Type 2 Diabetes Mellitus
Conditions
Keywords
Glucagon-like peptide-1 (GLP-1)
Brief summary
The purpose of this trial is to examine the efficacy and safety of once-weekly LY2189265 (dulaglutide) in participants with type 2 diabetes mellitus taking an oral antihyperglycemic medication (OAM).
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.
Interventions
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants who have had a diagnosis of type 2 diabetes mellitus for at least 6 months before screening * Participants who have been taking sulfonylurea (glibenclamide, gliclazide, or glimepiride) and/or biguanide (metformin or buformin). The dose of the drug(s) during the 8 weeks before screening must be stable * Participants who have a qualifying glycosylated hemoglobin (HbA1c) value of 7.0% to 10.0% at screening * Participants who have a body mass index (BMI) of 18.5 to 35.0 kilograms per meter squared (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 received therapy with an alpha-glucosidase inhibitor (a-GI), thiazolidinedione (TZD), glinide, or dipeptidyl peptidase-IV (DPP-IV) inhibitor within 3 months before screening * Participants who have been currently taking insulin or have had previous insulin 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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, oral antihyperglycemic medication regimen (sulfonylureas only, biguanides only, or both), and 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
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Glycosylated Hemoglobin (HbA1c) <=6.5% or <7% at 26 Weeks | Up to 26 weeks | The percentage of participants achieving HbA1c level less than 7.0% and less than or equal to 6.5% was analyzed with a longitudinal logistic regression model with treatment, visit, treatment-by-visit, oral antihyperglycemic medication regimen (sulfonylureas only, biguanides only, or both), and 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. |
| Change From Baseline in Fasting Blood Glucose (FBG) 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, oral antihyperglycemic medication regimen (sulfonylureas only, biguanides only, or both), and baseline body mass index (BMI) group (\<25 or \>=25 kilograms per meter squared \[kg/m\^2\]) as fixed effects, baseline FBG as a covariate, and participant as a random effect. |
| Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Baseline, Up to 26 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, at bedtime, and before breakfast the next morning (second pre-morning meal). Least squares (LS) means were calculated using analysis of covariance (ANCOVA) model with treatment, oral antihyperglycemic medication regimen (sulfonylureas only, biguanides only, or both), and baseline body mass index (BMI) group (\<25 or \>=25 kilograms per meter squared \[kg/m\^2\]) as fixed effects and baseline SMBG as a covariate. |
| Change From Baseline in Body Weight 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, oral antihyperglycemic medication regimen (sulfonylureas only, biguanides only, or both), and baseline body mass index (BMI) group (\<25 or \>=25 kilograms per meter squared \[kg/m\^2\]) 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 | 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 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. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LY2189265 + OAM LY2189265: 0.75 milligrams (mg), administered subcutaneously (SC), once weekly for 26 weeks
Participants were to continue on their stable, pre-study, physician-prescribed dose of oral antihyperglycemic medication (OAM) throughout the study. OAMs included sulfonylureas (SU; glibenclamide, gliclazide, or glimepiride) and/or biguanides (BG; metformin or buformin). | 181 |
| Insulin Glargine + OAM Insulin glargine: dose based on targeting fasting blood glucose ≤110 milligrams per deciliter (mg/dL), administered subcutaneously (SC), once daily for 26 weeks
Participants were to continue on their stable, pre-study, physician-prescribed dose of oral antihyperglycemic medication (OAM) throughout the study. OAMs included sulfonylureas (SU; glibenclamide, gliclazide, or glimepiride) and/or biguanides (BG; metformin or buformin). | 180 |
| Total | 361 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Insulin Glargine + OAM | Total | LY2189265 + OAM |
|---|---|---|---|
| Age, Continuous | 56.14 years STANDARD_DEVIATION 11.33 | 56.83 years STANDARD_DEVIATION 10.92 | 57.52 years STANDARD_DEVIATION 10.48 |
| Race/Ethnicity, Customized Asian | 180 participants | 361 participants | 181 participants |
| Region of Enrollment Japan | 180 participants | 361 participants | 181 participants |
| Sex: Female, Male Female | 47 Participants | 103 Participants | 56 Participants |
| Sex: Female, Male Male | 133 Participants | 258 Participants | 125 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 133 / 181 | 111 / 180 |
| serious Total, serious adverse events | 9 / 181 | 3 / 180 |
Outcome results
Primary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 26 Weeks
Least squares (LS) means were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, visit, treatment-by-visit, oral antihyperglycemic medication regimen (sulfonylureas only, biguanides only, or both), and 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.
