Type 2 Diabetes
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of investigational doses of dulaglutide in participants with type 2 diabetes on metformin monotherapy.
Interventions
DRUGPlacebo
Administered SC
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 had type 2 diabetes (T2D) for ≥6 months according to the World Health Organization (WHO) classification * Have HbA1c of 7.0% to 10.0%, inclusive, as assessed by the central laboratory * Have been treated with stable doses of metformin for at least 3 months * Have a body mass index (BMI) ≥25 kilograms per square meter
Exclusion criteria
* Have type 1 diabetes (T1D) * Have used any glucose-lowering medication other than metformin 3 months prior to study entry or during screening/lead-in period or have used any glucagon-like peptide-1 receptor agonists (GLP-1 RAs) at any time in the past * Have had any of the following cardiovascular conditions: acute myocardial infarction (MI), New York Heart Association Class III or Class IV heart failure, or cerebrovascular accident (stroke) * Have acute or chronic hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase (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 * Have had chronic or acute pancreatitis any time prior to study entry * Have an estimated glomerular filtration rate (eGFR) \<45 milliliters/minute/1.73 square meter, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation * Have serum calcitonin ≥20 picograms per milliliter, as determined by the central laboratory at study entry
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline, Week 18 | 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 as a covariate, pooled country, treatment, time, treatment\*time as fixed effects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Serum Glucose (FSG) | Baseline, Week 18 | Fasting serum glucose (FSG) is a test to determine how much glucose (sugar) is in a serum sample after an overnight fast. Least Squares (LS) means was determined by MMRM methodology with baseline as a covariate, pooled country, baseline HbA1c strata using \>=8% as cutoff, treatment, time, treatment\*time as fixed effects. |
| Change From Baseline in Body Weight | Baseline, Week 18 | Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline as a covariate, pooled country, baseline HbA1c strata using \>=8% as cutoff, treatment, time, treatment\*time as fixed effects. |
| Percentage of Participants Discontinuing Study Drug Due to Adverse Events | Baseline through Week 18 | Adverse event (AE) defined as any unfavorable medical event, newly emerged or a deterioration of a preexisting condition, in other words any untoward medical occurrence in a patient administered a pharmaceutical product, without regard to the possibility of a causal relationship, that occurred after the visit for informed consent and up to the visit for completion of administration, or discontinuation. |
| Percentage of Participants With HbA1c of <7.0% | Week 18 | Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. |
| Pharmacokinetics (PK): The Maximum Drug Concentration at Steady State (Cmax,ss) of Dulaglutide | 0, 2, 4, 6, 10, 18, 22 weeks and early termination | Plasma samples for PK analysis were combined measure obtained from 0, 2, 4, 6, 10, 18, 22 weeks and until early termination of the visit. Cmax takes all time points post dose into account and one value was reported. |
| Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 168 Hours (AUC[0-168], ss) of Dulaglutide | 0, 2, 4, 6, 10, 18, 22 weeks and early termination | AUC\[0-168h\] is a combined measure obtained from 0, 2, 4, 6, 10, 18, 22 weeks and until early termination of the visit. |
| Rate of Documented Symptomatic Hypoglycemia | Week 18 | Hypoglycemic events (HE) were classified as severe, documented symptomatic (defined as an HE with typical symptoms of hypoglycemia and a blood glucose level of ≤3.9 millimoles per liter \[mmol/L\]). Hypoglycemia rate per 30 days was summarized at each visit by treatment group. The rate of hypoglycemia was analyzed using a generalized estimation equations model with a negative binomial distribution and a Log link. LS mean was determined by MMRM methodology with baseline hypoglycemia rate, pooled country, HbA1c at Baseline, treatment, with log of exposure in days divided by 365.25 as the offset. |
Countries
Czechia, Mexico, Poland, Puerto Rico, Romania, United States
Participant flow
Recruitment details
The study consisted of 3 periods: an approximately 2-week lead-in period, followed by an 18-week treatment period, and a 4-week safety follow-up period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo once weekly (QW) by subcutaneous (SC) injection. | 81 |
| Dulaglutide 1.5mg Participants received 1.5mg of dulaglutide QW by SC injection. | 81 |
| Dulaglutide 3.0mg Participants received 3.0mg of dulaglutide QW by SC injection. | 79 |
| Dulaglutide 4.5mg Participants received 4.5mg of dulaglutide QW by SC injection. | 76 |
| Total | 317 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 1 | 2 |
| Overall Study | Failed to attend Safety followup period | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 1 | 1 | 0 |
| Overall Study | Notification of change in address | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 5 | 1 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | Dulaglutide 4.5mg | Dulaglutide 3.0mg | Dulaglutide 1.5mg |
|---|---|---|---|---|---|
| Age, Continuous | 56.52 Years STANDARD_DEVIATION 8.93 | 56.80 Years STANDARD_DEVIATION 9.77 | 57.13 Years STANDARD_DEVIATION 9.63 | 55.90 Years STANDARD_DEVIATION 10.74 | 57.65 Years STANDARD_DEVIATION 9.79 |
