Type 2 Diabetes
Conditions
Brief summary
The main purpose of this study is to evaluate the efficacy and safety of combination therapy with dulaglutide and insulin in Japanese participants with type 2 diabetes.
Interventions
DRUGDulaglutide
Administered subcutaneously (SC)
DRUGPlacebo
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
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants who have had a diagnosis of type 2 diabetes mellitus * Participants who have been treated with insulin therapy (basal insulin, premixed insulin, or basal/mealtime insulin regimen) with or without 1 or 2 oral antidiabetics (OADs) at stable dose for at least 3 months before screening * Participants who have an HbA1c value ≥7.0% and ≤10.5% at screening if the participant is washing out OADs (dipeptidyl peptidase-4 \[DPP-4\] inhibitors, sulfonylurea \[SU\], or glinides) or ≥7.5% and ≤10.5% at screening if the participant is not washing out OADs * Participants who have stable weight (±5%) ≥3 months prior to 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 received therapy with a glucagon-like peptide-1 receptor agonist within 3 months prior to screening * Participants who have been previously treated with dulaglutide prior to screening * Participants who have been treated with 2 of the following at screening: DPP-4 inhibitor, SU, and glinide (ie, DPP-4 inhibitor and SU, or DPP-4 inhibitor and glinide) * Participants who have been treated with continuous subcutaneous insulin infusion (CSII) at screening * Participants who have clinically significant gastric emptying abnormality, hepatitis, pancreatitis, renal dysfunction, or thyroid abnormalities * Participants who have a history of clinically significant cardiovascular disease, transplanted organ, or active or untreated malignancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline, Week 16 | HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least square (LS) mean in HbA1c was calculated using a restricted maximum likelihood (REML) based mixed-effects model for repeated measures (MMRM) and adjusted by, baseline HbA1c, treatment, visit, and treatment-by-visit insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin), where participant treated as a random effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HbA1c <7.0% or ≤6.5% | Week 16 | Percentage of participants whose HbA1c was \<7.0% or ≤6.5%. HbA1c \<7.0% is presented. |
| Change From Baseline in Fasting Serum Glucose (FSG) | Baseline, Week 16 | The LS mean change from baseline in FSG was calculated using a REML based MMRM and adjusted by, baseline value, treatment, visit, treatment-by-visit, baseline HbA1c Group (\<8.5%, \>=8.5%) + insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin), where participant treated as a random effect. |
| Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Baseline, Week 16 | The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: prebreakfast blood glucose (BG), breakfast 2-hour postprandial blood glucose (PPBG), prelunch BG, lunch 2-hour PPBG, predinner BG, dinner 2-hour PPBG, and bedtime BG. LS mean was calculated with fixed effect test of analysis of covariance (ANCOVA) model and adjusted by, baseline value, treatment, baseline HbA1c Group (\<8.5%, ≥8.5%), insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin). |
| Change From Baseline in Body Weight | Baseline, Week 16 | LS mean change from baseline in body weight was calculated using a REML based MMRM and was adjusted by, baseline value, treatment, visit, treatment-by-visit, baseline HbA1c group (\<8.5%, \>=8.5%), insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin), where participant treated as a random effect. |
| Change From Baseline in Daily Total Insulin Dose | Baseline, Week 16 | Mean change from baseline in total insulin dose was measured in each treatment groups. |
Countries
Japan
Participant flow
Pre-assignment details
After 16 weeks of the primary double-blind treatment period, participants taking placebo were switched to dulaglutide for an additional 36 weeks of open-label extension treatment. Efficacy was assessed for 16 weeks based on hypoglycemic agent evaluation.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo administered SC once weekly for 16 weeks. After 16-weeks, Dulaglutide 0.75 mg administered SC once weekly for 36 weeks. | 39 |
| Dulaglutide Dulaglutide 0.75 mg administered SC once weekly for 16 weeks. After 16-weeks, Dulaglutide 0.75 mg administered SC once weekly for 36 weeks. | 120 |
