Diabetes Mellitus, Type 2
Conditions
Brief summary
This is a pivotal phase III study, mandatory to seek approval by regulatory authorities for BI 10773 as an anti-diabetic agent compared to an active comparator in patients with type 2 diabetes mellitus and insufficient glycaemic control.
Interventions
DRUGBI 10773
Medium dose once daily
DRUGGlimepiride
1-4 mg once daily
DRUGPlacebo
Placebo matching BI 10773
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
* Diagnosis typ 2 diabetes mellitus * Male and female on diet and exercise regimen, pre-treated with metformin 12 weeks prior to randomisation * HbA1c equal or greater than 7.0% and less than or equal to 10% at visit 1 * 18 years or more * BMI equal or less than 45Kg/m2
Exclusion criteria
* Uncontrolled hyperglycemia defined as glucose more that 13.3 mmol/L after overnight fast during placebo run-in * Any other antidiabetic drug within 12 weeks prior to randomisation except metformin * Acute coronary syndrome (non-STEMI, STEMI unstable angina pectoris), stroke or transient ischemic attack within 12 weeks of informed consent * Indication of liver disease * Moderate to severe renal impairment * Bariatric surgery within past 2 years * Medical history of cancer or treatment for cancer within last 5 years * Blood dyscrasias or any disorders causing haemolysis or unstable red blood cell * Contraindications hypersensitivity to concomitant drugs * Treatment with anti-obesity drugs
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 104 Weeks of Treatment. | Baseline and 104 weeks |
Secondary
| Measure | Time frame |
|---|---|
| The Occurrence of Confirmed Hypoglycaemic Events During 104 Weeks of Treatment. | baseline and 104 weeks |
| The Change in Systolic Blood Pressure (SBP) From Baseline After 104 Weeks of Treatment. | baseline and 104 weeks |
| The Change in Diastolic Blood Pressure (DBP) From Baseline After 104 Weeks of Treatment. | baseline and 104 weeks |
| The Change From Baseline in HbA1c After 52 Weeks of Treatment. | baseline and 52 weeks |
| The Change in Body Weight From Baseline After 104 Weeks of Treatment. | baseline and 104 weeks |
| The Occurrence of Confirmed Hypoglycaemic Events During 52 Weeks of Treatment. | baseline and 52 weeks |
| The Change in Systolic Blood Pressure (SBP) From Baseline After 52 Weeks of Treatment. | baseline and 52 weeks |
| The Change in Diastolic Blood Pressure (DBP) From Baseline After 52 Weeks of Treatment. | baseline and 52 weeks |
| The Change in Body Weight From Baseline After 52 Weeks of Treatment. | baseline and 52 weeks |
Countries
Argentina, Austria, Canada, Colombia, Czechia, Finland, Hong Kong, India, Italy, Malaysia, Mexico, Netherlands, Norway, Philippines, Portugal, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand, United Kingdom, United States
Participant flow
Pre-assignment details
An optional 2-year extension was implemented in this trial through a protocol amendment, which brought the total length of treatment to 4 years. However, some sites did not participate in the 2-year extension, and so considered patients to have completed treatment after 2 years.
Participants by arm
| Arm | Count |
|---|---|
| Empaglifozin 25 mg Patients received one Empagliflozin 25 mg tablet and one placebo Glimepiride capsule orally once daily.
Empagliflozin: 25 mg once daily
Placebo: Placebo matching Glimepiride | 765 |
| Glimepiride Patients received one Glimepiride capsule and one placebo Empagliflozin tablet orally once daily.
Glimepiride: 1-4 mg once daily
Placebo: Placebo matching Empagliflozin | 780 |
| Total | 1,545 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 47 | 51 |
| Overall Study | Lack of Efficacy | 4 | 7 |
| Overall Study | Lost to Follow-up | 19 | 20 |
| Overall Study | Non compliant with protocol | 9 | 18 |
| Overall Study | Not treated | 4 | 0 |
| Overall Study | Other not defined above | 31 | 55 |
| Overall Study | Patient refusal to cont., not due to AE | 45 | 40 |
Baseline characteristics
| Characteristic | Empaglifozin 25 mg | Glimepiride | Total |
|---|---|---|---|
| Age, Continuous | 56.2 years STANDARD_DEVIATION 10.3 | 55.7 years STANDARD_DEVIATION 10.4 | 55.9 years STANDARD_DEVIATION 10.4 |
| Sex: Female, Male Female | 333 Participants | 359 Participants | 692 Participants |
| Sex: Female, Male Male | 432 Participants | 421 Participants | 853 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 580 / 765 | 637 / 780 |
| serious Total, serious adverse events | 161 / 765 | 153 / 780 |
Outcome results
Primary
The Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 104 Weeks of Treatment.
