A Study of LY2189265 in Japanese Participants With Type 2 Diabetes Mellitus

Phase 3

Completed

Conditions: Type 2 Diabetes Mellitus

Interventions: Drug: LY2189265
Drug: Liraglutide
Drug: Placebo

Registration Number: NCT01558271

Lead Sponsor: Eli Lilly and Company

Brief Summary: The purpose of this trial is to examine the efficacy and safety of once-weekly LY2189265 in participants with type 2 diabetes mellitus who are not taking oral antidiabetic medication.

Detailed Description: Rescue therapy (defined as alternative antihyperglycemic medication use or dose modification of oral antihyperglycemic medication \[OAM\]) may have been initiated during the planned treatment period if the participant discontinued study drug or met prespecified thresholds for severe, persistent hyperglycemia. Efficacy data, as well as data for hypoglycemic episodes from participants who permanently discontinued study treatment but switched to another diabetes medication and remained in the study, were censored from the point of initiating new treatment onwards.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 492

Inclusion Criteria

Participants who have had a diagnosis of type 2 diabetes mellitus before screening.
Participants who have been Oral Antihyperglycemic Medication (OAM)-naïve (diet and exercise only) or been taking OAM monotherapy except for thiazolidinedione (TZD) and are willing to discontinue this medication. Participants taking OAM monotherapy must complete 8-week washout period prior to randomization.
Participants who are OAM naïve with a screening glycosylated hemoglobin (HbA1c) value of 7.0% to 10.0% and randomization HbA1c value of 7.0% to 10.0%, or who are taking OAM monotherapy with screening HbA1c value of 6.5% to 9.0% and randomization HbA1c value of 7.0% to 10.0%.
Participants who have a body mass index (BMI) of 18.5 kilograms per meter squared (kg/m^2) to 35.0 kg/m^2.

