A Study of Dose Titration of LY2189265 in Overweight Participants With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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To study once weekly injections of LY2189265 compared to placebo on blood glucose by measuring glycosylated hemoglobin (HbA1c) change from baseline after 16 weeks in overweight Type 2 Diabetes Mellitus participants.

Official Title
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The Effect of Dose Titration of LY2189265 in Overweight and Obese Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus Type 2

Intervention / Treatment
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* Drug: LY2189265
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 Diabetes Mellitus >3 months by history prior to entering the trial, based on disease diagnostic criteria from the American Diabetes Association (ADA 2007). Men or women 18 years of age or older. Women must have a negative pregnancy test and be willing to use birth control during study duration and one month post. Have glycosylated hemoglobin (HbA1c) of >7.0% to ≤10.5% as determined by central laboratory at screening. Have a body mass index (BMI) between 27 and 40 kilograms/meter squared (kg/m^2), inclusive. Have been on the same doses for 3 months of any approved combination of 2 oral antihyperglycemic medications in any combination of the following: sulfonylureas (e.g. Chlorpropamide or Diabinese, Glimepiride or Amaryl, Tolbutamide or Orinase, Tolazamide or Tolinase, Glipizide or Glucotrol, Glyburide also known as Micronase, Diabeta, or Glynase), biguanides (e.g. Glucophage or metformin), thiazolidinediones (e.g. Rosiglitazone or Avandia, or Pioglitazone or Actos), or dipeptidyl peptidase 4 (DPP-IV) inhibitors (e.g. Sitagliptin or Januvia). A combination pill of any 2 of these drugs is allowed (1 only), (e.g. Metformin and Glipizide or Metaglip), (e.g. Metformin and Glyburide or Glucovance), (e.g. Pioglitazone and Glimepiride or Duetact), or (e.g. Sitagliptin and Metformin or Janumet). Exclusion Criteria: Have known Type 1 Diabetes Mellitus Have taken glucagon-like peptide-1 (GLP-1) or any GLP-1 analog drug (Byetta) Have a history of unstable angina, heart attack (myocardial infarction), heart arrhythmia (ventricular), congestive heart failure, or other coronary intervention (percutaneous transluminal coronary angioplasty [PTCA], open heart surgery, or coronary artery bypass graft [CABG]), a transient ischemic attack (TIA) or stroke (cerebrovascular accident) in the last 6 months prior to screening. Have acute or chronic hepatitis or elevated liver function tests (alanine transaminase), a history of chronic or recurrent pancreatitis. Have renal disease or a serum creatinine (blood test) >2 milligrams per deciliter (mg/dL). If taking biguanides (e.g. metformin or Glucophage), or DPP-IV inhibitors (e.g. Sitagliptin or Januvia or Janumet), creatinine must be ≤1.5 mg/dL. Currently taking prescription or over the counter medications to prevent weight loss.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.0/2.0 milligram (mg) LY2189265<br>LY2189265: 1.0 milligram (mg), subcutaneous (SC) injection, once weekly (QW) for 4 weeks; followed by 2.0 mg, SC injection, QW for 12 weeks | Drug: LY2189265<br> <br> * Other names: Dulaglutide;|
| Experimental: 1.0/1.0 milligram (mg) LY2189265<br>LY2189265: 1.0 mg, subcutaneous (SC) injection, once weekly (QW) for 16 weeks | Drug: LY2189265<br> <br> * Other names: Dulaglutide;|
| Experimental: 0.5/1.0 milligram (mg) LY2189265<br>LY2189265: 0.5 milligram (mg), subcutaneous (SC) injection, once weekly (QW) for 4 weeks; followed by 1.0 mg, SC injection, QW for 12 weeks | Drug: LY2189265<br> <br> * Other names: Dulaglutide;|
| Placebo Comparator: Placebo<br>Placebo: subcutaneous (SC) injection, once weekly (QW) for 16 weeks | Drug: Placebo<br> <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) in Overweight and Obese Participants With Type 2 Diabetes Mellitus | Once weekly injections of LY2189265 (titrated and non-titrated doses) compared to placebo on blood glucose were evaluated. Least Squares (LS) means of change from baseline were calculated using analysis of covariance (ANCOVA) adjusting for treatment, combination of oral medications, and baseline glycosylated hemoglobin (HbA1c). | Baseline, 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 of change were calculated using analysis of covariance (ANCOVA) adjusting for treatment, combination of oral medications, and baseline. | Baseline, 16 weeks | 
| Meal Test Glucose Excursion (Change in Blood Glucose to Test Meal) | Glucose excursion in response to a standardized solid mixed meal test was evaluated at baseline (randomization) and at Week 16, or at early termination. Each of the 2 standardized meal tests required participants to fast starting at 2200 hours the night prior to the test. A standardized breakfast meal was provided to the participant (approximately 550 kilocalorie [Kcal], 103 grams [g] carbohydrates, 22 g protein, and 8.5 g fat) and was to be consumed within 15 minutes. Serial venous blood samples were taken at the start of the meal (fasting [0]) and 30, 60, 90, 120, and 180 minutes after the start of the meal. Least Squares (LS) means of change in mean glucose area under the curve excursion following a test meal were calculated adjusting for treatment, combination of oral medications, and baseline. | Baseline and 16 weeks | 