Time frame: Baseline and 104 weeks
Population: FAS (LOCF) - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF); 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 |
|---|---|---|---|
| Empaglifozin 25 mg | The Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 104 Weeks of Treatment. | -0.66 percentage of HbA1c | Standard Error 0.03 |
| Glimepiride | The Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 104 Weeks of Treatment. | -0.55 percentage of HbA1c | Standard Error 0.03 |
Comparison: Testing Hierarchy for main analysis (104 weeks):~1. Non-inferiority in HbA1c change from baseline at 104 weeks,~2. Superiority in body weight change from baseline at 104 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 104 weeks,~4. Superiority in HbA1c change from baseline at 104 weeks,~5. Superiority in systolic blood pressure change from baseline at 104 weeks,~6. Superiority in diastolic blood pressure change from baseline at 104 weeks.p-value: <0.000197.5% CI: [-0.2, -0.01]ANCOVA
Comparison: Testing Hierarchy for main analysis (104 weeks):~1. Non-inferiority in HbA1c change from baseline at 104 weeks,~2. Superiority in body weight change from baseline at 104 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 104 weeks,~4. Superiority in HbA1c change from baseline at 104 weeks,~5. Superiority in systolic blood pressure change from baseline at 104 weeks,~6. Superiority in diastolic blood pressure change from baseline at 104 weeks.p-value: 0.015397.5% CI: [-0.2, -0.01]ANCOVA
Secondary
The Change From Baseline in HbA1c After 52 Weeks of Treatment.
Time frame: baseline and 52 weeks
Population: FAS (LOCF) - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF); 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 |
|---|---|---|---|
| Empaglifozin 25 mg | The Change From Baseline in HbA1c After 52 Weeks of Treatment. | -0.73 percentage of HbA1c | Standard Error 0.03 |
| Glimepiride | The Change From Baseline in HbA1c After 52 Weeks of Treatment. | -0.66 percentage of HbA1c | Standard Error 0.03 |
Comparison: Testing Hierarchy for first interim analysis (52 weeks):~1. Non-inferiority in HbA1c change from baseline at 52 weeks,~2. Superiority in body weight change from baseline at 52 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 52 weeks,~4. Superiority in systolic blood pressure change from baseline at 52 weeks,~5. Superiority in diastolic blood pressure change from baseline at 52 weeks.p-value: <0.000197.5% CI: [-0.16, 0.02]ANCOVA
Secondary
The Change in Body Weight From Baseline After 104 Weeks of Treatment.
Time frame: baseline and 104 weeks
Population: FAS (LOCF) - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF); 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 |
|---|---|---|---|
| Empaglifozin 25 mg | The Change in Body Weight From Baseline After 104 Weeks of Treatment. | -3.11 kilograms | Standard Error 0.13 |
| Glimepiride | The Change in Body Weight From Baseline After 104 Weeks of Treatment. | 1.33 kilograms | Standard Error 0.13 |
Comparison: Testing Hierarchy for main analysis (104 weeks):~1. Non-inferiority in HbA1c change from baseline at 104 weeks,~2. Superiority in body weight change from baseline at 104 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 104 weeks,~4. Superiority in HbA1c change from baseline at 104 weeks,~5. Superiority in systolic blood pressure change from baseline at 104 weeks,~6. Superiority in diastolic blood pressure change from baseline at 104 weeks.p-value: <0.000197.5% CI: [-4.87, -4.05]ANCOVA
Secondary
The Change in Body Weight From Baseline After 52 Weeks of Treatment.
Time frame: baseline and 52 weeks
Population: FAS (LOCF) - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF); 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 |
|---|---|---|---|
| Empaglifozin 25 mg | The Change in Body Weight From Baseline After 52 Weeks of Treatment. | -3.21 kilograms | Standard Error 0.12 |
| Glimepiride | The Change in Body Weight From Baseline After 52 Weeks of Treatment. | 1.59 kilograms | Standard Error 0.11 |
Comparison: Testing Hierarchy for first interim analysis (52 weeks):~1. Non-inferiority in HbA1c change from baseline at 52 weeks,~2. Superiority in body weight change from baseline at 52 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 52 weeks,~4. Superiority in systolic blood pressure change from baseline at 52 weeks,~5. Superiority in diastolic blood pressure change from baseline at 52 weeks.p-value: <0.000197.5% CI: [-5.16, -4.46]ANCOVA
Secondary
The Change in Diastolic Blood Pressure (DBP) From Baseline After 104 Weeks of Treatment.