| Baseline Hemoglobin A1c (HbA1c) | 8.08 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.79 | 8.09 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.83 | 8.12 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.81 | 8.16 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.92 | 8.02 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 35 Participants | 135 Participants | 30 Participants | 38 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 180 Participants | 45 Participants | 40 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 10 Participants | 31 Participants | 6 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 3 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 24 Participants | 6 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 5 Participants | 12 Participants | 2 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 59 Participants | 244 Participants | 59 Participants | 58 Participants | 68 Participants |
| Region of Enrollment Czechia | 10 Participants | 37 Participants | 8 Participants | 10 Participants | 9 Participants |
| Region of Enrollment Mexico | 10 Participants | 41 Participants | 11 Participants | 10 Participants | 10 Participants |
| Region of Enrollment Poland | 13 Participants | 44 Participants | 10 Participants | 10 Participants | 11 Participants |
| Region of Enrollment Romania | 6 Participants | 21 Participants | 4 Participants | 5 Participants | 6 Participants |
| Region of Enrollment United States | 42 Participants | 174 Participants | 43 Participants | 44 Participants | 45 Participants |
| Sex: Female, Male Female | 33 Participants | 159 Participants | 40 Participants | 44 Participants | 42 Participants |
| Sex: Female, Male Male | 48 Participants | 158 Participants | 36 Participants | 35 Participants | 39 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 / 81 | 0 / 81 | 0 / 79 | 0 / 76 |
| other Total, other adverse events | 29 / 81 | 36 / 81 | 49 / 79 | 39 / 76 |
| serious Total, serious adverse events | 4 / 81 | 3 / 81 | 7 / 79 | 3 / 76 |
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 as a covariate, pooled country, treatment, time, treatment\*time as fixed effects.
Time frame: Baseline, Week 18
Population: All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for Hemoglobin A1c.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) | -0.44 Percentage of glycosylated hemoglobin | Standard Error 0.101 |
| Dulaglutide 1.5mg | Change From Baseline in Hemoglobin A1c (HbA1c) | -1.23 Percentage of glycosylated hemoglobin | Standard Error 0.099 |
| Dulaglutide 3.0mg | Change From Baseline in Hemoglobin A1c (HbA1c) | -1.31 Percentage of glycosylated hemoglobin | Standard Error 0.099 |
| Dulaglutide 4.5mg | Change From Baseline in Hemoglobin A1c (HbA1c) | -1.40 Percentage of glycosylated hemoglobin | Standard Error 0.103 |
p-value: <0.00195% CI: [-1.07, -0.53]Mixed Models Analysis
p-value: <0.00195% CI: [-1.14, -0.6]Mixed Models Analysis
p-value: <0.00195% CI: [-1.24, -0.69]Mixed Models Analysis
Secondary
Change From Baseline in Body Weight
Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline as a covariate, pooled country, baseline HbA1c strata using \>=8% as cutoff, treatment, time, treatment\*time as fixed effects.
Time frame: Baseline, Week 18
Population: All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for body weight.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight | -1.6 Kilograms (Kg) | Standard Error 0.39 |
| Dulaglutide 1.5mg | Change From Baseline in Body Weight | -2.8 Kilograms (Kg) | Standard Error 0.39 |
| Dulaglutide 3.0mg | Change From Baseline in Body Weight | -3.9 Kilograms (Kg) | Standard Error 0.39 |
| Dulaglutide 4.5mg | Change From Baseline in Body Weight | -4.1 Kilograms (Kg) | Standard Error 0.41 |
p-value: 0.02595% CI: [-2.3, -0.2]Mixed Models Analysis
p-value: <0.00195% CI: [-3.4, -1.3]Mixed Models Analysis
p-value: <0.00195% CI: [-3.7, -1.5]Mixed Models Analysis
Secondary
Change From Baseline in Fasting Serum Glucose (FSG)
Fasting serum glucose (FSG) is a test to determine how much glucose (sugar) is in a serum sample after an overnight fast. Least Squares (LS) means was determined by MMRM methodology with baseline as a covariate, pooled country, baseline HbA1c strata using \>=8% as cutoff, treatment, time, treatment\*time as fixed effects.
Time frame: Baseline, Week 18
Population: All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for FSG.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Serum Glucose (FSG) | -0.69 millimole/liter (mmol/L) | Standard Error 0.257 |
| Dulaglutide 1.5mg | Change From Baseline in Fasting Serum Glucose (FSG) | -2.01 millimole/liter (mmol/L) | Standard Error 0.261 |
| Dulaglutide 3.0mg | Change From Baseline in Fasting Serum Glucose (FSG) | -1.92 millimole/liter (mmol/L) | Standard Error 0.25 |
| Dulaglutide 4.5mg | Change From Baseline in Fasting Serum Glucose (FSG) | -2.11 millimole/liter (mmol/L) | Standard Error 0.263 |
p-value: <0.00195% CI: [-2.02, -0.62]Mixed Models Analysis
p-value: <0.00195% CI: [-1.91, -0.54]Mixed Models Analysis
p-value: <0.00195% CI: [-2.12, -0.72]Mixed Models Analysis
Secondary
Percentage of Participants Discontinuing Study Drug Due to Adverse Events
Adverse event (AE) defined as any unfavorable medical event, newly emerged or a deterioration of a preexisting condition, in other words any untoward medical occurrence in a patient administered a pharmaceutical product, without regard to the possibility of a causal relationship, that occurred after the visit for informed consent and up to the visit for completion of administration, or discontinuation.
