Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the current study is to investigate the efficacy, safety and tolerability of two doses of BI 10773 compared to placebo given for 24 weeks as add-on therapy to metformin or metformin plus sulfonylurea in patients with Typ 2 Diabetes Mellitus with insufficient glycaemic control.
Interventions
DRUGPlacebo identical to BI 10773 high dose
Placebo tablets matching BI 10773 high dose
DRUGPlacebo identical to BI 10773 low dose
Placebo tablets matching BI 10773 low dose
DRUGBI 10773
BI 10773 tablets once daily high dose open label
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of type 2 diabetes mellitus prior to informed consent 2. Male and female patients on a diet and exercise regimen who are pre-treated with immediate release metformin or immediate release metformin plus sulfonylurea (see below for minimum doses). The treatment regimen has to be unchanged for 12 weeks prior to randomisation. Minimum dose for metformin: \> or = 1500 mg/day or maximum tolerated dose or maximum dose according to local label Minimum dose for sulfonylurea: \> or = half of the maximal recommended dose or maximum tolerated dose or maximum dose according to local label 3. HbA1c of \> or = 7.0% and \< or = 11% at Visit 1 (screening) in order to be eligible for randomised treatment HbA1c of \> 11% at Visit 1 (screening) in order to be eligible for the open-label treatment arm (25 mg BI 10773) 4. Age\> or = 18 5. Body Mass Index (BM)I \< or = 45 kg/m2 (Body Mass Index) at Visit 1 (Screening) 6. Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
1. Uncontrolled hyperglycaemia with a glucose level \> 240 mg/dl (\>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day) 2. Any other antidiabetic drug within 12 weeks prior to randomisation except those mentioned in inclusion criterion 2 3. Myocardial infarction, stroke or transient ischemic attack (TIA) within 3 months prior to informed consent 4. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening and/or run-in phase 5. Impaired renal function, defined as eGFR\<30 ml/min (severe renal impairment) as determined during screening and/or run-in phase 6. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption 7. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years 8. Contraindications to metformin and/or sulfonylurea according to the local label for those patients that enter the study with the respective background therapy 9. Blood dyscrasias or any disorders causing haemolysis or unstable Red Blood Cell (e.g. malaria, babesiosis, haemolytic anaemia) 10. Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight 11. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except Typ 2 Diabetes 12. Pre-menopausal women (last menstruation ¿ 1 year prior to informed consent) who: * are nursing or pregnant or * are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if acceptable by local authorities), double barrier method and vasectomised partner 13. Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake 14. Participation in another trial with an investigational drug within 30 days prior to informed consent 15. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline | Baseline and 24 weeks | Change from baseline in HbA1c after 24 weeks. For open-label groups the descriptive mean is provided, for randomised groups adjusted means are provided. The means are adjusted separately for metformin alone and metformin plus sulphonylurea background medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Body Weight Change From Baseline | Baseline and 24 weeks | Body weight change from baseline after 24 weeks. For open-label groups the descriptive mean is provided, for randomised groups adjusted means are provided. The means are adjusted separately for metformin alone and metformin plus sulphonylurea background medication. |
| Mean Daily Plasma Glucose (MDG) Change From Baseline | Baseline and 24 weeks | Change from baseline in mean daily glucose (MDG) using the 8-point blood glucose profile, after 24 weeks of treatment. For open-label groups the descriptive mean is provided, for randomised groups adjusted means are provided. The means are adjusted separately for metformin alone and metformin plus sulphonylurea background medication. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Hypoglycaemic Adverse Events | From first intake of randomised trial medication until 7 days after last trial medication intake, up to 231 days | Number of patients with confirmed hypoglycaemic events, as reported as adverse events. |
Countries
Canada, China, France, Germany, India, Mexico, Slovakia, Slovenia, South Korea, Taiwan, Turkey (Türkiye), United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Met: Placebo A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks in patients with background medication of metformin only. | 207 |
| Met: Empa 10mg Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks in patients with background medication of metformin only. | 217 |
| Met: Empa 25mg Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks in patients with background medication of metformin only. | 213 |
| Met: Empa 25mg Open Label Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks in patients with background medication of metformin only. | 69 |
| Met+SU: Placebo A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks in patients with background medication of metformin plus sulphonylurea (SU). | 225 |
| Met+SU: Empa 10mg Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks in patients with background medication of metformin plus sulphonylurea (SU). | 225 |