| Total | 159 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Treatment Period | Adverse Event | 2 | 2 |
| Double-Blind Treatment Period | Withdrawal by Subject | 0 | 1 |
| Open-Label Extension Period | Adverse Event | 5 | 3 |
| Open-Label Extension Period | Protocol Violation | 0 | 1 |
| Open-Label Extension Period | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Dulaglutide | Total |
|---|---|---|---|
| Age, Continuous | 59.1 years STANDARD_DEVIATION 10.68 | 59.3 years STANDARD_DEVIATION 10.23 | 59.3 years STANDARD_DEVIATION 10.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 120 Participants | 159 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Percentage of Hemoglobin A1c (HbA1c) at Baseline | 8.64 Percentage of HbA1c STANDARD_DEVIATION 0.72 | 8.50 Percentage of HbA1c STANDARD_DEVIATION 0.69 | 8.53 Percentage of HbA1c STANDARD_DEVIATION 0.7 |
| Percentage of Participants with Insulin regimen Basal | 43.6 percentage of insulin regimen | 43.3 percentage of insulin regimen | 43.4 percentage of insulin regimen |
| Percentage of Participants with Insulin regimen Basal/meal time | 33.3 percentage of insulin regimen | 35.0 percentage of insulin regimen | 34.6 percentage of insulin regimen |
| Percentage of Participants with Insulin regimen Premixed | 23.1 percentage of insulin regimen | 21.7 percentage of insulin regimen | 22.0 percentage of insulin regimen |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 39 Participants | 120 Participants | 159 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 Japan | 39 Participants | 120 Participants | 159 Participants |
| Sex: Female, Male Female | 19 Participants | 42 Participants | 61 Participants |
| Sex: Female, Male Male | 20 Participants | 78 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 39 | 0 / 120 | 0 / 39 | 0 / 120 |
| other Total, other adverse events | 18 / 39 | 47 / 120 | 28 / 39 | 59 / 120 |
| serious Total, serious adverse events | 0 / 39 | 3 / 120 | 1 / 39 | 6 / 120 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c)
HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least square (LS) mean in HbA1c was calculated using a restricted maximum likelihood (REML) based mixed-effects model for repeated measures (MMRM) and adjusted by, baseline HbA1c, treatment, visit, and treatment-by-visit insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin), where participant treated as a random effect.
Time frame: Baseline, Week 16
Population: All randomized participants who received at least one dose of study drug and had evaluable baseline and post-baseline HbA1c.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) | 0.06 percentage of HbA1c | Standard Error 0.099 |
| Dulaglutide | Change From Baseline in Hemoglobin A1c (HbA1c) | -1.45 percentage of HbA1c | Standard Error 0.057 |
p-value: <0.00195% CI: [-1.73, -1.28]Mixed Models Analysis
Secondary
Change From Baseline in Body Weight
LS mean change from baseline in body weight was calculated using a REML based MMRM and was adjusted by, baseline value, treatment, visit, treatment-by-visit, baseline HbA1c group (\<8.5%, \>=8.5%), insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin), where participant treated as a random effect.
Time frame: Baseline, Week 16
Population: All randomized participants who received at least one dose of study drug and had evaluable post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight | -0.30 kilogram (kg) | Standard Error 0.302 |
| Dulaglutide | Change From Baseline in Body Weight | -0.20 kilogram (kg) | Standard Error 0.171 |
p-value: 0.77695% CI: [-0.59, 0.78]Mixed Models Analysis
Secondary
Change From Baseline in Daily Total Insulin Dose
Mean change from baseline in total insulin dose was measured in each treatment groups.
Time frame: Baseline, Week 16
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Daily Total Insulin Dose | -0.3 International Units (IU)/Day | Standard Deviation 1.2 |
| Dulaglutide | Change From Baseline in Daily Total Insulin Dose | -1.1 International Units (IU)/Day | Standard Deviation 3.1 |
Secondary
Change From Baseline in Fasting Serum Glucose (FSG)
The LS mean change from baseline in FSG was calculated using a REML based MMRM and adjusted by, baseline value, treatment, visit, treatment-by-visit, baseline HbA1c Group (\<8.5%, \>=8.5%) + insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin), where participant treated as a random effect.
