Diabetes Mellitus, Type 2
Conditions
Brief summary
The aim of this study is to investigate the efficacy and safety of two doses (high and low) of empagliflozin as add-on therapy to metformin in patients with type 2 diabetes mellitus (T2DM) and insufficient glycaemic control. Both doses may be given once daily or split to a twice daily dosage. This results in 4 different dosage regimens of empagliflozin (high dose once daily or split vs. low dose once daily or split). This is done to evaluate whether a twice daily dose regimen of empagliflozin results in a loss of efficacy relative to once daily dosing when given on top of metformin background therapy.
Interventions
DRUGPlacebo
Patients receive placebo matching empagliflozin (low dose qd)
DRUGempagliflozin (low dose qd)
Patients receive Empagliflozin low dose once daily
DRUGEmpagliflozin (high dose qd)
Patients receive Empagliflozin high dose once daily
DRUGempagliflozin (high dose bid)
Patients receive Empagliflozin high dose split twice daily
DRUGempagliflozin (low dose bid)
Patients receive Empagliflozin low dose split twice daily
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. confirmed diagnosis of T2DM 2. Glycated hemoglobin (HbA1c) \>=7.0 and \<=10/0% at Visit 1 3. Metformin therapy (at least 1500 mg/day, BID) 4. age\>=18 at Visit 1 5. body mass index \<=45 kg/m2
Exclusion criteria
1. estimated creatinine clearance rate (eCCr) \<60 ml/min (Cockcroft-Gault formula) screening and/or run-in 2. a confirmed glucose level \>240 mg/dl (\>13.3 mmol/L) after an overnight fast during placebo run-in
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 16 | Baseline and 16 weeks | Change from baseline in HbA1c (%) after 16 weeks of treatment. The term 'baseline' refers to the last observation prior to the first intake of any randomised study medication. Means provided are the adjusted means. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Plasma Glucose (FPG) Change From Baseline at Week 16 | Baseline and 16 weeks | Change from baseline in FPG (mg/dL) after 16 weeks of treatment. The term 'baseline' refers to the last observation prior to the first intake of any randomised study medication. Means provided are the adjusted means. |
Countries
Australia, Canada, Estonia, France, Georgia, Germany, Guatemala, Italy, Latvia, Lithuania, Mexico, New Zealand, Poland, Russia, South Africa, Spain, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Empa 12.5mg BID Oral administration of Empagliflozin (Empa) 12.5 mg twice daily (BID) | 215 |
| Empa 25mg QD Oral administration of Empagliflozin (Empa) 25 mg once daily (QD) | 214 |
| Empa 5mg BID Oral administration of Empagliflozin (Empa) 5 mg twice daily (BID) | 215 |
| Empa 10mg QD Oral administration of Empagliflozin (Empa) 10 mg once daily (QD) | 214 |
| Placebo Oral administration of Placebo tablets matching empagliflozin 25 mg, 10 mg, 5 mg, and 2.5 mg | 107 |
| Total | 965 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 5 | 4 | 13 | 1 |
| Overall Study | For other reason | 4 | 1 | 2 | 0 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 | 4 | 3 | 0 |
| Overall Study | Non compliant with Protocol | 1 | 0 | 3 | 2 | 1 |
| Overall Study | Patient withdrawal (not due to AE) | 3 | 6 | 4 | 1 | 1 |
Baseline characteristics
| Characteristic | Empa 12.5mg BID | Empa 25mg QD | Empa 5mg BID | Empa 10mg QD | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 9.9 | 58.2 years STANDARD_DEVIATION 10.2 | 58.8 years STANDARD_DEVIATION 9.8 | 58.5 years STANDARD_DEVIATION 10.8 | 57.9 years STANDARD_DEVIATION 11.2 | 58.2 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 92 Participants | 100 Participants | 95 Participants | 106 Participants | 52 Participants | 445 Participants |
| Sex: Female, Male Male | 123 Participants | 114 Participants | 120 Participants | 108 Participants | 55 Participants | 520 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 | 10 / 219 | 10 / 218 | 8 / 219 | 15 / 220 | 4 / 107 |
| serious Total, serious adverse events | 5 / 219 | 2 / 218 | 7 / 219 | 5 / 220 | 1 / 107 |
Outcome results
Primary
HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 16
Change from baseline in HbA1c (%) after 16 weeks of treatment. The term 'baseline' refers to the last observation prior to the first intake of any randomised study medication. Means provided are the adjusted means.