Time frame: Baseline, 26 weeks
Population: Participants who were randomized and received at least 1 dose of LY2189265 or insulin glargine with evaluable HbA1c data. Only pre-rescue measurements were used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2189265 + OAM | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 26 Weeks | -1.44 percentage of HbA1c | Standard Error 0.05 |
| Insulin Glargine + OAM | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at 26 Weeks | -0.90 percentage of HbA1c | Standard Error 0.05 |
Comparison: Approximately 360 participants were to be randomized in a 1:1 ratio to LY2189265 or insulin glargine (IG). Assuming no difference in HbA1c change from baseline at Week 26 between LY2189265 and IG, this sample size would provide approximately 90% power to confirm non-inferiority of LY2189265 to IG. This computation was based on a non-inferiority margin of 0.4% with a standard deviation of 1.1%, a 1-sided alpha level of 0.025, and an 11% dropout rate between randomization and Week 26.p-value: <0.00195% CI: [-0.67, -0.41]Mixed Models Analysis
Secondary
Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 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, at bedtime, and before breakfast the next morning (second pre-morning meal). Least squares (LS) means were calculated using analysis of covariance (ANCOVA) model with treatment, oral antihyperglycemic medication regimen (sulfonylureas only, biguanides only, or both), and baseline body mass index (BMI) group (\<25 or \>=25 kilograms per meter squared \[kg/m\^2\]) as fixed effects and baseline SMBG as a covariate.
Time frame: Baseline, Up to 26 weeks
Population: Participants who were randomized and received at least 1 dose of LY2189265 or insulin glargine with evaluable SMBG data. Only pre-rescue measurements were used. Missing endpoints were imputed with the last observation carried forward (LOCF), using only postbaseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2189265 + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Pre-evening meal (n=178, 179) | -31.14 milligrams per deciliter (mg/dL) | Standard Error 2.77 |
| LY2189265 + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Pre-morning meal (n=178, 179) | -33.49 milligrams per deciliter (mg/dL) | Standard Error 1.65 |
| LY2189265 + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Bedtime (n=177, 172) | -41.53 milligrams per deciliter (mg/dL) | Standard Error 2.95 |
| LY2189265 + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | 2 hours post-morning meal (n=178, 179) | -49.54 milligrams per deciliter (mg/dL) | Standard Error 3.33 |
| LY2189265 + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | 2 hours post-evening meal (n=177, 178) | -46.68 milligrams per deciliter (mg/dL) | Standard Error 3.05 |
| LY2189265 + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Pre-midday meal (n=178, 179) | -36.16 milligrams per deciliter (mg/dL) | Standard Error 2.68 |
| LY2189265 + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Second pre-morning meal (n=178, 179) | -30.81 milligrams per deciliter (mg/dL) | Standard Error 1.6 |
| LY2189265 + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | 2 hours post-midday meal (n=178, 179) | -43.51 milligrams per deciliter (mg/dL) | Standard Error 3.27 |
| Insulin Glargine + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Second pre-morning meal (n=178, 179) | -37.02 milligrams per deciliter (mg/dL) | Standard Error 1.59 |
| Insulin Glargine + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | 2 hours post-midday meal (n=178, 179) | -20.30 milligrams per deciliter (mg/dL) | Standard Error 3.25 |
| Insulin Glargine + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | 2 hours post-evening meal (n=177, 178) | -15.55 milligrams per deciliter (mg/dL) | Standard Error 3.03 |
| Insulin Glargine + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Bedtime (n=177, 172) | -17.79 milligrams per deciliter (mg/dL) | Standard Error 2.96 |
| Insulin Glargine + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Pre-evening meal (n=178, 179) | -17.50 milligrams per deciliter (mg/dL) | Standard Error 2.75 |
| Insulin Glargine + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Pre-morning meal (n=178, 179) | -38.66 milligrams per deciliter (mg/dL) | Standard Error 1.64 |
| Insulin Glargine + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | 2 hours post-morning meal (n=178, 179) | -36.14 milligrams per deciliter (mg/dL) | Standard Error 3.31 |
| Insulin Glargine + OAM | Change From Baseline in 8-Point Self-Monitored Blood Glucose (SMBG) at 26 Weeks | Pre-midday meal (n=178, 179) | -27.94 milligrams per deciliter (mg/dL) | Standard Error 2.66 |
p-value: 0.02295% CI: [0.76, 9.56]ANCOVA
p-value: 0.00395% CI: [-22.28, -4.52]ANCOVA
p-value: 0.02595% CI: [-15.37, -1.06]ANCOVA
p-value: <0.00195% CI: [-31.92, -14.51]ANCOVA
p-value: <0.00195% CI: [-21.03, -6.24]ANCOVA
p-value: <0.00195% CI: [-39.26, -23]ANCOVA
p-value: <0.00195% CI: [-31.68, -15.79]ANCOVA
p-value: 0.00595% CI: [1.92, 10.5]ANCOVA
Secondary
Change From Baseline in Body Weight at 26 Weeks
Least squares (LS) means were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, visit, treatment-by-visit, oral antihyperglycemic medication regimen (sulfonylureas only, biguanides only, or both), and baseline body mass index (BMI) group (\<25 or \>=25 kilograms per meter squared \[kg/m\^2\]) as fixed effects, baseline body weight as a covariate, and participant as a random effect.