Time frame: Baseline, Week 16
Population: All randomized participants who received at least one dose of study drug and had evaluable post baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Serum Glucose (FSG) | -4.1 milligram/deciliter (mg/dL) | Standard Error 4.94 |
| Dulaglutide | Change From Baseline in Fasting Serum Glucose (FSG) | -34.2 milligram/deciliter (mg/dL) | Standard Error 2.78 |
p-value: <0.00195% CI: [-41.37, -18.91]Mixed Models Analysis
Secondary
Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG)
The self-monitored plasma glucose (SMBG) data were collected at the following 7 time points: prebreakfast blood glucose (BG), breakfast 2-hour postprandial blood glucose (PPBG), prelunch BG, lunch 2-hour PPBG, predinner BG, dinner 2-hour PPBG, and bedtime BG. LS mean was calculated with fixed effect test of analysis of covariance (ANCOVA) model and adjusted by, baseline value, treatment, baseline HbA1c Group (\<8.5%, ≥8.5%), insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin).
Time frame: Baseline, Week 16
Population: All randomized participants who received at least one dose of study drug and had evaluable post baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Lunch 2-hour PPBG | 10.74 mg/dL | Standard Error 7.39 |
| Placebo | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Prebreakfast BG | 12.30 mg/dL | Standard Error 4.37 |
| Placebo | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Predinner BG | 5.66 mg/dL | Standard Error 5.74 |
| Placebo | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Dinner 2-hour PPBG | 3.97 mg/dL | Standard Error 7.91 |
| Placebo | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Prelunch BG | 8.08 mg/dL | Standard Error 5.56 |
| Placebo | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Bedtime BG | 13.21 mg/dL | Standard Error 7.78 |
| Placebo | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Breakfast 2-hour PPBG | 13.15 mg/dL | Standard Error 7.35 |
| Dulaglutide | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Bedtime BG | -28.24 mg/dL | Standard Error 4.45 |
| Dulaglutide | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Prebreakfast BG | -14.28 mg/dL | Standard Error 2.52 |
| Dulaglutide | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Breakfast 2-hour PPBG | -32.24 mg/dL | Standard Error 4.19 |
| Dulaglutide | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Prelunch BG | -28.74 mg/dL | Standard Error 3.18 |
| Dulaglutide | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Lunch 2-hour PPBG | -39.42 mg/dL | Standard Error 4.54 |
| Dulaglutide | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Dinner 2-hour PPBG | -30.99 mg/dL | Standard Error 4.48 |
| Dulaglutide | Change From Baseline in Plasma Glucose From 7-Point Self-Monitored Blood Glucose Profiles (SMBG) | Predinner BG | -25.61 mg/dL | Standard Error 3.28 |
Comparison: Prebreakfast BGp-value: <0.00195% CI: [-36.39, -16.78]t-test, 2 sided
Comparison: Breakfast 2-hour PPBGp-value: <0.00195% CI: [-61.77, -29]t-test, 2 sided
Comparison: Prelunch BGp-value: <0.00195% CI: [-49.2, -24.45]t-test, 2 sided
Comparison: Lunch 2-hour PPBGp-value: <0.00195% CI: [-67.85, -32.46]t-test, 2 sided
Comparison: Predinner BGp-value: <0.00195% CI: [-44.05, -18.48]t-test, 2 sided
Comparison: Dinner 2-hour PPBGp-value: <0.00195% CI: [-52.55, -17.38]t-test, 2 sided
Comparison: Bedtime BGp-value: <0.00195% CI: [-58.81, -24.09]t-test, 2 sided
Secondary
Percentage of Participants With HbA1c <7.0% or ≤6.5%
Percentage of participants whose HbA1c was \<7.0% or ≤6.5%. HbA1c \<7.0% is presented.
Time frame: Week 16
Population: All randomized participants who received at least one dose of study drug had evaluable post-baseline HbA1c data. HbA1c ≤6.5% had no results since model did not converge.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With HbA1c <7.0% or ≤6.5% | 47.4 percentage of participants |
| Dulaglutide | Percentage of Participants With HbA1c <7.0% or ≤6.5% | 0 percentage of participants |
Comparison: analysis was based on repeated measures logistic regressionp-value: 0.00395% CI: [0.028, 0.479]Regression, Logistic