Diabetes Mellitus, Type 2
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of investigational doses of once weekly dulaglutide when added to metformin in participants with type 2 diabetes with inadequate blood sugar control.
Interventions
DRUGDulaglutide
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 mellitus (T2DM) for at least 6 months * Have been treated with stable metformin dose for at least 3 months * Have HbA1c ≥7.5% and ≤11.0% at study entry * Have body mass index (BMI) ≥25 kilograms per meter squared (kg/m\^2)
Exclusion criteria
* Have type 1 diabetes mellitus * Have used any glucagon-like peptide-1 receptor agonist (GLP-1 RA) or insulin, not including prior short term insulin use (≤14 days) * Have been taking any other medicine for diabetes (other than metformin) during the last 3 months * Have used in the last 3 months (or plan to use) prescription weight loss medications * Have disorders associated with slowed emptying of the stomach contents, or have had any stomach surgeries for the purpose of weight loss * Current participation in or intent to begin during the study an organized diet and/or exercise weight reduction program (other than the lifestyle and dietary measures for diabetes) * Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (NAFLD), or alanine transaminase (ALT) level \>2.5 times the upper limit of the reference range, as determined by the central laboratory at study entry; participants with NAFLD are eligible for participation in this trial * Had chronic or acute pancreatitis any time prior to study entry * Have had a heart attack or stroke in the past 2 months, or have heart failure that significantly limits their physical activity * Estimated glomerular filtration rate (eGFR) \<30 milliliters/minute/1.73m\^2 (or lower than the country-specific threshold for discontinuing metformin therapy per local label), calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, as determined by the central laboratory at study entry and confirmed at lead-in * Have a personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia syndrome type 2 * Have proliferative retinopathy or maculopathy requiring acute treatment according to the opinion of the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin A1c (HbA1c) From Baseline | Baseline, Week 36 | HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. The Least Squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included the independent variables:Baseline + Pooled Country + Treatment + Time + Treatment\*Time (Type III sum of squares). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving HbA1c Target <7.0% | Week 36 | Percentage of participants achieving HbA1c target \<7.0%. |
| Change in Fasting Serum Glucose (FSG) From Baseline | Baseline, Week 36 | Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Baseline HbA1c group + Pooled Country + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Change in Body Weight From Baseline | Baseline, Week 36 | Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with independent variables: Baseline + Baseline HbA1c group + Pooled Country + Treatment + Time + Treatment\*Time (Type III sum of squares). |
| Pharmacokinetic (PK): Steady-state Maximum Concentration(Cmax,ss) | Week 4, Week 12, Week 36, Week 52 | Pharmacokinetic (PK): Steady-state Maximum Concentration(Cmax,ss). |
| Pharmacokinetic (PK): Area Under the Curve AUC (0-168)ss at Steady State | Week 4, Week 12, Week 36, Week 52 | Pharmacokinetic (PK): Area Under the Curve AUC (0-168)ss at Steady State. |
| Rate of Documented Symptomatic Hypoglycemic Episodes | Week 36 | Hypoglycemia was defined as blood glucose \< 54 mg/dL, excluding post-rescue records. Estimate is based on Group Mean from negative binomial model. The negative binomial model for post-baseline comparisons between treatments and control group: Number of episodes = Pooled Country + HbA1c at Baseline (%) + Treatment, with log (exposure in days/365.25) as an offset variable. |
Countries
Argentina, Austria, Canada, Greece, Hungary, Israel, Italy, Mexico, Poland, Puerto Rico, Romania, Russia, Slovakia, Spain, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dulaglutide 1.5 mg Dulaglutide 1.5 mg administered subcutaneously (SC) once a week. | 612 |
| Dulaglutide 3 mg Dulaglutide 3 mg administered SC once a week. | 616 |
| Dulaglutide 4.5 mg Dulaglutide 4.5 mg administered SC once a week. | 614 |
| Total | 1,842 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 7 | 10 |
| Overall Study | Death | 3 | 4 | 4 |
| Overall Study | Lost to Follow-up | 15 | 16 | 17 |
| Overall Study | Non-compliance | 1 | 0 | 0 |
| Overall Study | Participant Duplicated at Another Site | 0 | 0 | 1 |
| Overall Study | Participant was in Rehabilitation | 1 | 0 | 0 |
| Overall Study | Physician Decision | 2 | 0 | 2 |
| Overall Study | Primary Care Physician Recommendation | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 | 0 |
| Overall Study | Relocated to Another Country | 0 | 1 | 0 |
| Overall Study | Site Closure | 3 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 25 | 36 | 18 |
Baseline characteristics
| Characteristic | Total | Dulaglutide 4.5 mg | Dulaglutide 3 mg | Dulaglutide 1.5 mg |
|---|---|---|---|---|