Time frame: Baseline and 16 weeks
Population: Full Analysis Set (FAS) is the basis for the intention-to-treat analysis. FAS with last observation carried forward (LOCF) imputation is used as the primary method of accounting for missing data.~Values after the patient started rescue medication were excluded from analysis (and imputed with an LOCF procedure).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empa 12.5mg BID | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 16 | -0.83 percentage of HbA1c | Standard Error 0.05 |
| Empa 25mg QD | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 16 | -0.72 percentage of HbA1c | Standard Error 0.05 |
| Empa 5mg BID | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 16 | -0.66 percentage of HbA1c | Standard Error 0.05 |
| Empa 10mg QD | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 16 | -0.64 percentage of HbA1c | Standard Error 0.05 |
| Placebo | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 16 | -0.22 percentage of HbA1c | Standard Error 0.07 |
Comparison: The primary objective was to test the non-inferiority of empagliflozin 5 mg BID versus empagliflozin 10 mg QD, and non-inferiority of empagliflozin 12.5 mg BID versus empagliflozin 25 mg QD, assuming a non-inferiority margin of 0.35%p-value: <0.000195% CI: [-0.16, 0.13]ANCOVA
Comparison: The primary objective was to test the non-inferiority of empagliflozin 5 mg BID versus empagliflozin 10 mg QD, and non-inferiority of empagliflozin 12.5 mg BID versus empagliflozin 25 mg QD, assuming a non-inferiority margin of 0.35%p-value: <0.000195% CI: [-0.26, 0.03]ANCOVA
Comparison: Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing HbA1c after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided).p-value: <0.000195% CI: [-0.79, -0.44]ANCOVA
Comparison: Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing HbA1c after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided).p-value: <0.000195% CI: [-0.68, -0.32]ANCOVA
Comparison: Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing HbA1c after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided).p-value: <0.000195% CI: [-0.62, -0.27]ANCOVA
Comparison: Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing HbA1c after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided).p-value: <0.000195% CI: [-0.6, -0.25]ANCOVA
Secondary
Fasting Plasma Glucose (FPG) Change From Baseline at Week 16
Change from baseline in FPG (mg/dL) after 16 weeks of treatment. The term 'baseline' refers to the last observation prior to the first intake of any randomised study medication. Means provided are the adjusted means.
Time frame: Baseline and 16 weeks
Population: FAS with LOCF has been used for FPG analyses
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empa 12.5mg BID | Fasting Plasma Glucose (FPG) Change From Baseline at Week 16 | -27.7 mg/dL | Standard Error 2 |
| Empa 25mg QD | Fasting Plasma Glucose (FPG) Change From Baseline at Week 16 | -22.7 mg/dL | Standard Error 2 |
| Empa 5mg BID | Fasting Plasma Glucose (FPG) Change From Baseline at Week 16 | -21.2 mg/dL | Standard Error 2 |
| Empa 10mg QD | Fasting Plasma Glucose (FPG) Change From Baseline at Week 16 | -17.6 mg/dL | Standard Error 2 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline at Week 16 | -0.2 mg/dL | Standard Error 2.8 |
95% CI: [-9, 1.8]ANCOVA
95% CI: [-10.4, 0.5]ANCOVA
Comparison: Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing FPG after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided)p-value: <0.000195% CI: [-34.2, -20.9]ANCOVA
Comparison: Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing FPG after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided)p-value: <0.000195% CI: [-29.2, -15.9]ANCOVA
Comparison: Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing FPG after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided)p-value: <0.000195% CI: [-27.7, -14.4]ANCOVA
Comparison: Superiority of once daily dose of empagliflozin (10 mg and 25 mg) versus placebo and superiority of twice daily dose of empagliflozin (5 mg and 12.5 mg) versus placebo in reducing FPG after 16 weeks of treatment was tested in an exploratory manner, to demonstrate assay sensitivity against placebo at 0.05 level (two-sided)p-value: <0.000195% CI: [-24.1, -10.8]ANCOVA