Diabetes Mellitus, Type 2, Hyperglycemia
Conditions
Brief summary
This study will investigate the efficacy and safety of two doses (high and low) of empagliflozin in combination with metformin (500 mg and 1000 mg) administered twice daily in patients with type 2 diabetes mellitus (T2DM). Study will compare four dose combinations of empagliflozin + metformin versus each individual component after 24 weeks of treatment.
Interventions
DRUGMetformin 500 mg bid
Metformin 500 mg twice daily
DRUGMetformin 1000 mg bid
Metformin 1000 mg twice daily
DRUGEmpagliflozin low dose qd
Empagliflozin low dose once daily
DRUGEmpagliflozin high dose qd
Empagliflozin high dose once daily
DRUGEmpagliflozin low dose bid
Empagliflozin low dose split twice daily
DRUGEmpagliflozin high dose bid
Empagliflozin high 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. Diagnosis of type 2 diabetes mellitus prior to informed consent 2. Male and female patients on diet and exercise regimen who are drug-naive, defined as absence of any oral antidiabetic therapy for 12 weeks prior to randomization 3. HbA1c \>=7.5% and \<= 12% (\>=58.5 mmol/mol and \<=107.7 mmol/mol) 4. Body Mass Index (BMI) \<= 45 kg/m2 at screening
Exclusion criteria
1. Uncontrolled hyperglycemia with a glucose level \>240 mg/dl (\>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second laboratory measurement (not on the same day) 2. Any antidiabetic drug within 12 weeks prior to randomization 3. Impaired renal function, defined as estimated creatinine clearance rate (eCCr) \<60 ml/min (Cockcroft-Gault formula) as determined during screening and/or run-in period 4. Contraindications to metformin according to the local label
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 | baseline and 24 weeks | Change from baseline in HbA1c (%) after 24 weeks of treatment. Baseline refers to the last observation before the start of any randomised trial treatment medication. Means presented are the adjusted means |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 | baseline and 24 weeks | Change from baseline in FPG (mg/dL) after 24 weeks of treatment. Baseline refers to the last observation before the start of any randomised trial treatment medication. Means presented are the adjusted means. |
| Body Weight Change From Baseline at Week 24 | baseline and 24 weeks | Change from baseline in body weight (kg) after 24 weeks of treatment. Baseline refers to the last observation before the start of any randomised trial treatment. medication. Means presented are the adjusted means. |
Countries
Brazil, Canada, Czechia, Egypt, France, Germany, Guatemala, Lebanon, Malaysia, Mexico, Peru, Philippines, Russia, Serbia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
With the first global protocol amendment (13-Dec-2012), the HbA1c inclusion criterion changed and further enrolment in the open label (OL) group was stopped, but the patients already entered in the OL group could continue until the scheduled end of the study.
Pre-assignment details
Patients with an (Glycosylated Haemoglobin) HbA1c \>10.0% at screening and meeting all other inclusion criteria were initially directly included in an OL treatment group
Participants by arm
| Arm | Count |
|---|---|
| Empagliflozin 12.5 mg Bid+ Metformin 1000 mg Bid Oral administration of Empagliflozin 12.5 mg and Metformin 1000 mg twice daily (bid) | 169 |
| Empagliflozin 12.5 mg Bid+ Metformin 500 mg Bid Oral administration of Empagliflozin 12.5 mg and Metformin 500 mg bid | 165 |
| Empagliflozin 5 mg Bid + Metformin 1000 mg Bid Oral administration of Empagliflozin 5 mg and Metformin 1000 mg bid | 167 |
| Empagliflozin 5 mg Bid + Metformin 500 mg Bid Oral administration of Empagliflozin 5 mg and Metformin 500 mg bid | 161 |
| Empagliflozin 25 mg qd Oral administration of Empagliflozin 25 mg once daily (qd) | 164 |
| Empagliflozin 10 mg qd Oral administration of Empagliflozin 10 mg qd | 169 |
| Metformin 1000 mg Bid Oral administration of Metformin 1000 mg bid | 164 |
| Metformin 500 mg Bid Oral administration of Metformin 500 mg bid | 168 |
| Total | 1,327 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 5 | 4 | 3 | 4 | 3 | 6 | 5 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 6 | 7 | 2 | 3 | 4 | 3 | 2 | 2 |
| Overall Study | Non compliant with protocol | 1 | 1 | 0 | 1 | 2 | 1 | 2 | 3 | 0 |