Exclusion Criteria

Participants who have a diagnosis of type 1 diabetes.
Participants who have previously been treated with any other glucagon-like peptide-1 (GLP-1) analog.
Participants who have been receiving more than half of the maximum dose of sulfonylureas at screening.
Participants who have been currently taking insulin or TZD, or have had previous insulin or TZD treatment within 3 months before screening.
Participants who have obvious clinical signs or symptoms of pancreatitis, a history of chronic pancreatitis or acute pancreatitis at screening, as determined by the investigator. Participants who have a serum amylase concentration ≥3 times the upper limit of the reference range and/or a serum lipase concentration ≥2 times the upper limit of the reference range, as determined by the central laboratory at screening.
Participants who have self or family history of medullary C-cell hyperplasia, focal hyperplasia, or medullary thyroid carcinoma (MTC).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo/LY2189265	Placebo	Once-weekly SC injection of placebo for 26 weeks of blinded therapy, followed by once-weekly SC injection of 0.75 mg LY2189265 for an additional 26 weeks of open therapy.
LY2189265	LY2189265	Once-weekly subcutaneous (SC) injection of 0.75 milligrams (mg) of LY2189265 for 26 weeks of blinded therapy, followed by once-weekly SC injection of 0.75 mg LY2189265 for an additional 26 weeks of open therapy.
Placebo/LY2189265	LY2189265	Once-weekly SC injection of placebo for 26 weeks of blinded therapy, followed by once-weekly SC injection of 0.75 mg LY2189265 for an additional 26 weeks of open therapy.
Liraglutide	Liraglutide	Once-daily SC injection of 0.3 mg of Liraglutide for the first week, followed by 0.6 mg of Liraglutide for the second week, and then 0.9 mg of Liraglutide for the remaining 50 weeks of open therapy.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 26 Weeks	Baseline, 26 weeks	Least squares (LS) means were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, visit, treatment-by-visit, prestudy therapy (oral antihyperglycemic medication \[OAM\] yes/no), baseline body mass index (BMI) group (\<25 or \>=25 kilograms per meter squared \[kg/m\^2\]) as fixed effects, baseline HbA1c as a covariate, and participant as a random effect.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 52 Weeks	Baseline, 52 weeks	LS means were calculated using MMRM analysis with treatment, visit, treatment-by-visit, prestudy therapy (OAM yes/no), baseline BMI group (\<25 or \>=25 kg/m\^2) as fixed effects, baseline HbA1c as a covariate, and participant as a random effect.
Percentage of Participants Who Achieved HbA1c <=6.5% or <7%	Up to 26 and 52 weeks	The percentage of participants achieving HbA1c level less than 7.0% and less than or equal to 6.5% at Week 26 and Week 52 was analyzed with a Cochran-Mantel-Haenszel test stratified by prestudy therapy (OAM yes/no) and baseline BMI group (\<25 or \>=25 kg/m\^2).
Change From Baseline in Fasting Blood Glucose (FBG) at 26 Weeks and 52 Weeks	Baseline, 26 weeks, 52 weeks	LS means were calculated using MMRM analysis with treatment, visit, treatment-by-visit, prestudy therapy (OAM yes/no), baseline BMI group (\<25 or \>=25 kg/m\^2) as fixed effects, baseline FBG as a covariate, and participant as a random effect.
Change From Baseline in Insulin Sensitivity Using Updated Homeostasis Model Assessment (HOMA 2) at 26 Weeks and 52 Weeks	Baseline, 26 weeks, 52 weeks	HOMA 2 quantifies insulin resistance and beta-cell function. HOMA2-S is a computer model that uses fasting plasma insulin and glucose concentrations to estimate insulin sensitivity (%S) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. Change in insulin sensitivity was assessed based on change from baseline of HOMA2-%S using fasting insulin (FI) and fasting C-peptide (FCP). LS means were calculated using ANCOVA model with treatment, prestudy therapy (OAM yes/no), and baseline BMI group (\<25 or \>=25 kg/m\^2) as fixed effects and baseline HOMA2-%S as a covariate.
Change From Baseline in Pulse Rate at 26 Weeks and 52 Weeks	Baseline, 26 weeks, 52 weeks	Sitting pulse rate was measured. LS means were calculated using ANCOVA model with treatment, prestudy therapy (OAM yes/no), and baseline BMI group (\<25 or \>=25 kg/m\^2) as fixed effects and baseline pulse rate as a covariate.
Number of Participants Requiring Additional Intervention Due to Hyperglycemia at 26 Weeks and 52 Weeks	Baseline through 26 weeks and Baseline through 52 weeks	Additional intervention was defined as any additional therapeutic intervention in participants who developed persistent, severe hyperglycemia despite full compliance with the assigned therapeutic regimen, or initiation of an alternative antihyperglycemic medication following study drug discontinuation. The number of participants requiring additional intervention due to hyperglycemia is summarized cumulatively at 26 and 52 weeks.
