Type 2 Diabetes Mellitus
Conditions
Keywords
T2DM, LY2189265
Brief summary
The main purpose of this study is to evaluate the safety and efficacy of once weekly dulaglutide when added to insulin glargine, with metformin and/or acarbose in Chinese participants with type 2 diabetes mellitus.
Interventions
DRUGDulaglutide
Administered SC
DRUGPlacebo
Administered SC
DRUGInsulin Glargine
Administered SC
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* have type 2 diabetes * are men or nonpregnant women aged ≥18 years at screening * have been treated with basal insulin glargine once daily and metformin and/or acarbose for at least 3 months prior to screening * doses of once daily insulin glargine and OAMs must be stable during the 3-month period prior to screening. Insulin glargine dose is considered stable when all doses during this period are within the range defined by ±20% of the most commonly used insulin glargine dose during this same period. Doses of metformin and/or acarbose are considered stable when doses are unchanged during the same period, and the doses should be in the inclusive range of the half maximum to maximum approved daily dose per the locally-approved label * have an HbA1c value ≥7.0% and ≤11.0% as assessed by the central laboratory at screening * require further insulin glargine dose increase at baseline per the TTT algorithm based on the SMBG data (FBG ≥5.6mmol/L) collected during the prior week * have stable weight (±5%) ≥3 months prior to screening * have body mass index (BMI) between ≥19.0 and ≤35.0 kg/m2 at screening
Exclusion criteria
* have type 1 diabetes (T1D) * have a history of ≥1 episode of ketoacidosis or hyperosmolar state/coma * have a history of severe hypoglycemia and/or hypoglycemia unawareness within the 6 months prior to screening * have had any of the following CV conditions within the 2 months prior to screening: acute myocardial infarction (MI), New York Heart Association (NYHA) Class III or Class IV heart failure, or cerebrovascular accident (stroke) * have a known clinically significant gastric emptying abnormality (eg, severe diabetic gastroparesis or gastric outlet obstruction) or have undergone or plan to have a gastric bypass (bariatric) surgery or restrictive bariatric surgery (eg, Lap-Band®) during the course of the study, or chronically take drugs that directly affect gastrointestinal (GI) motility * have a history of chronic pancreatitis or acute idiopathic pancreatitis, or were diagnosed with any type of acute pancreatitis within the 3 months prior to screening * for participants on metformin or metformin and acarbose, have renal disease or renal dysfunction (eGFR \[CKD-EPI\] \<45 mL/min/1.73 m2), as determined by the central laboratory; for participants on acarbose, have renal disease or renal dysfunction (eGFR \[CKD-EPI\] \<25 mL/min/1.73 m2), as determined by the central laboratory * have any self or family history of type 2A or type 2B multiple endocrine neoplasia (MEN 2A or 2B) syndrome in the absence of known C-cell hyperplasia (the only exception for this exclusion will be for participants whose family members with MEN 2A or 2B syndrome have a known RET mutation and the potential participant for the study is negative for the RET mutation) * have any self or family history of medullary C-cell hyperplasia, focal hyperplasia, or carcinoma (including sporadic, familial, or part of MEN 2A or 2B syndrome) * have serum calcitonin ≥20 pg/mL at screening, as determined by the central laboratory * have any hematologic condition that may interfere with HbA1c measurement (eg, hemolytic anemias, sickle-cell disease) * have been treated with any other antihyperglycemia regimen, other than basal insulin glargine once daily and metformin and/or acarbose, within the 3 months prior to screening or between screening and baseline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline, Week 28 | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed model repeated measures (MMRM) model with Baseline + Oral Antihyperglycemic Medications (OAM) use + Treatment + Visit + Treatment\*Visit (Type III sum of squares) as variables. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Weight | Baseline, Week 28 | Change from baseline in body weight was reported here. LS mean was determined by MMRM model with Baseline + Baseline HbA1c strata (\<8.5%, \>=8.5%) + OAM use + Treatment + Visit + Treatment\*Visit (Type III sum of squares) as variables. |
| Change From Baseline in Fasting Serum Glucose (FSG) | Baseline, Week 28 | Change from baseline in FSG was reported here. LS mean was determined using MMRM model with Baseline + Baseline HbA1c strata (\<8.5%, \>=8.5%) + OAM use + Treatment + Visit + Treatment\*Visit (Type III sum of squares) as variables. |
| Percentage of Participants Achieving HbA1c <7.0% With no Weight Gain (<0.1 kg) and Without Documented Symptomatic Hypoglycemia (Blood Glucose <3.0 mmol/L) | Week 28 | Percentage of Participants Achieving HbA1c \<7.0% With no Weight Gain (\<0.1 kg) and Without Documented Symptomatic Hypoglycemia (Blood Glucose \<3.0 mmol/L) was reported here. |