| Overall Study | Reason other than those specified | 0 | 0 | 2 | 3 | 4 | 1 | 0 | 3 | 1 |
| Overall Study | Refusal to continue, not due to AE | 2 | 5 | 4 | 4 | 4 | 3 | 8 | 7 | 1 |
Baseline characteristics
| Characteristic | Empagliflozin 12.5 mg Bid+ Metformin 1000 mg Bid | Empagliflozin 12.5 mg Bid+ Metformin 500 mg Bid | Empagliflozin 5 mg Bid + Metformin 1000 mg Bid | Empagliflozin 5 mg Bid + Metformin 500 mg Bid | Empagliflozin 25 mg qd | Empagliflozin 10 mg qd | Metformin 1000 mg Bid | Metformin 500 mg Bid | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 53.6 years STANDARD_DEVIATION 10.7 | 51.0 years STANDARD_DEVIATION 10.7 | 52.3 years STANDARD_DEVIATION 11.3 | 52.2 years STANDARD_DEVIATION 11.7 | 53.3 years STANDARD_DEVIATION 10.7 | 53.1 years STANDARD_DEVIATION 10.7 | 51.6 years STANDARD_DEVIATION 10.8 | 53.4 years STANDARD_DEVIATION 10.9 | 52.6 years STANDARD_DEVIATION 10.9 |
| Sex: Female, Male Female | 81 Participants | 60 Participants | 68 Participants | 64 Participants | 81 Participants | 72 Participants | 72 Participants | 82 Participants | 580 Participants |
| Sex: Female, Male Male | 88 Participants | 105 Participants | 99 Participants | 97 Participants | 83 Participants | 97 Participants | 92 Participants | 86 Participants | 747 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 | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 48 / 170 | 40 / 170 | 35 / 171 | 42 / 169 | 41 / 167 | 36 / 172 | 53 / 170 | 38 / 171 | 16 / 53 |
| serious Total, serious adverse events | 2 / 170 | 6 / 170 | 3 / 171 | 2 / 169 | 3 / 167 | 1 / 172 | 3 / 170 | 3 / 171 | 2 / 53 |
Outcome results
Primary
HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24
Change from baseline in HbA1c (%) after 24 weeks of treatment. Baseline refers to the last observation before the start of any randomised trial treatment medication. Means presented are the adjusted means
Time frame: baseline and 24 weeks
Population: FAS observed cases (OC) (Only patients with available data are analysed)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 12.5 mg Bid+ Metformin 1000 mg Bid | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 | -2.08 percentage of HbA1c | Standard Error 0.08 |
| Empagliflozin 12.5 mg Bid+ Metformin 500 mg Bid | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 | -1.93 percentage of HbA1c | Standard Error 0.08 |
| Empagliflozin 5 mg Bid + Metformin 1000 mg Bid | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 | -2.07 percentage of HbA1c | Standard Error 0.08 |
| Empagliflozin 5 mg Bid + Metformin 500 mg Bid | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 | -1.98 percentage of HbA1c | Standard Error 0.08 |
| Empagliflozin 25 mg qd | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 | -1.36 percentage of HbA1c | Standard Error 0.08 |
| Empagliflozin 10 mg qd | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 | -1.35 percentage of HbA1c | Standard Error 0.08 |
| Metformin 1000 mg Bid | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 | -1.75 percentage of HbA1c | Standard Error 0.09 |
| Metformin 500 mg Bid | HbA1c (Glycosylated Haemoglobin) Change From Baseline at Week 24 | -1.18 percentage of HbA1c | Standard Error 0.08 |
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment.p-value: 0.005695% CI: [-0.56, -0.1]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-0.95, -0.48]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-0.98, -0.51]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-0.81, -0.34]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatmentp-value: 0.006295% CI: [-0.56, -0.09]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-0.95, -0.49]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-1.03, -0.56]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-0.86, -0.4]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment.p-value: 0.624695% CI: [0.15, 0.62]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of HbA1c (in units of %) after 24 weeks of double-blind treatment.p-value: 0.655895% CI: [0.16, 0.63]Mixed Models Analysis
Secondary
Body Weight Change From Baseline at Week 24
Change from baseline in body weight (kg) after 24 weeks of treatment. Baseline refers to the last observation before the start of any randomised trial treatment. medication. Means presented are the adjusted means.