| Met+SU: Empa 25mg Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks in patients with background medication of metformin plus sulphonylurea (SU). | 216 |
| Met+SU: Empa 25mg Open Label Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks in patients with background medication of metformin plus sulphonylurea (SU). | 101 |
| Total | 1,473 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 2 | 5 | 1 | 8 | 6 | 7 | 5 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 3 | 4 | 3 | 3 | 0 | 3 | 2 |
| Overall Study | Non compliant with protocol | 2 | 1 | 0 | 0 | 2 | 0 | 2 | 0 |
| Overall Study | Not treated | 0 | 0 | 1 | 0 | 0 | 1 | 2 | 2 |
| Overall Study | Other reason not defined above | 3 | 0 | 4 | 2 | 5 | 7 | 3 | 3 |
| Overall Study | Patient refusal to continue,not due toAE | 7 | 2 | 4 | 5 | 4 | 4 | 2 | 5 |
Baseline characteristics
| Characteristic | Met: Placebo | Met: Empa 10mg | Met: Empa 25mg | Met: Empa 25mg Open Label | Met+SU: Placebo | Met+SU: Empa 10mg | Met+SU: Empa 25mg | Met+SU: Empa 25mg Open Label | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.0 years STANDARD_DEVIATION 9.7 | 55.5 years STANDARD_DEVIATION 9.9 | 55.6 years STANDARD_DEVIATION 10.2 | 49.8 years STANDARD_DEVIATION 11.5 | 56.9 years STANDARD_DEVIATION 9.2 | 57.0 years STANDARD_DEVIATION 9.2 | 57.4 years STANDARD_DEVIATION 9.3 | 53.4 years STANDARD_DEVIATION 10.5 | 55.9 years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 91 Participants | 92 Participants | 93 Participants | 28 Participants | 113 Participants | 112 Participants | 102 Participants | 47 Participants | 678 Participants |
| Sex: Female, Male Male | 116 Participants | 125 Participants | 120 Participants | 41 Participants | 112 Participants | 113 Participants | 114 Participants | 54 Participants | 795 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 56 / 206 | 29 / 217 | 38 / 214 | 18 / 69 | 76 / 225 | 77 / 224 | 67 / 217 | 28 / 101 |
| serious Total, serious adverse events | 7 / 206 | 7 / 217 | 5 / 214 | 1 / 69 | 14 / 225 | 11 / 224 | 1 / 217 | 5 / 101 |
Outcome results
Primary
HbA1c Change From Baseline
Change from baseline in HbA1c after 24 weeks. For open-label groups the descriptive mean is provided, for randomised groups adjusted means are provided. The means are adjusted separately for metformin alone and metformin plus sulphonylurea background medication.
Time frame: Baseline and 24 weeks
Population: Full analysis set. Treatment assignment as randomised.~Open-label analysis: Open-label set which included all patients entered in the empa 25mg open-label treatment arm.~Values after start of antidiabetic rescue therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Met: Placebo | HbA1c Change From Baseline | -0.13 percentage of HbA1c | Standard Error 0.05 |
| Met: Empa 10mg | HbA1c Change From Baseline | -0.70 percentage of HbA1c | Standard Error 0.05 |
| Met: Empa 25mg | HbA1c Change From Baseline | -0.77 percentage of HbA1c | Standard Error 0.05 |
| Met: Empa 25mg Open Label | HbA1c Change From Baseline | -2.78 percentage of HbA1c | Standard Error 0.21 |
| Met+SU: Placebo | HbA1c Change From Baseline | -0.17 percentage of HbA1c | Standard Error 0.05 |
| Met+SU: Empa 10mg | HbA1c Change From Baseline | -0.82 percentage of HbA1c | Standard Error 0.05 |
| Met+SU: Empa 25mg | HbA1c Change From Baseline | -0.77 percentage of HbA1c | Standard Error 0.05 |
| Met+SU: Empa 25mg Open Label | HbA1c Change From Baseline | -2.53 percentage of HbA1c | Standard Error 0.15 |
Comparison: Null hypothesis: No difference in change from baseline to week 24 in HbA1c between Empagliflozin 10mg and placebo. The study consisted of two substudies as defined by the two background medications 'metformin' and 'metformin + SU'. Within each group of background medication, each of the two hypotheses (10mg vs placebo and 25mg vs. placebo) was tested in a two-sided test.p-value: <0.000197.5% CI: [-0.72, -0.42]ANCOVA
Comparison: Null hypothesis: No difference in change from baseline to week 24 in HbA1c between Empagliflozin 25mg and placebo. The study consisted of two substudies as defined by the two background medications 'metformin' and 'metformin + SU'. Within each group of background medication, each of the two hypotheses (10mg vs placebo and 25mg vs. placebo) was tested in a two-sided test.p-value: <0.000197.5% CI: [-0.79, -0.48]ANCOVA
Comparison: Null hypothesis: No difference in change from baseline to week 24 in HbA1c between Empagliflozin 10mg and placebo. The study consisted of two substudies as defined by the two background medications 'metformin' and 'metformin + SU'. Within each group of background medication, each of the two hypotheses (10mg vs placebo and 25mg vs. placebo) was tested in a two-sided test.p-value: <0.000197.5% CI: [-0.79, -0.49]ANCOVA
Comparison: Null hypothesis: No difference in change from baseline to week 24 in HbA1c between Empagliflozin 25mg and placebo. The study consisted of two substudies as defined by the two background medications 'metformin' and 'metformin + SU'. Within each group of background medication, each of the two hypotheses (10mg vs placebo and 25mg vs. placebo) was tested in a two-sided test.p-value: <0.000197.5% CI: [-0.74, -0.44]ANCOVA
Secondary
Body Weight Change From Baseline
Body weight change from baseline after 24 weeks. For open-label groups the descriptive mean is provided, for randomised groups adjusted means are provided. The means are adjusted separately for metformin alone and metformin plus sulphonylurea background medication.