| Percentage of Participants Achieving HbA1c <7.0% | Week 28 | HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Odds Ratio (OR) was determined using longitudinal logistic regression model with Baseline HbA1c value + OAM use + Treatment + Visit + Treatment\*Visit as variables. |
| Percentage of Participants Achieving HbA1c <7.0% Without Weight Gain (<0.1 kg) | Week 28 | Percentage of Participants Achieving HbA1c \<7.0% Without Weight Gain (\<0.1 kg) was reported here. |
| Change From Baseline in Blood Glucose From Daily Self-Monitored Blood Glucose (SMBG) Profile | Baseline, Week 28 | The SMBG data was collected at the following 7 time points: Pre morning meal BG, 2-hour postprandial measurement for morning meal BG, Pre midday meal BG, 2-hour postprandial measurement for midday meal BG, Pre evening meal BG, 2-hour postprandial measurement for evening meals BG, and Bedtime BG. LS mean was determined using MMRM model with Baseline + OAM (metformin and/or acarbose) usage + HbA1c Group at Baseline + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. |
| Change From Baseline in Daily Mean Insulin Glargine Doses | Baseline, Week 28 | LS mean was determined using MMRM model with Baseline + Baseline HbA1c strata (\<8.5%, \>=8.5%) + OAM use + Treatment + Visit + Treatment\*Visit (Type III sum of squares) as variables. |
| Percentage of Participants Achieving HbA1c <7.0% Without Documented Symptomatic Hypoglycemia (Blood Glucose <3.0 mmol/L) | Week 28 | Percentage of Participants Achieving HbA1c \<7.0% Without Documented Symptomatic Hypoglycemia (Blood Glucose \<3.0 mmol/L) was reported here. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1.5 mg Dulaglutide Participants received 1.5 mg Dulaglutide administered QW SC as add-on to titrated TTT dose of insulin glargine given SC, along with metformin and/or acarbose. | 144 |
| Placebo Participants received placebo administered QW SC as add-on to titrated TTT dose of insulin glargine given SC, along with metformin and/or acarbose. | 147 |
| Total | 291 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Non-Compliance with Study Drug | 1 | 0 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | 1.5 mg Dulaglutide | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57.80 years STANDARD_DEVIATION 9.33 | 58.30 years STANDARD_DEVIATION 9.48 | 58.10 years STANDARD_DEVIATION 9.39 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 144 Participants | 147 Participants | 291 Participants |
| Hemoglobin A1c (HbA1c) | 8.60 Percentage of HbA1c STANDARD_DEVIATION 1 | 8.58 Percentage of HbA1c STANDARD_DEVIATION 0.97 | 8.59 Percentage of HbA1c STANDARD_DEVIATION 0.98 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 144 Participants | 147 Participants | 291 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment China | 144 Participants | 147 Participants | 291 Participants |
| Sex: Female, Male Female | 52 Participants | 57 Participants | 109 Participants |
| Sex: Female, Male Male | 92 Participants | 90 Participants | 182 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 144 | 1 / 147 |
| other Total, other adverse events | 113 / 144 | 99 / 147 |
| serious Total, serious adverse events | 8 / 144 | 12 / 147 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c)
HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed model repeated measures (MMRM) model with Baseline + Oral Antihyperglycemic Medications (OAM) use + Treatment + Visit + Treatment\*Visit (Type III sum of squares) as variables.
Time frame: Baseline, Week 28
Population: All randomized participants with baseline and at least one post-baseline HbA1c data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in Hemoglobin A1c (HbA1c) | -2.03 Percentage of HbA1c | Standard Error 0.076 |
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) | -1.08 Percentage of HbA1c | Standard Error 0.073 |
p-value: <0.00195% CI: [-1.14, -0.77]Mixed Models Analysis
Secondary
Change From Baseline in Blood Glucose From Daily Self-Monitored Blood Glucose (SMBG) Profile
The SMBG data was collected at the following 7 time points: Pre morning meal BG, 2-hour postprandial measurement for morning meal BG, Pre midday meal BG, 2-hour postprandial measurement for midday meal BG, Pre evening meal BG, 2-hour postprandial measurement for evening meals BG, and Bedtime BG. LS mean was determined using MMRM model with Baseline + OAM (metformin and/or acarbose) usage + HbA1c Group at Baseline + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
Time frame: Baseline, Week 28
Population: All randomized participants with baseline and at least one post-baseline blood glucose data from SMBG profile.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in Blood Glucose From Daily Self-Monitored Blood Glucose (SMBG) Profile | -64.0 milligrams per deciliter (mg/dL) | Standard Error 2.42 |
| Placebo | Change From Baseline in Blood Glucose From Daily Self-Monitored Blood Glucose (SMBG) Profile | -37.7 milligrams per deciliter (mg/dL) | Standard Error 2.36 |
p-value: <0.00195% CI: [-33, -19.6]Mixed Models Analysis
Secondary
Change From Baseline in Body Weight
Change from baseline in body weight was reported here. LS mean was determined by MMRM model with Baseline + Baseline HbA1c strata (\<8.5%, \>=8.5%) + OAM use + Treatment + Visit + Treatment\*Visit (Type III sum of squares) as variables.
