Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective is to investigate the efficacy, safety and pharmacokinetics of three different doses of BI 10773 compared to placebo given for 12 weeks in patients with type 2 diabetes mellitus with insufficient glycemic control. In addition an open-label metformin arm will be assessed
Interventions
DRUGBI 10773
DRUGplacebo
DRUGmetformin
Sponsors
Boehringer Ingelheim
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients with a diagnosis of type 2 diabetes mellitus * either treatment-naïve or on a maximum of 1 oral antidiabetic therapy on a stable dose for the10 weeks prior to screening * HbA1c ≥6.5 to ≤9.0% and for treatment-naïve patients:HbA1c \>7.0 to ≤10.0% * HbA1c \>7.0 to ≤10.0% at Visit 2 (start of run-in) for all patients * Age between 18 and 80 years * BMI less than 40 kg/m2 * Signed and dated informed consent prior to admission to the study in accordance with GCP and local legislation
Exclusion criteria
1. Myocardial infarction, stroke or TIA within 6 months prior to informed consent 2. Impaired hepatic function 3. Renal insufficiency or impaired renal function 4. Disease of central nervous system, or psychiatric disorders or clinically relevant neurologic disorders that may interfere with trial participation 5. Chronic or clinically relevant acute infections 6. Current or chronic urogenital tract infection determined by medical history 7. History of clinically relevant allergy/hypersensitivity 8. Treatment with glitazones, GLP-1 analogues or insulin within 3 months prior to informed consent 9. Treatment with anti obesity drugs 10. Current treatment with systemic steroids 11. Alcohol abuse 12. Treatment with an investigational drug within 2 months prior to informed consent 13. known intolerance to metformin 14. Dehydration 15. Unstable or acute CHF 16. Acute or chronic acidosis 17. Hereditary galactose intolerance 18. Woman of child bearing potential who are nursing or pregnant or not practicing an acceptable method of birth control
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change of Glycosilated Haemoglobin A1c (HbA1c) From Baseline After 12 Weeks of Treatment | Baseline and 12 weeks | Change of HbA1c from baseline after 12 weeks of treatment. Note, adjusted means are presented. For the placebo and empa groups, measured values presented are for the model including only these treatment groups, for the metformin group the measured values presented are for the model including only placebo and metformin groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of HbA1c From Baseline Over Time | Baseline and weeks 4, 8 and 12 | Change of HbA1c from baseline over time. Results presented stem from a repeated measures analysis. |
| Proportion of Patients Who Achieve an HbA1c ≤7.0% After 12 Weeks of Treatment | 12 weeks | Results for HbA1c categories at week 12 (Proportion of patients with HbA1c less than equal to 7%). |
| Proportion of Patients Who Achieve an HbA1c Lowering of at Least 0.5% After 12 Weeks of Treatment | 12 weeks | Results for HbA1c categories at week 12 (Proportion of patients with HbA1c lowered at least 0.5%). |
| Change From Baseline to Week 12 in Fasting Plasma Insulin (FPI) | Baseline and 12 weeks | Results for change of FPI from baseline at week 12 based on ANCOVA. |
| Change of FPG From Baseline After 12 Weeks of Treatment | Baseline and 12 weeks | Change of Fasting Plasma Glucose (FPG) from baseline after 12 weeks of treatment. Results presented stem from a repeated measures analysis. Note, adjusted means are presented. For the placebo and empa groups, measured values presented are for the model including only these treatment groups, for the metformin group the measured values presented are for the model including only placebo and metformin groups. |
| Change in Homeostasis Model Assessment Index for Beta Cell Function (HOMA-%B) | Baseline and 12 weeks | HOMA-%B (to assess insulin beta cell function) is defined as (20 x FPI)/(FPG-3.5). Results are based on ANCOVA. |
| Change of Body Weight After 12 Weeks of Treatment | Baseline and 12 weeks | Results for change of body weight after 12 weeks of treatment based on ANCOVA. |