Change From Baseline in 7-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks and 52 Weeks	Baseline, 26 weeks, 52 weeks	Participants were to test and record SMBG concentrations in their study diaries before each meal (breakfast, lunch, and dinner), approximately 2 hours after the start of each meal, and at bedtime. LS means were calculated using analysis of covariance (ANCOVA) model with treatment, prestudy therapy (OAM yes/no), and baseline BMI group (\<25 or \>=25 kg/m\^2) as fixed effects and baseline SMBG as a covariate.
Change From Baseline in Body Weight at 26 Weeks and 52 Weeks	Baseline, 26 weeks, 52 weeks	LS means were calculated using MMRM analysis with treatment, visit, treatment-by-visit, prestudy therapy (OAM yes/no), baseline BMI group (\<25 or \>=25 kg/m\^2) as fixed effects, baseline body weight as a covariate, and participant as a random effect.
Percentage of Participants With Hypoglycemic Episodes	Baseline through 26 weeks and Baseline through 52 weeks	The percentage of participants with hypoglycemic episodes was calculated by dividing the number of participants with at least one hypoglycemic episode over the 26-week or 52-week treatment period by the total number of participants analyzed, multiplied by 100%. All classifications of hypoglycemia (documented symptomatic, asymptomatic, severe, nocturnal, non-nocturnal, probable symptomatic, relative, and unspecified) were included, except for episodes of relative hypoglycemia that were not severe. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Number of Participants With Treatment-Emergent LY2189265 Anti-Drug Antibodies (ADAs) at 26 Weeks and 52 Weeks	Baseline through 26 weeks and Baseline through 52 weeks	A participant was considered to have treatment-emergent LY2189265 ADAs if the participant had at least 1 titer that was treatment-emergent relative to baseline, defined as a 4-fold or greater increase in titer from the baseline measurement.
Number of Participants With Adjudicated Cardiovascular Events at 26 Weeks and 52 Weeks	Baseline through 26 weeks and Baseline through 52 weeks	Deaths and nonfatal cardiovascular adverse events were adjudicated by a committee of physicians with cardiology expertise external to the Sponsor. The nonfatal cardiovascular events subjected to adjudication included myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, coronary interventions (such as coronary artery bypass graft or percutaneous coronary intervention), and cerebrovascular events including cerebrovascular accident (stroke) and transient ischemic attack. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Change From Baseline in Serum Calcitonin at 26 Weeks and 52 Weeks	Baseline, 26 weeks, 52 weeks
Change From Baseline in Beta-cell Function Using Updated Homeostasis Model Assessment (HOMA 2) at 26 Weeks and 52 Weeks	Baseline, 26 weeks, 52 weeks	HOMA 2 quantifies insulin resistance and beta-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%. Change in beta-cell function was assessed based on change from baseline of HOMA2-%B using fasting insulin (FI) and fasting C-peptide (FCP). LS means were calculated using ANCOVA model with treatment, prestudy therapy (OAM yes/no), and baseline BMI group (\<25 or \>=25 kg/m\^2) as fixed effects and baseline HOMA2-%B as a covariate.
30-Day Rate of Hypoglycemic Episodes	Baseline through 26 weeks and Baseline through 52 weeks	The 30-day total hypoglycemia rate over 26 weeks and 52 weeks of treatment is summarized. All classifications of hypoglycemia (documented symptomatic, asymptomatic, severe, nocturnal, non-nocturnal, probable symptomatic, relative, and unspecified) were included, except for episodes of relative hypoglycemia that were not severe. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Change From Baseline in Pancreatic Enzymes at 26 Weeks and 52 Weeks	Baseline, 26 weeks, 52 weeks	Pancreatic enzyme (lipase and total amylase) concentrations were measured.
Change From Baseline in Electrocardiogram Parameters at 26 Weeks and 52 Weeks	Baseline, 26 weeks, 52 weeks	Fridericia Corrected QT (QTcF) Interval and PR Interval are summarized. 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: QTcF = 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. PR is the interval between the P wave and the QRS complex. LS means were calculated using ANCOVA model with treatment as a fixed effect and the baseline ECG parameter as the covariate.
Change From Baseline in Blood Pressure at 26 Weeks and 52 Weeks	Baseline, 26 weeks, 52 weeks	Sitting systolic blood pressure (SBP) and sitting diastolic blood pressure (DBP) were measured. LS means were calculated using ANCOVA model with treatment, prestudy therapy (OAM yes/no), and baseline BMI group (\<25 or \>=25 kg/m\^2) as fixed effects and baseline blood pressure as a covariate.
Number of Participants With Adjudicated Pancreatitis at 26 Weeks and 52 Weeks	Baseline through 26 weeks and Baseline through 52 weeks	Events of pancreatitis (including suspected pancreatitis and severe or serious abdominal pain) were adjudicated by a committee of expert physicians external to the Sponsor. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

Trial Locations

Locations (1): For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
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Yokohama, Japan