Time frame: Baseline, Week 28
Population: All randomized participants with baseline and at least one post-baseline body weight data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in Body Weight | -0.76 kilogram (kg) | Standard Error 0.224 |
| Placebo | Change From Baseline in Body Weight | 0.42 kilogram (kg) | Standard Error 0.217 |
p-value: <0.00195% CI: [-1.77, -0.6]Mixed Models Analysis
Secondary
Change From Baseline in Daily Mean Insulin Glargine Doses
LS mean was determined using MMRM model with Baseline + Baseline HbA1c strata (\<8.5%, \>=8.5%) + OAM use + Treatment + Visit + Treatment\*Visit (Type III sum of squares) as variables.
Time frame: Baseline, Week 28
Population: All randomized participants with a baseline and at least one post-baseline insulin glargine dose data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in Daily Mean Insulin Glargine Doses | 10.0 International Units per day(IU/day) | Standard Error 1.045 |
| Placebo | Change From Baseline in Daily Mean Insulin Glargine Doses | 14.0 International Units per day(IU/day) | Standard Error 1.015 |
p-value: 0.00695% CI: [-6.86, -1.14]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Serum Glucose (FSG)
Change from baseline in FSG was reported here. LS mean was determined using MMRM model with Baseline + Baseline HbA1c strata (\<8.5%, \>=8.5%) + OAM use + Treatment + Visit + Treatment\*Visit (Type III sum of squares) as variables.
Time frame: Baseline, Week 28
Population: All randomized participants with baseline and at least one post-baseline fasting serum glucose data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1.5 mg Dulaglutide | Change From Baseline in Fasting Serum Glucose (FSG) | -58.47 milligrams per deciliter (mg/dL) | Standard Error 2.339 |
| Placebo | Change From Baseline in Fasting Serum Glucose (FSG) | -43.64 milligrams per deciliter (mg/dL) | Standard Error 2.269 |
p-value: <0.00195% CI: [-20.57, -9.08]Mixed Models Analysis
Secondary
Percentage of Participants Achieving HbA1c <7.0%
HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Odds Ratio (OR) was determined using longitudinal logistic regression model with Baseline HbA1c value + OAM use + Treatment + Visit + Treatment\*Visit as variables.
Time frame: Week 28
Population: All randomized participants with baseline and at least one post-baseline HbA1c data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.5 mg Dulaglutide | Percentage of Participants Achieving HbA1c <7.0% | 75.9 Percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c <7.0% | 33.8 Percentage of participants |
p-value: <0.00195% CI: [5.35, 22.28]Regression, Logistic
Secondary
Percentage of Participants Achieving HbA1c <7.0% With no Weight Gain (<0.1 kg) and Without Documented Symptomatic Hypoglycemia (Blood Glucose <3.0 mmol/L)
Percentage of Participants Achieving HbA1c \<7.0% With no Weight Gain (\<0.1 kg) and Without Documented Symptomatic Hypoglycemia (Blood Glucose \<3.0 mmol/L) was reported here.
Time frame: Week 28
Population: All randomized participants with HbA1c, hypoglycemia and body weight data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.5 mg Dulaglutide | Percentage of Participants Achieving HbA1c <7.0% With no Weight Gain (<0.1 kg) and Without Documented Symptomatic Hypoglycemia (Blood Glucose <3.0 mmol/L) | 51.8 Percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c <7.0% With no Weight Gain (<0.1 kg) and Without Documented Symptomatic Hypoglycemia (Blood Glucose <3.0 mmol/L) | 21.1 Percentage of participants |
p-value: <0.00195% CI: [2.64, 7.95]Regression, Logistic
Secondary
Percentage of Participants Achieving HbA1c <7.0% Without Documented Symptomatic Hypoglycemia (Blood Glucose <3.0 mmol/L)
Percentage of Participants Achieving HbA1c \<7.0% Without Documented Symptomatic Hypoglycemia (Blood Glucose \<3.0 mmol/L) was reported here.
Time frame: Week 28
Population: All randomized participants with HbA1c and hypoglycemia data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.5 mg Dulaglutide | Percentage of Participants Achieving HbA1c <7.0% Without Documented Symptomatic Hypoglycemia (Blood Glucose <3.0 mmol/L) | 74.8 Percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c <7.0% Without Documented Symptomatic Hypoglycemia (Blood Glucose <3.0 mmol/L) | 33.3 Percentage of participants |
p-value: <0.00195% CI: [4.27, 13.48]Regression, Logistic
Secondary
Percentage of Participants Achieving HbA1c <7.0% Without Weight Gain (<0.1 kg)
Percentage of Participants Achieving HbA1c \<7.0% Without Weight Gain (\<0.1 kg) was reported here.
Time frame: Week 28
Population: All randomized participants with HbA1c and body weight data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1.5 mg Dulaglutide | Percentage of Participants Achieving HbA1c <7.0% Without Weight Gain (<0.1 kg) | 51.8 Percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c <7.0% Without Weight Gain (<0.1 kg) | 21.1 Percentage of participants |
p-value: <0.00195% CI: [2.64, 7.95]Regression, Logistic