| Trough Concentrations of Empagliflozin in Plasma | Days 28, 56 and 84 | Pre-dose (within 30 minutes before dosing) trough concentrations of Empagliflozin in plasma |
| Change in Homeostasis Model Assessment Index for Insulin Resistance (HOMA-IR) | Baseline and 12 weeks | HOMA-IR (to assess insulin resistance) is defined as (FPI x FPG)/22.5. Results based on ANCOVA. |
Countries
Argentina, Croatia, Estonia, Germany, Italy, Lithuania, Romania, Russia, Slovakia, South Korea, Sweden, Taiwan, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients receive Placebo in tablets matching the Empagliflozin tablets in appearance once daily. | 82 |
| Empagliflozin 5 mg Patients receive 5 mg Empagliflozin in tablets once daily. | 81 |
| Empagliflozin 10 mg Patients receive 10 mg Empagliflozin in tablets once daily. | 81 |
| Empagliflozin 25 mg Patients receive 25 mg Empagliflozin in tablets once daily. | 82 |
| Metformin OL Patients were to take a dose of 500 mg Metformin (open-label) twice daily for the first 4 weeks. For the remaining 8 weeks, if the fasted blood glucose values were above 110 mg/dL (6.1 mmol/L), the dose was to be increased to 2 x 500 mg tablets twice daily or up to the maximum tolerated. | 80 |
| Total | 406 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 | 1 | 3 |
| Overall Study | Lack of Efficacy | 3 | 0 | 0 | 0 | 2 |
| Overall Study | Other reason not defined above | 2 | 3 | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Empagliflozin 5 mg | Empagliflozin 10 mg | Empagliflozin 25 mg | Metformin OL | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 10.2 | 58.4 years STANDARD_DEVIATION 9.7 | 58.2 years STANDARD_DEVIATION 9.9 | 56.4 years STANDARD_DEVIATION 10.3 | 57.0 years STANDARD_DEVIATION 8.9 | 57.5 years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 37 Participants | 35 Participants | 41 Participants | 41 Participants | 41 Participants | 195 Participants |
| Sex: Female, Male Male | 45 Participants | 46 Participants | 40 Participants | 41 Participants | 39 Participants | 211 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 82 | 3 / 81 | 5 / 81 | 1 / 82 | 7 / 80 |
| serious Total, serious adverse events | 0 / 82 | 2 / 81 | 0 / 81 | 1 / 82 | 3 / 80 |
Outcome results
Primary
Change of Glycosilated Haemoglobin A1c (HbA1c) From Baseline After 12 Weeks of Treatment
Change of HbA1c from baseline after 12 weeks of treatment. Note, adjusted means are presented. For the placebo and empa groups, measured values presented are for the model including only these treatment groups, for the metformin group the measured values presented are for the model including only placebo and metformin groups.
Time frame: Baseline and 12 weeks
Population: The full analysis set (FAS) consists of all randomised patients who were treated with at least 1 dose of study drug and had a baseline measurement of the primary endpoint. Modified last observation carried forward was used as the imputation method (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change of Glycosilated Haemoglobin A1c (HbA1c) From Baseline After 12 Weeks of Treatment | 0.09 percentage of HbA1c | Standard Error 0.09 |
| Empagliflozin 5 mg | Change of Glycosilated Haemoglobin A1c (HbA1c) From Baseline After 12 Weeks of Treatment | -0.43 percentage of HbA1c | Standard Error 0.09 |
| Empagliflozin 10 mg | Change of Glycosilated Haemoglobin A1c (HbA1c) From Baseline After 12 Weeks of Treatment | -0.48 percentage of HbA1c | Standard Error 0.09 |
| Empagliflozin 25 mg | Change of Glycosilated Haemoglobin A1c (HbA1c) From Baseline After 12 Weeks of Treatment | -0.63 percentage of HbA1c | Standard Error 0.09 |
| Metformin OL | Change of Glycosilated Haemoglobin A1c (HbA1c) From Baseline After 12 Weeks of Treatment | -0.75 percentage of HbA1c | Standard Error 0.09 |
p-value: <0.000195% CI: [-0.74, -0.29]ANCOVA
p-value: <0.000195% CI: [-0.8, -0.35]ANCOVA
p-value: <0.000195% CI: [-0.94, -0.5]ANCOVA
Secondary
Change From Baseline to Week 12 in Fasting Plasma Insulin (FPI)
Results for change of FPI from baseline at week 12 based on ANCOVA.
