and baseline HOMA2-%S as covariate. | Baseline, 12 weeks | 
| Change From Baseline in Electrocardiograms (ECGs) - Fridericia-corrected QT (QTcF) and PR Interval | The QT interval is a measure of the time between the start of the Q wave and the end of the T wave and was calculated from electrocardiogram (ECG) data using Fridericia's formula: QTc = QT/RR^0.33. Corrected QT (QTc) is the QT interval corrected for heart rate and RR, which is the interval between two R waves. The PR segment begins at the endpoint of the P wave and ends at the onset of the QRS complex. Least Squares (LS) means were calculated using a mixed-effects model for repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and baseline measurement as covariate. | Baseline, 12 weeks | 
| Change From Baseline in Electrocardiograms (ECGs) - Heart Rate | Least Squares (LS) means were calculated using a mixed-effects model for repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and baseline measurement as covariate. | Baseline, 12 weeks | 
| Change From Baseline in Pulse Rate | Sitting pulse rate was measured. Least Squares (LS) means were calculated using a mixed-effects model for repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and baseline measurement as covariate. | Baseline, 12 weeks | 
| Change From Baseline in Blood Pressure (BP) | Sitting systolic blood pressure (SBP) and sitting diastolic blood pressure (DBP) were measured. Least Squares (LS) means of change were calculated using a mixed-effects model for repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and baseline measurement as covariate. | Baseline, 12 weeks | 
| Number of Participants With Self-reported Hypoglycemic Events | Hypoglycemic events were classified as severe (defined as episodes requiring the assistance of another person to actively administer resuscitative actions), documented symptomatic (defined an event during which typical symptoms of hypoglycemia were accompanied by a blood glucose level of ≤3.9 millimoles per liter [mmol/L]), asymptomatic (defined as events not accompanied by typical symptoms of hypoglycemia but with a measured blood glucose of ≤3.9 mmol/L), or nocturnal (defined as any hypoglycemic event that occurred between bedtime and breakfast with a measured blood glucose of ≤3.9 mmol/L). Participant reports of hypoglycemic events were collected at the beginning of each visit starting at Baseline. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 12 weeks | 
| Rate of Self-reported Hypoglycemic Events | Hypoglycemic events (HE) were classified as severe (defined as events requiring the assistance of another person to actively administer resuscitative actions), documented symptomatic (defined an event during which typical symptoms of hypoglycemia were accompanied by a blood glucose level of ≤3.9 millimoles per liter [mmol/L]), asymptomatic (defined as events not accompanied by typical symptoms of hypoglycemia but with a measured blood glucose of ≤3.9 mmol/L), or nocturnal (defined as any HE that occurred between bedtime and breakfast with a measured blood glucose of ≤3.9 mmol/L). Participant reports of HE were collected at the beginning of each visit starting at Baseline and the annualized rate was reported. Least Squares (LS) means rates were adjusted for pre-study therapy, country, and baseline body mass index. A summary of AEs regardless of causality is located in the Reported AEs module. Some model-adjusted LS means are less than 0 and may be interpreted as very low rates. | Baseline through 12 weeks | 
| Treatment Emergent Adverse Events | A treatment emergent adverse event is any untoward medical occurrence that either occurs or worsens at any time after the first injection of study drug following randomization and which does not necessarily have to have a causal relationship. The number of participants with one or more treatment emergent adverse event was reported. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 12 weeks | 
| Change From Baseline in Body Weight | Least Squares (LS) means was calculated using a mixed-effects model for repeated measures (MMRM) with pre-study therapy, country, dose, visit, and dose-by-visit interaction as fixed effects and baseline measurement as covariate. | Baseline, 12 weeks | 
| Antibody Production and Effects to LY2189265 | LY2189265 anti-drug antibodies (ADA) were assessed at baseline, 4 and 12 weeks, and at the safety follow-up visit 4 weeks after study drug discontinuation (16 weeks). The number of participants with initial postbaseline detection of treatment emergent (defined as a 4-fold increase in the ADA titer from baseline) LY2189265 ADA at each time point were summarized. | Baseline, 4 weeks, 12 weeks, 16 weeks | 
| Collection and Evaluation of Plasma Levels (Pharmacokinetics [PK]) of LY2189265 | The population mean estimates and standard deviations were calculated for pharmacokinetic parameters (area under the concentration time curve (AUC) from zero to 168 hours). Evaluable PK concentrations from the 4 week, 8 week, and 12 week timepoints were combined and utilized in a population approach to determine the population mean estimate and standard deviation at steady-state. | 4 weeks, 8 weeks, 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, type 2 diabetes