| Age, Continuous | 57.1 years STANDARD_DEVIATION 10 | 56.6 years STANDARD_DEVIATION 10.2 | 56.9 years STANDARD_DEVIATION 10.2 | 57.8 years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 641 Participants | 213 Participants | 214 Participants | 214 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1103 Participants | 371 Participants | 363 Participants | 369 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 98 Participants | 30 Participants | 39 Participants | 29 Participants |
| Hemoglobin A1C (HbA1c) at Baseline | 8.64 Percentage of HbA1c STANDARD_DEVIATION 0.95 | 8.64 Percentage of HbA1c STANDARD_DEVIATION 0.91 | 8.63 Percentage of HbA1c STANDARD_DEVIATION 1 | 8.64 Percentage of HbA1c STANDARD_DEVIATION 0.94 |
| Race (NIH/OMB) American Indian or Alaska Native | 88 Participants | 32 Participants | 26 Participants | 30 Participants |
| Race (NIH/OMB) Asian | 45 Participants | 14 Participants | 18 Participants | 13 Participants |
| Race (NIH/OMB) Black or African American | 82 Participants | 23 Participants | 31 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 42 Participants | 12 Participants | 19 Participants | 11 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 5 Participants | 3 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1580 Participants | 530 Participants | 521 Participants | 529 Participants |
| Region of Enrollment Argentina | 290 Participants | 97 Participants | 97 Participants | 96 Participants |
| Region of Enrollment Austria | 13 Participants | 5 Participants | 4 Participants | 4 Participants |
| Region of Enrollment Canada | 35 Participants | 12 Participants | 11 Participants | 12 Participants |
| Region of Enrollment Greece | 100 Participants | 33 Participants | 34 Participants | 33 Participants |
| Region of Enrollment Hungary | 73 Participants | 24 Participants | 24 Participants | 25 Participants |
| Region of Enrollment Israel | 54 Participants | 18 Participants | 18 Participants | 18 Participants |
| Region of Enrollment Italy | 25 Participants | 8 Participants | 8 Participants | 9 Participants |
| Region of Enrollment Mexico | 111 Participants | 36 Participants | 38 Participants | 37 Participants |
| Region of Enrollment Poland | 167 Participants | 55 Participants | 56 Participants | 56 Participants |
| Region of Enrollment Romania | 233 Participants | 78 Participants | 78 Participants | 77 Participants |
| Region of Enrollment Russia | 29 Participants | 10 Participants | 10 Participants | 9 Participants |
| Region of Enrollment Slovakia | 131 Participants | 44 Participants | 44 Participants | 43 Participants |
| Region of Enrollment Spain | 58 Participants | 19 Participants | 20 Participants | 19 Participants |
| Region of Enrollment Taiwan | 15 Participants | 5 Participants | 5 Participants | 5 Participants |
| Region of Enrollment United States | 508 Participants | 170 Participants | 169 Participants | 169 Participants |
| Sex: Female, Male Female | 898 Participants | 296 Participants | 288 Participants | 314 Participants |
| Sex: Female, Male Male | 944 Participants | 318 Participants | 328 Participants | 298 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 612 | 4 / 616 | 4 / 614 |
| other Total, other adverse events | 156 / 612 | 190 / 616 | 195 / 614 |
| serious Total, serious adverse events | 53 / 612 | 45 / 616 | 38 / 614 |
Outcome results
Primary
Change in Hemoglobin A1c (HbA1c) From Baseline
HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. The Least Squares (LS) mean was estimated from a mixed-effects model with repeated measures (MMRM) that included the independent variables:Baseline + Pooled Country + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 36
Population: All participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline HbA1c value, excluding data post treatment discontinuation and/or initiation of new antihyperglycemic medications.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dulaglutide 1.5 mg | Change in Hemoglobin A1c (HbA1c) From Baseline | -1.53 Percentage of HbA1c | Standard Error 0.04 |
| Dulaglutide 3 mg | Change in Hemoglobin A1c (HbA1c) From Baseline | -1.71 Percentage of HbA1c | Standard Error 0.04 |
| Dulaglutide 4.5 mg | Change in Hemoglobin A1c (HbA1c) From Baseline | -1.87 Percentage of HbA1c | Standard Error 0.04 |
p-value: 0.00395% CI: [-0.29, -0.06]Mixed Models Analysis
p-value: <0.00195% CI: [-0.45, -0.22]Mixed Models Analysis
Secondary
Change in Body Weight From Baseline
Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with independent variables: Baseline + Baseline HbA1c group + Pooled Country + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 36
Population: All participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline body weight value, excluding data post treatment discontinuation and/or initiation of new antihyperglycemic medications.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dulaglutide 1.5 mg | Change in Body Weight From Baseline | -3.1 Kilograms (Kg) | Standard Deviation 0.19 |
| Dulaglutide 3 mg | Change in Body Weight From Baseline | -4.0 Kilograms (Kg) | Standard Deviation 0.19 |
| Dulaglutide 4.5 mg | Change in Body Weight From Baseline | -4.7 Kilograms (Kg) | Standard Deviation 0.19 |
p-value: 0.00195% CI: [-1.4, -0.4]Mixed Models Analysis
p-value: <0.00195% CI: [-2.1, -1.1]Mixed Models Analysis
Secondary
Change in Fasting Serum Glucose (FSG) From Baseline
Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with covariates: Baseline + Baseline HbA1c group + Pooled Country + Treatment + Time + Treatment\*Time (Type III sum of squares).