Time frame: Baseline and 12 weeks
Population: FAS (CLOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in Fasting Plasma Insulin (FPI) | -0.95 mU/L | Standard Error 0.53 |
| Empagliflozin 5 mg | Change From Baseline to Week 12 in Fasting Plasma Insulin (FPI) | -0.90 mU/L | Standard Error 0.53 |
| Empagliflozin 10 mg | Change From Baseline to Week 12 in Fasting Plasma Insulin (FPI) | -1.02 mU/L | Standard Error 0.53 |
| Empagliflozin 25 mg | Change From Baseline to Week 12 in Fasting Plasma Insulin (FPI) | -0.90 mU/L | Standard Error 0.5 |
| Metformin OL | Change From Baseline to Week 12 in Fasting Plasma Insulin (FPI) | -0.01 mU/L | Standard Error 0.54 |
Secondary
Change in Homeostasis Model Assessment Index for Beta Cell Function (HOMA-%B)
HOMA-%B (to assess insulin beta cell function) is defined as (20 x FPI)/(FPG-3.5). Results are based on ANCOVA.
Time frame: Baseline and 12 weeks
Population: FAS (CLOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Homeostasis Model Assessment Index for Beta Cell Function (HOMA-%B) | -5.20 mU / mmol | Standard Error 2.56 |
| Empagliflozin 5 mg | Change in Homeostasis Model Assessment Index for Beta Cell Function (HOMA-%B) | 4.22 mU / mmol | Standard Error 2.57 |
| Empagliflozin 10 mg | Change in Homeostasis Model Assessment Index for Beta Cell Function (HOMA-%B) | 1.09 mU / mmol | Standard Error 2.54 |
| Empagliflozin 25 mg | Change in Homeostasis Model Assessment Index for Beta Cell Function (HOMA-%B) | 2.13 mU / mmol | Standard Error 2.43 |
| Metformin OL | Change in Homeostasis Model Assessment Index for Beta Cell Function (HOMA-%B) | 6.69 mU / mmol | Standard Error 2.58 |
Secondary
Change in Homeostasis Model Assessment Index for Insulin Resistance (HOMA-IR)
HOMA-IR (to assess insulin resistance) is defined as (FPI x FPG)/22.5. Results based on ANCOVA.
Time frame: Baseline and 12 weeks
Population: FAS (CLOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Homeostasis Model Assessment Index for Insulin Resistance (HOMA-IR) | -0.19 mU/L x mmol/L | Standard Error 0.26 |
| Empagliflozin 5 mg | Change in Homeostasis Model Assessment Index for Insulin Resistance (HOMA-IR) | -0.85 mU/L x mmol/L | Standard Error 0.27 |
| Empagliflozin 10 mg | Change in Homeostasis Model Assessment Index for Insulin Resistance (HOMA-IR) | -0.83 mU/L x mmol/L | Standard Error 0.26 |
| Empagliflozin 25 mg | Change in Homeostasis Model Assessment Index for Insulin Resistance (HOMA-IR) | -0.79 mU/L x mmol/L | Standard Error 0.25 |
| Metformin OL | Change in Homeostasis Model Assessment Index for Insulin Resistance (HOMA-IR) | -0.37 mU/L x mmol/L | Standard Error 0.27 |
Secondary
Change of Body Weight After 12 Weeks of Treatment
Results for change of body weight after 12 weeks of treatment based on ANCOVA.
Time frame: Baseline and 12 weeks
Population: FAS (CLOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change of Body Weight After 12 Weeks of Treatment | -0.75 kg | Standard Error 0.26 |
| Empagliflozin 5 mg | Change of Body Weight After 12 Weeks of Treatment | -1.81 kg | Standard Error 0.26 |
| Empagliflozin 10 mg | Change of Body Weight After 12 Weeks of Treatment | -2.33 kg | Standard Error 0.26 |
| Empagliflozin 25 mg | Change of Body Weight After 12 Weeks of Treatment | -2.03 kg | Standard Error 0.26 |
| Metformin OL | Change of Body Weight After 12 Weeks of Treatment | -1.32 kg | Standard Error 0.26 |
Secondary
Change of FPG From Baseline After 12 Weeks of Treatment
Change of Fasting Plasma Glucose (FPG) from baseline after 12 weeks of treatment. Results presented stem from a repeated measures analysis. Note, adjusted means are presented. For the placebo and empa groups, measured values presented are for the model including only these treatment groups, for the metformin group the measured values presented are for the model including only placebo and metformin groups.