Time frame: Baseline and 24 weeks
Population: Full analysis set. Treatment assignment as randomised.~Open-label analysis: Open-label set which included all patients entered in the empa 25mg open-label treatment arm.~Values after start of antidiabetic rescue therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Met: Placebo | Body Weight Change From Baseline | -0.45 kg | Standard Error 0.17 |
| Met: Empa 10mg | Body Weight Change From Baseline | -2.08 kg | Standard Error 0.17 |
| Met: Empa 25mg | Body Weight Change From Baseline | -2.46 kg | Standard Error 0.17 |
| Met: Empa 25mg Open Label | Body Weight Change From Baseline | -1.33 kg | Standard Error 0.43 |
| Met+SU: Placebo | Body Weight Change From Baseline | -0.39 kg | Standard Error 0.15 |
| Met+SU: Empa 10mg | Body Weight Change From Baseline | -2.16 kg | Standard Error 0.15 |
| Met+SU: Empa 25mg | Body Weight Change From Baseline | -2.39 kg | Standard Error 0.16 |
| Met+SU: Empa 25mg Open Label | Body Weight Change From Baseline | -1.29 kg | Standard Error 0.3 |
Comparison: Null hypothesis: No difference in change from baseline to week 24 in body weight between Empagliflozin 10mg and placebo. A hierarchical testing approach was applied to each of the two dose comparisons (10mg vs placebo and 25mg vs placebo) within each background therapy group (metformin and metformin + SU). If for a specific dose the null hypothesis was rejected for the primary endpoint, the same dose was tested against placebo for the change from baseline in body weight.p-value: <0.000197.5% CI: [-2.17, -1.08]ANCOVA
Comparison: Null hypothesis: No difference in change from baseline to week 24 in body weight between Empagliflozin 25mg and placebo. A hierarchical testing approach was applied to each of the two dose comparisons (10mg vs placebo and 25mg vs placebo) within each background therapy group (metformin and metformin + SU). If for a specific dose the null hypothesis was rejected for the primary endpoint, the same dose was tested against placebo for the change from baseline in body weight.p-value: <0.000197.5% CI: [-2.56, -1.46]ANCOVA
Comparison: Null hypothesis: No difference in change from baseline to week 24 in body weight between Empagliflozin 10mg and placebo. A hierarchical testing approach was applied to each of the two dose comparisons (10mg vs placebo and 25mg vs placebo) within each background therapy group (metformin and metformin + SU). If for a specific dose the null hypothesis was rejected for the primary endpoint, the same dose was tested against placebo for the change from baseline in body weight.p-value: <0.000197.5% CI: [-2.25, -1.28]ANCOVA
Comparison: Null hypothesis: No difference in change from baseline to week 24 in body weight between Empagliflozin 25mg and placebo. A hierarchical testing approach was applied to each of the two dose comparisons (10mg vs placebo and 25mg vs placebo) within each background therapy group (metformin and metformin + SU). If for a specific dose the null hypothesis was rejected for the primary endpoint, the same dose was tested against placebo for the change from baseline in body weight.p-value: <0.000197.5% CI: [-2.48, -1.5]ANCOVA
Secondary
Mean Daily Plasma Glucose (MDG) Change From Baseline
Change from baseline in mean daily glucose (MDG) using the 8-point blood glucose profile, after 24 weeks of treatment. For open-label groups the descriptive mean is provided, for randomised groups adjusted means are provided. The means are adjusted separately for metformin alone and metformin plus sulphonylurea background medication.