Time frame: Baseline, Week 36
Population: All participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline FSG value, excluding data post treatment discontinuation and/or initiation of new antihyperglycemic medications.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dulaglutide 1.5 mg | Change in Fasting Serum Glucose (FSG) From Baseline | -44.2 milligrams per deciliter (mg/dL) | Standard Error 1.5 |
| Dulaglutide 3 mg | Change in Fasting Serum Glucose (FSG) From Baseline | -47.9 milligrams per deciliter (mg/dL) | Standard Error 1.5 |
| Dulaglutide 4.5 mg | Change in Fasting Serum Glucose (FSG) From Baseline | -52.3 milligrams per deciliter (mg/dL) | Standard Error 1.5 |
p-value: 0.08495% CI: [-7.8, 0.5]Mixed Models Analysis
p-value: <0.00195% CI: [-12.3, -3.9]Mixed Models Analysis
Secondary
Percentage of Participants Achieving HbA1c Target <7.0%
Percentage of participants achieving HbA1c target \<7.0%.
Time frame: Week 36
Population: All participants who received at least one dose of study drug and had a baseline and at least 1 post-baseline HbA1c value, excluding data post treatment discontinuation and/or initiation of new antihyperglycemic medications.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dulaglutide 1.5 mg | Percentage of Participants Achieving HbA1c Target <7.0% | 56.98 percentage of participants |
| Dulaglutide 3 mg | Percentage of Participants Achieving HbA1c Target <7.0% | 64.68 percentage of participants |
| Dulaglutide 4.5 mg | Percentage of Participants Achieving HbA1c Target <7.0% | 71.48 percentage of participants |
p-value: 0.00695% CI: [1.12, 1.98]Regression, Logistic
p-value: <0.00195% CI: [1.65, 3.01]Regression, Logistic
Secondary
Pharmacokinetic (PK): Area Under the Curve AUC (0-168)ss at Steady State
Pharmacokinetic (PK): Area Under the Curve AUC (0-168)ss at Steady State.
Time frame: Week 4, Week 12, Week 36, Week 52
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dulaglutide 1.5 mg | Pharmacokinetic (PK): Area Under the Curve AUC (0-168)ss at Steady State | 11200 nanogram*hour/milliliter (ng*h/mL) |
| Dulaglutide 3 mg | Pharmacokinetic (PK): Area Under the Curve AUC (0-168)ss at Steady State | 22300 nanogram*hour/milliliter (ng*h/mL) |
| Dulaglutide 4.5 mg | Pharmacokinetic (PK): Area Under the Curve AUC (0-168)ss at Steady State | 33400 nanogram*hour/milliliter (ng*h/mL) |
Secondary
Pharmacokinetic (PK): Steady-state Maximum Concentration(Cmax,ss)
Pharmacokinetic (PK): Steady-state Maximum Concentration(Cmax,ss).
Time frame: Week 4, Week 12, Week 36, Week 52
Population: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dulaglutide 1.5 mg | Pharmacokinetic (PK): Steady-state Maximum Concentration(Cmax,ss) | 79.6 nanogram/milliliter (ng/mL) |
| Dulaglutide 3 mg | Pharmacokinetic (PK): Steady-state Maximum Concentration(Cmax,ss) | 159 nanogram/milliliter (ng/mL) |
| Dulaglutide 4.5 mg | Pharmacokinetic (PK): Steady-state Maximum Concentration(Cmax,ss) | 238 nanogram/milliliter (ng/mL) |
Secondary
Rate of Documented Symptomatic Hypoglycemic Episodes
Hypoglycemia was defined as blood glucose \< 54 mg/dL, excluding post-rescue records. Estimate is based on Group Mean from negative binomial model. The negative binomial model for post-baseline comparisons between treatments and control group: Number of episodes = Pooled Country + HbA1c at Baseline (%) + Treatment, with log (exposure in days/365.25) as an offset variable.
Time frame: Week 36
Population: All participants who received at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dulaglutide 1.5 mg | Rate of Documented Symptomatic Hypoglycemic Episodes | 0.02 Episodes/participant/365.25 days | Standard Error 0.01 |
| Dulaglutide 3 mg | Rate of Documented Symptomatic Hypoglycemic Episodes | 0.00 Episodes/participant/365.25 days | Standard Error 0 |
| Dulaglutide 4.5 mg | Rate of Documented Symptomatic Hypoglycemic Episodes | 0.02 Episodes/participant/365.25 days | Standard Error 0.01 |