Time frame: Baseline and 12 weeks
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change of FPG From Baseline After 12 Weeks of Treatment | 0.79 mg/dL | Standard Error 3.54 |
| Empagliflozin 5 mg | Change of FPG From Baseline After 12 Weeks of Treatment | -23.26 mg/dL | Standard Error 3.59 |
| Empagliflozin 10 mg | Change of FPG From Baseline After 12 Weeks of Treatment | -28.92 mg/dL | Standard Error 3.59 |
| Empagliflozin 25 mg | Change of FPG From Baseline After 12 Weeks of Treatment | -31.08 mg/dL | Standard Error 3.59 |
| Metformin OL | Change of FPG From Baseline After 12 Weeks of Treatment | -29.96 mg/dL | Standard Error 4.02 |
Secondary
Change of HbA1c From Baseline Over Time
Change of HbA1c from baseline over time. Results presented stem from a repeated measures analysis.
Time frame: Baseline and weeks 4, 8 and 12
Population: FAS, classical last observation carried forward (CLOCF) was used as the imputation method.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change of HbA1c From Baseline Over Time | Week 12 | 0.07 percentage of HbA1c | Standard Error 0.08 |
| Placebo | Change of HbA1c From Baseline Over Time | Week 4 | -0.01 percentage of HbA1c | Standard Error 0.06 |
| Placebo | Change of HbA1c From Baseline Over Time | Week 8 | 0.04 percentage of HbA1c | Standard Error 0.07 |
| Empagliflozin 5 mg | Change of HbA1c From Baseline Over Time | Week 12 | -0.47 percentage of HbA1c | Standard Error 0.08 |
| Empagliflozin 5 mg | Change of HbA1c From Baseline Over Time | Week 8 | -0.43 percentage of HbA1c | Standard Error 0.08 |
| Empagliflozin 5 mg | Change of HbA1c From Baseline Over Time | Week 4 | -0.27 percentage of HbA1c | Standard Error 0.06 |
| Empagliflozin 10 mg | Change of HbA1c From Baseline Over Time | Week 4 | -0.24 percentage of HbA1c | Standard Error 0.06 |
| Empagliflozin 10 mg | Change of HbA1c From Baseline Over Time | Week 8 | -0.53 percentage of HbA1c | Standard Error 0.08 |
| Empagliflozin 10 mg | Change of HbA1c From Baseline Over Time | Week 12 | -0.53 percentage of HbA1c | Standard Error 0.08 |
| Empagliflozin 25 mg | Change of HbA1c From Baseline Over Time | Week 4 | -0.39 percentage of HbA1c | Standard Error 0.06 |
| Empagliflozin 25 mg | Change of HbA1c From Baseline Over Time | Week 8 | -0.58 percentage of HbA1c | Standard Error 0.07 |
| Empagliflozin 25 mg | Change of HbA1c From Baseline Over Time | Week 12 | -0.66 percentage of HbA1c | Standard Error 0.08 |
| Metformin OL | Change of HbA1c From Baseline Over Time | Week 4 | -0.26 percentage of HbA1c | Standard Error 0.07 |
| Metformin OL | Change of HbA1c From Baseline Over Time | Week 8 | -0.59 percentage of HbA1c | Standard Error 0.08 |
| Metformin OL | Change of HbA1c From Baseline Over Time | Week 12 | -0.78 percentage of HbA1c | Standard Error 0.08 |
Secondary
Proportion of Patients Who Achieve an HbA1c ≤7.0% After 12 Weeks of Treatment
Results for HbA1c categories at week 12 (Proportion of patients with HbA1c less than equal to 7%).