Time frame: baseline and 24 weeks
Population: FAS observed cases (OC) (Only patients with available data are analysed)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 12.5 mg Bid+ Metformin 1000 mg Bid | Body Weight Change From Baseline at Week 24 | -3.78 kg | Standard Error 0.29 |
| Empagliflozin 12.5 mg Bid+ Metformin 500 mg Bid | Body Weight Change From Baseline at Week 24 | -3.04 kg | Standard Error 0.3 |
| Empagliflozin 5 mg Bid + Metformin 1000 mg Bid | Body Weight Change From Baseline at Week 24 | -3.48 kg | Standard Error 0.3 |
| Empagliflozin 5 mg Bid + Metformin 500 mg Bid | Body Weight Change From Baseline at Week 24 | -2.77 kg | Standard Error 0.3 |
| Empagliflozin 25 mg qd | Body Weight Change From Baseline at Week 24 | -2.38 kg | Standard Error 0.3 |
| Empagliflozin 10 mg qd | Body Weight Change From Baseline at Week 24 | -2.39 kg | Standard Error 0.29 |
| Metformin 1000 mg Bid | Body Weight Change From Baseline at Week 24 | -1.27 kg | Standard Error 0.3 |
| Metformin 500 mg Bid | Body Weight Change From Baseline at Week 24 | -0.52 kg | Standard Error 0.3 |
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of body weight after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-3.33, -1.68]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of body weight after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-3.35, -1.69]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of body weight after 24 weeks of double-blind treatmentp-value: <0.000195% CI: [-3.03, -1.37]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of body weight after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-3.09, -1.43]Mixed Models Analysis
Secondary
FPG (Fasting Plasma Glucose) Change From Baseline at Week 24
Change from baseline in FPG (mg/dL) after 24 weeks of treatment. Baseline refers to the last observation before the start of any randomised trial treatment medication. Means presented are the adjusted means.
Time frame: baseline and 24 weeks
Population: FAS observed cases (OC) (Only patients with available data are analysed)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 12.5 mg Bid+ Metformin 1000 mg Bid | FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 | -51.0 mg/dL | Standard Error 2.4 |
| Empagliflozin 12.5 mg Bid+ Metformin 500 mg Bid | FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 | -44.0 mg/dL | Standard Error 2.4 |
| Empagliflozin 5 mg Bid + Metformin 1000 mg Bid | FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 | -47.8 mg/dL | Standard Error 2.4 |
| Empagliflozin 5 mg Bid + Metformin 500 mg Bid | FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 | -45.5 mg/dL | Standard Error 2.4 |
| Empagliflozin 25 mg qd | FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 | -28.0 mg/dL | Standard Error 2.5 |
| Empagliflozin 10 mg qd | FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 | -32.9 mg/dL | Standard Error 2.4 |
| Metformin 1000 mg Bid | FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 | -32.1 mg/dL | Standard Error 2.4 |
| Metformin 500 mg Bid | FPG (Fasting Plasma Glucose) Change From Baseline at Week 24 | -17.2 mg/dL | Standard Error 2.5 |
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-25.5, -12.2]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-29.7, -16.3]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-33.5, -20]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-22.8, -9.2]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG of double-blind treatmentp-value: <0.000195% CI: [-22.3, -8.9]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-21.4, -8.2]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment.p-value: <0.000195% CI: [-35, -21.5]Mixed Models Analysis
Comparison: Restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach comparing the change from baseline of FPG after 24 weeks of double-blind treatment.p-value: 0.000295% CI: [-19.1, -6]Mixed Models Analysis