Time frame: Baseline and 24 weeks
Population: Full analysis set. Treatment assignment as randomised.~Open-label analysis: Open-label set which included all patients entered in the empa 25mg open-label treatment arm.~Values after start of antidiabetic rescue therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Met: Placebo | Mean Daily Plasma Glucose (MDG) Change From Baseline | -1.99 mg/dL | Standard Error 1.99 |
| Met: Empa 10mg | Mean Daily Plasma Glucose (MDG) Change From Baseline | -9.64 mg/dL | Standard Error 1.89 |
| Met: Empa 25mg | Mean Daily Plasma Glucose (MDG) Change From Baseline | -14.36 mg/dL | Standard Error 1.89 |
| Met: Empa 25mg Open Label | Mean Daily Plasma Glucose (MDG) Change From Baseline | -35.47 mg/dL | Standard Error 7.34 |
| Met+SU: Placebo | Mean Daily Plasma Glucose (MDG) Change From Baseline | 0.00 mg/dL | Standard Error 1.78 |
| Met+SU: Empa 10mg | Mean Daily Plasma Glucose (MDG) Change From Baseline | -10.01 mg/dL | Standard Error 1.8 |
| Met+SU: Empa 25mg | Mean Daily Plasma Glucose (MDG) Change From Baseline | -13.06 mg/dL | Standard Error 2.03 |
| Met+SU: Empa 25mg Open Label | Mean Daily Plasma Glucose (MDG) Change From Baseline | -29.34 mg/dL | Standard Error 6.58 |
Comparison: Null hypothesis (H0): No difference in change from baseline to week 24 in MDG between Empa 10mg and placebo. A hierarchical testing approach was applied to each of the two dose comparisons within each background therapy group. If for a specific dose H0 was rejected for the primary endpoint, the same dose was tested against placebo for change from baseline in body weight. If superiority over placebo was shown at this gate level, then testing proceeded to change from baseline in MDG with that dosep-value: 0.005597.5% CI: [-13.81, -1.48]ANCOVA
Comparison: Null hypothesis (H0): No difference in change from baseline to week 24 in MDG between Empa 25mg and placebo. A hierarchical testing approach was applied to each of the two dose comparisons within each background therapy group. If for a specific dose H0 was rejected for the primary endpoint, the same dose was tested against placebo for change from baseline in body weight. If superiority over placebo was shown at this gate level, then testing proceeded to change from baseline in MDG with that dosep-value: <0.000197.5% CI: [-18.55, -6.19]ANCOVA
Comparison: Null hypothesis (H0): No difference in change from baseline to week 24 in MDG between Empa 10mg and placebo. A hierarchical testing approach was applied to each of the two dose comparisons within each background therapy group. If for a specific dose H0 was rejected for the primary endpoint, the same dose was tested against placebo for change from baseline in body weight. If superiority over placebo was shown at this gate level, then testing proceeded to change from baseline in MDG with that dosep-value: <0.000197.5% CI: [-15.72, -4.32]ANCOVA
Comparison: Null hypothesis (H0): No difference in change from baseline to week 24 in MDG between Empa 25mg and placebo. A hierarchical testing approach was applied to each of the two dose comparisons within each background therapy group. If for a specific dose H0 was rejected for the primary endpoint, the same dose was tested against placebo for change from baseline in body weight. If superiority over placebo was shown at this gate level, then testing proceeded to change from baseline in MDG with that dosep-value: <0.000197.5% CI: [-19.15, -6.98]ANCOVA
Other Pre-specified
Confirmed Hypoglycaemic Adverse Events
Number of patients with confirmed hypoglycaemic events, as reported as adverse events.
Time frame: From first intake of randomised trial medication until 7 days after last trial medication intake, up to 231 days
Population: Treated set, which included all patients treated with at least one dose of randomised trial medication. Treatment assignment as first medication taken.~Open label set which included all patients entered into the open-label arm.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Met: Placebo | Confirmed Hypoglycaemic Adverse Events | 0.5 percentage of participants | 0.01 |
| Met: Empa 10mg | Confirmed Hypoglycaemic Adverse Events | 1.8 percentage of participants | 0.01 |
| Met: Empa 25mg | Confirmed Hypoglycaemic Adverse Events | 1.4 percentage of participants | 0.03 |
| Met: Empa 25mg Open Label | Confirmed Hypoglycaemic Adverse Events | 2.9 percentage of participants | 0.02 |
| Met+SU: Placebo | Confirmed Hypoglycaemic Adverse Events | 8.4 percentage of participants | 0.01 |
| Met+SU: Empa 10mg | Confirmed Hypoglycaemic Adverse Events | 16.1 percentage of participants | 0.01 |
| Met+SU: Empa 25mg | Confirmed Hypoglycaemic Adverse Events | 11.5 percentage of participants | 0.03 |
| Met+SU: Empa 25mg Open Label | Confirmed Hypoglycaemic Adverse Events | 6.9 percentage of participants | 0.02 |