| Change From Baseline in Daily Mean Blood Glucose Values From the 8-point Self Monitored Blood Glucose (SMBG) Profiles | Change from baseline in mean daily blood glucose values were measured using self-monitored blood glucose (SMBG) data collected at the following 8 time points: pre-morning meal; 2 hours post-morning meal; pre-midday meal; 2 hours post-midday meal; pre-evening meal; 2 hours post-evening meal; bedtime; and 2:00 am. The daily mean was calculated as the average of the 8 blood glucose values collected on a particular day. Least Squares (LS) means of change from baseline of the mean of the 8 time points (Daily Mean) were calculated using analysis of covariance (ANCOVA) adjusting for treatment, combination of oral medications, and baseline. | 2 separate days in the week preceding the Baseline, Week 4, Week 8, and Week 16 visits. | 
| Change From Baseline in Beta (β)-Cell Function and Insulin Sensitivity as Estimated by the Updated Homeostasis Model Assessment Method (HOMA2) | Homeostasis Model Assessment tool (HOMA2) of β-cell function is a technique for estimating beta-cell function (HOMA2-%B) and insulin sensitivity (HOMA2-%S) using basal serum glucose, and c-peptide concentrations. A fasting blood glucose, c-peptide, and serum insulin level were drawn for purposes of this determination just prior to the mixed meal test. | Baseline, 16 weeks | 
| Percentage of Participants Achieving a Glycosylated Hemoglobin (HbA1c) of <7% or ≤6.5% | Percentages of participants who achieved glycosylated hemoglobin (HbA1c) levels of <7% or ≤6.5% were analyzed with a logistic regression model with baseline, combination of oral medications, and treatment as factors included in the model. | Baseline and 4 and 8 and 16 weeks | 
| Change From Baseline in Body Weight | LS means of change from baseline were calculated using analysis of covariance (ANCOVA) adjusting for treatment, combination of oral medications, and baseline. | Baseline, 4, 8, and 16 weeks | 
| Change From Baseline in Waist Circumference | Mean change from baseline in waist circumference (a measure of central obesity). | Baseline, 16 weeks | 
| Nausea and Dyspepsia Measured by Visual Analog Scale | Participants were asked to score nausea and dyspepsia (abdominal pain and bloating) on a scale of 0 (none) to 100 after the largest meal of the day. | One week before and one week after each of the Baseline and Week 4 and Week 8 and Week 16 visits | 
| Change From Baseline in Gastroparesis Cardinal Symptom Index (GCSI) Scores | Gastroparesis Cardinal Symptom Index (GCSI) is a participant-completed questionnaire designed to assess the severity of symptoms consistent with delayed gastric emptying (nausea/vomiting, abdominal bloating, and stomach fullness) at each study visit. GCSI scores ranged from 0=none, 1=very mild, 2=mild, 3=moderate, 4=severe, to 5=very severe. | Baseline and 4 and 8 and 16 weeks | 
| Number of Participants With a Hypoglycemic Event | A documented hypoglycemic episode is defined as an event which is associated with a measured blood glucose of ≤70 milligrams per deciliter (mg/dL) (3.9 millimoles per liter [mmol/L]), even if it was not associated with symptoms, signs, or treatment. A severe hypoglycemic episode is defined as an event with a measured blood glucose of <50mg/dL. 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 4, 8, and 16 weeks | 
| Rate of Hypoglycemia Per 30 Days | Hypoglycemic episodes are defined as an event which is associated with reported signs and/or symptoms of hypoglycemia (for example, sweating, shakiness, tachycardia, etc.) or a documented blood glucose (BG) concentration of ≤70 milligrams per deciliter (mg/dL) (3.9 millimoles per liter [mmol/L]), even if it was not associated with symptoms, signs, or treatment. The rate is the average number of days out of 30 that a participant reported hypoglycemia. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through 16 weeks | 
| Change From Baseline in Lipids | Lipids include total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides. | Baseline, 16 weeks | 
| Participants Perception of Medication Effectiveness Using the Perceptions About Medications - Diabetes, Short Version (PAM-D-S) Questionnaire | The Perceptions about Medications - Diabetes, Short Version (PAM-D-S) questionnaire consisted of: 2 items in which respondents were asked about their satisfaction with their diabetes medication over the past week using a 6-point scale ranging from 1 completely dissatisfied to 6 completely satisfied; 10 items in which respondents were asked about the effectiveness of their diabetes medications in the past week using a 4-point scale ranging from 1 all of the time to 4 none of the time; and 15 items asking respondents to indicate the frequency of physical side effects in the past week using a 4-point scale ranging from 1 all of the time to 4 none of the time. These items were exploratory items taken from a Diabetes Medicines Survey and had not been validated as a scale. The percentage of participants that rated their general health as good or better are summarized. | Baseline and 4 and 8 and 16 weeks | 
| Validation of the Psychometric Properties of the Perceptions About Medications - Diabetes, Short Version (PAM-D-S) Questionnaire | This purpose of this outcome measure was to validate the PAM-D-S questionnaire for future use. Please refer to Outcome Measure #14 for a description of the PAM-D-S questionnaire and results collected. A preliminary analysis indicated modifications to the questionnaire were required and further study is necessary to complete the validation. Therefore, the PAM-D-S questionnaire was not validated as a part of Study H9X-MC-GBCJ. | Baseline and 4 and 8 and 16 weeks | 
| Pharmacokinetics (PK) of LY2189265 - Area Under the Concentration Time Curve (AUC) | The population mean estimates and standard deviations were calculated for pharmacokinetic parameters (area under the concentration time curve [AUC] at steady state from time zero to 168 hours after study drug administration). | Time zero to 168 hours after study drug administration at 4, 8, and 16 weeks |