Time frame: Baseline through Week 18
Population: All randomized participants who received study drug and had postbaseline data for safety analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Discontinuing Study Drug Due to Adverse Events | 4.9 Percentage of Participants |
| Dulaglutide 1.5mg | Percentage of Participants Discontinuing Study Drug Due to Adverse Events | 6.2 Percentage of Participants |
| Dulaglutide 3.0mg | Percentage of Participants Discontinuing Study Drug Due to Adverse Events | 10.1 Percentage of Participants |
| Dulaglutide 4.5mg | Percentage of Participants Discontinuing Study Drug Due to Adverse Events | 13.2 Percentage of Participants |
Secondary
Percentage of Participants With HbA1c of <7.0%
Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time.
Time frame: Week 18
Population: All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for Hemoglobin A1c.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With HbA1c of <7.0% | 20 Percentage of Participants |
| Dulaglutide 1.5mg | Percentage of Participants With HbA1c of <7.0% | 71.2 Percentage of Participants |
| Dulaglutide 3.0mg | Percentage of Participants With HbA1c of <7.0% | 71.2 Percentage of Participants |
| Dulaglutide 4.5mg | Percentage of Participants With HbA1c of <7.0% | 68.2 Percentage of Participants |
p-value: <0.00195% CI: [8.368, 71.667]Regression, Logistic
p-value: <0.00195% CI: [9.238, 84.3]Regression, Logistic
p-value: <0.00195% CI: [7.672, 62.242]Regression, Logistic
Secondary
Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 168 Hours (AUC[0-168], ss) of Dulaglutide
AUC\[0-168h\] is a combined measure obtained from 0, 2, 4, 6, 10, 18, 22 weeks and until early termination of the visit.
Time frame: 0, 2, 4, 6, 10, 18, 22 weeks and early termination
Population: All randomized participants who received at least one dose of the study drug and have evaluable PK data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 168 Hours (AUC[0-168], ss) of Dulaglutide | 11800 nanogram*hour per milliliter (ng*h/mL) |
| Dulaglutide 1.5mg | Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 168 Hours (AUC[0-168], ss) of Dulaglutide | 26700 nanogram*hour per milliliter (ng*h/mL) |
| Dulaglutide 3.0mg | Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 168 Hours (AUC[0-168], ss) of Dulaglutide | 36600 nanogram*hour per milliliter (ng*h/mL) |
Secondary
Pharmacokinetics (PK): The Maximum Drug Concentration at Steady State (Cmax,ss) of Dulaglutide
Plasma samples for PK analysis were combined measure obtained from 0, 2, 4, 6, 10, 18, 22 weeks and until early termination of the visit. Cmax takes all time points post dose into account and one value was reported.
Time frame: 0, 2, 4, 6, 10, 18, 22 weeks and early termination
Population: All randomized participants who received at least one dose of the study drug and have evaluable PK data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Pharmacokinetics (PK): The Maximum Drug Concentration at Steady State (Cmax,ss) of Dulaglutide | 90.4 nanogram per milliliter (ng/mL) |
| Dulaglutide 1.5mg | Pharmacokinetics (PK): The Maximum Drug Concentration at Steady State (Cmax,ss) of Dulaglutide | 151 nanogram per milliliter (ng/mL) |
| Dulaglutide 3.0mg | Pharmacokinetics (PK): The Maximum Drug Concentration at Steady State (Cmax,ss) of Dulaglutide | 204 nanogram per milliliter (ng/mL) |
Secondary
Rate of Documented Symptomatic Hypoglycemia
Hypoglycemic events (HE) were classified as severe, documented symptomatic (defined as an HE with typical symptoms of hypoglycemia and a blood glucose level of ≤3.9 millimoles per liter \[mmol/L\]). Hypoglycemia rate per 30 days was summarized at each visit by treatment group. The rate of hypoglycemia was analyzed using a generalized estimation equations model with a negative binomial distribution and a Log link. LS mean was determined by MMRM methodology with baseline hypoglycemia rate, pooled country, HbA1c at Baseline, treatment, with log of exposure in days divided by 365.25 as the offset.
Time frame: Week 18
Population: All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue values for hypoglycemic episodes.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Rate of Documented Symptomatic Hypoglycemia | 0.00 Episodes/participant/365.25 days | Standard Error 0 |
| Dulaglutide 1.5mg | Rate of Documented Symptomatic Hypoglycemia | 0.00 Episodes/participant/365.25 days | Standard Error 0 |
| Dulaglutide 3.0mg | Rate of Documented Symptomatic Hypoglycemia | 0.00 Episodes/participant/365.25 days | Standard Error 0 |
| Dulaglutide 4.5mg | Rate of Documented Symptomatic Hypoglycemia | 0.00 Episodes/participant/365.25 days | Standard Error 0.001 |