Time frame: Baseline, 26 weeks
Population: Participants who were randomized and received at least 1 dose of LY2189265 or insulin glargine with evaluable body weight data. Only pre-rescue measurements were used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2189265 + OAM | Change From Baseline in Body Weight at 26 Weeks | -0.48 kilograms (kg) | Standard Error 0.17 |
| Insulin Glargine + OAM | Change From Baseline in Body Weight at 26 Weeks | 0.94 kilograms (kg) | Standard Error 0.17 |
p-value: <0.00195% CI: [-1.89, -0.94]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Blood Glucose (FBG) at 26 Weeks
Least squares (LS) means were calculated using a mixed-effects model for repeated measures (MMRM) analysis with treatment, visit, treatment-by-visit, oral antihyperglycemic medication regimen (sulfonylureas only, biguanides only, or both), and baseline body mass index (BMI) group (\<25 or \>=25 kilograms per meter squared \[kg/m\^2\]) as fixed effects, baseline FBG as a covariate, and participant as a random effect.
Time frame: Baseline, 26 weeks
Population: Participants who were randomized and received at least 1 dose of LY2189265 or insulin glargine with evaluable fasting blood glucose data. Only pre-rescue measurements were used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2189265 + OAM | Change From Baseline in Fasting Blood Glucose (FBG) at 26 Weeks | -34.3 milligrams per deciliter (mg/dL) | Standard Error 1.9 |
| Insulin Glargine + OAM | Change From Baseline in Fasting Blood Glucose (FBG) at 26 Weeks | -37.8 milligrams per deciliter (mg/dL) | Standard Error 1.9 |
p-value: 0.18395% CI: [-1.7, 8.7]Mixed Models Analysis
Secondary
Percentage of Participants Who Achieved Glycosylated Hemoglobin (HbA1c) <=6.5% or <7% at 26 Weeks
The percentage of participants achieving HbA1c level less than 7.0% and less than or equal to 6.5% was analyzed with a longitudinal logistic regression model with treatment, visit, treatment-by-visit, oral antihyperglycemic medication regimen (sulfonylureas only, biguanides only, or both), and 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.
Time frame: Up to 26 weeks
Population: Participants who were randomized and received at least 1 dose of LY2189265 or insulin glargine with evaluable HbA1c data. Only pre-rescue measurements were used. Missing endpoints were imputed with the last observation carried forward (LOCF), using only postbaseline data.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2189265 + OAM | Percentage of Participants Who Achieved Glycosylated Hemoglobin (HbA1c) <=6.5% or <7% at 26 Weeks | HbA1c <=6.5% | 51.1 percentage of participants |
| LY2189265 + OAM | Percentage of Participants Who Achieved Glycosylated Hemoglobin (HbA1c) <=6.5% or <7% at 26 Weeks | HbA1c <7% | 71.3 percentage of participants |
| Insulin Glargine + OAM | Percentage of Participants Who Achieved Glycosylated Hemoglobin (HbA1c) <=6.5% or <7% at 26 Weeks | HbA1c <=6.5% | 24.0 percentage of participants |
| Insulin Glargine + OAM | Percentage of Participants Who Achieved Glycosylated Hemoglobin (HbA1c) <=6.5% or <7% at 26 Weeks | HbA1c <7% | 45.8 percentage of participants |
p-value: <0.001Regression, Logistic
p-value: <0.001Regression, Logistic
Secondary
Percentage of Participants With Hypoglycemic Episodes
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 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.
Time frame: Baseline through 26 Weeks
Population: Participants who were randomized and received at least 1 dose of LY2189265 or insulin glargine. Only pre-rescue data was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2189265 + OAM | Percentage of Participants With Hypoglycemic Episodes | 26.0 percentage of participants |
| Insulin Glargine + OAM | Percentage of Participants With Hypoglycemic Episodes | 47.8 percentage of participants |
p-value: <0.001Fisher Exact