Time frame: 12 weeks
Population: FAS (CLOCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Patients Who Achieve an HbA1c ≤7.0% After 12 Weeks of Treatment | 22.0 percentage of participants |
| Empagliflozin 5 mg | Proportion of Patients Who Achieve an HbA1c ≤7.0% After 12 Weeks of Treatment | 33.3 percentage of participants |
| Empagliflozin 10 mg | Proportion of Patients Who Achieve an HbA1c ≤7.0% After 12 Weeks of Treatment | 29.6 percentage of participants |
| Empagliflozin 25 mg | Proportion of Patients Who Achieve an HbA1c ≤7.0% After 12 Weeks of Treatment | 45.1 percentage of participants |
| Metformin OL | Proportion of Patients Who Achieve an HbA1c ≤7.0% After 12 Weeks of Treatment | 45.0 percentage of participants |
Secondary
Proportion of Patients Who Achieve an HbA1c Lowering of at Least 0.5% After 12 Weeks of Treatment
Results for HbA1c categories at week 12 (Proportion of patients with HbA1c lowered at least 0.5%).
Time frame: 12 weeks
Population: FAS (CLOCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Proportion of Patients Who Achieve an HbA1c Lowering of at Least 0.5% After 12 Weeks of Treatment | 25.6 percentage of participants |
| Empagliflozin 5 mg | Proportion of Patients Who Achieve an HbA1c Lowering of at Least 0.5% After 12 Weeks of Treatment | 46.9 percentage of participants |
| Empagliflozin 10 mg | Proportion of Patients Who Achieve an HbA1c Lowering of at Least 0.5% After 12 Weeks of Treatment | 59.3 percentage of participants |
| Empagliflozin 25 mg | Proportion of Patients Who Achieve an HbA1c Lowering of at Least 0.5% After 12 Weeks of Treatment | 59.8 percentage of participants |
| Metformin OL | Proportion of Patients Who Achieve an HbA1c Lowering of at Least 0.5% After 12 Weeks of Treatment | 71.3 percentage of participants |
Secondary
Trough Concentrations of Empagliflozin in Plasma
Pre-dose (within 30 minutes before dosing) trough concentrations of Empagliflozin in plasma
Time frame: Days 28, 56 and 84
Population: All patients who received at least one dose of Empagliflozin and have some Pharmacokinetic (PK) data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Trough Concentrations of Empagliflozin in Plasma | Day 56 (N=69, 73, 75) | 20.3 nmol/L | Geometric Coefficient of Variation 128 |
| Placebo | Trough Concentrations of Empagliflozin in Plasma | Day 28 (N=67, 75, 77) | 31.6 nmol/L | Geometric Coefficient of Variation 158 |
| Placebo | Trough Concentrations of Empagliflozin in Plasma | Day 84 (N=70, 77, 75) | 22.9 nmol/L | Geometric Coefficient of Variation 132 |
| Empagliflozin 5 mg | Trough Concentrations of Empagliflozin in Plasma | Day 56 (N=69, 73, 75) | 51.6 nmol/L | Geometric Coefficient of Variation 190 |
| Empagliflozin 5 mg | Trough Concentrations of Empagliflozin in Plasma | Day 28 (N=67, 75, 77) | 61.7 nmol/L | Geometric Coefficient of Variation 169 |
| Empagliflozin 5 mg | Trough Concentrations of Empagliflozin in Plasma | Day 84 (N=70, 77, 75) | 55.3 nmol/L | Geometric Coefficient of Variation 156 |
| Empagliflozin 10 mg | Trough Concentrations of Empagliflozin in Plasma | Day 28 (N=67, 75, 77) | 117 nmol/L | Geometric Coefficient of Variation 154 |
| Empagliflozin 10 mg | Trough Concentrations of Empagliflozin in Plasma | Day 84 (N=70, 77, 75) | 118 nmol/L | Geometric Coefficient of Variation 179 |
| Empagliflozin 10 mg | Trough Concentrations of Empagliflozin in Plasma | Day 56 (N=69, 73, 75) | 127 nmol/L | Geometric Coefficient of Variation 140 |