Time frame: baseline and 104 weeks
Population: FAS (LOCF-H) - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF); Values after start of antidiabetic rescue therapy or change of antihypertensive therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empaglifozin 25 mg | The Change in Diastolic Blood Pressure (DBP) From Baseline After 104 Weeks of Treatment. | -1.8 mmHg | Standard Error 0.3 |
| Glimepiride | The Change in Diastolic Blood Pressure (DBP) From Baseline After 104 Weeks of Treatment. | 0.9 mmHg | Standard Error 0.3 |
Comparison: Testing Hierarchy for main analysis (104 weeks):~1. Non-inferiority in HbA1c change from baseline at 104 weeks,~2. Superiority in body weight change from baseline at 104 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 104 weeks,~4. Superiority in HbA1c change from baseline at 104 weeks,~5. Superiority in systolic blood pressure change from baseline at 104 weeks,~6. Superiority in diastolic blood pressure change from baseline at 104 weeks.p-value: <0.000197.5% CI: [-3.5, -1.8]ANCOVA
Secondary
The Change in Diastolic Blood Pressure (DBP) From Baseline After 52 Weeks of Treatment.
Time frame: baseline and 52 weeks
Population: FAS (LOCF-H) - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF); Values after start of antidiabetic rescue therapy or change of antihypertensive therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empaglifozin 25 mg | The Change in Diastolic Blood Pressure (DBP) From Baseline After 52 Weeks of Treatment. | -1.9 mmHg | Standard Error 0.3 |
| Glimepiride | The Change in Diastolic Blood Pressure (DBP) From Baseline After 52 Weeks of Treatment. | 1.0 mmHg | Standard Error 0.3 |
Comparison: Testing Hierarchy for first interim analysis (52 weeks):~1. Non-inferiority in HbA1c change from baseline at 52 weeks,~2. Superiority in body weight change from baseline at 52 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 52 weeks,~4. Superiority in systolic blood pressure change from baseline at 52 weeks,~5. Superiority in diastolic blood pressure change from baseline at 52 weeks.p-value: <0.000197.5% CI: [-3.7, -2]ANCOVA
Secondary
The Change in Systolic Blood Pressure (SBP) From Baseline After 104 Weeks of Treatment.
Time frame: baseline and 104 weeks
Population: FAS (LOCF-H) - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF); Values after start of antidiabetic rescue therapy or change of antihypertensive therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.~.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empaglifozin 25 mg | The Change in Systolic Blood Pressure (SBP) From Baseline After 104 Weeks of Treatment. | -3.1 mmHg | Standard Error 0.5 |
| Glimepiride | The Change in Systolic Blood Pressure (SBP) From Baseline After 104 Weeks of Treatment. | 2.5 mmHg | Standard Error 0.5 |
Comparison: Testing Hierarchy for main analysis (104 weeks):~1. Non-inferiority in HbA1c change from baseline at 104 weeks,~2. Superiority in body weight change from baseline at 104 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 104 weeks,~4. Superiority in HbA1c change from baseline at 104 weeks,~5. Superiority in systolic blood pressure change from baseline at 104 weeks,~6. Superiority in diastolic blood pressure change from baseline at 104 weeks.p-value: <0.000197.5% CI: [-7, -4.2]ANCOVA
Secondary
The Change in Systolic Blood Pressure (SBP) From Baseline After 52 Weeks of Treatment.
Time frame: baseline and 52 weeks
Population: FAS (LOCF-H) - Full Analysis Set (FAS) with Last Observation Carried Forward (LOCF); Values after start of antidiabetic rescue therapy or change of antihypertensive therapy were set to missing and last observation carried forward (LOCF) was used for imputation of missing values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empaglifozin 25 mg | The Change in Systolic Blood Pressure (SBP) From Baseline After 52 Weeks of Treatment. | -3.6 mmHg | Standard Error 0.5 |
| Glimepiride | The Change in Systolic Blood Pressure (SBP) From Baseline After 52 Weeks of Treatment. | 2.2 mmHg | Standard Error 0.5 |
Comparison: Testing Hierarchy for first interim analysis (52 weeks):~1. Non-inferiority in HbA1c change from baseline at 52 weeks,~2. Superiority in body weight change from baseline at 52 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 52 weeks,~4. Superiority in systolic blood pressure change from baseline at 52 weeks,~5. Superiority in diastolic blood pressure change from baseline at 52 weeks.p-value: <0.000197.5% CI: [-7.3, -4.4]ANCOVA
Secondary
The Occurrence of Confirmed Hypoglycaemic Events During 104 Weeks of Treatment.
Time frame: baseline and 104 weeks
Population: Treated set, all patients treated with at least one dose of randomised study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Empaglifozin 25 mg | The Occurrence of Confirmed Hypoglycaemic Events During 104 Weeks of Treatment. | 19 participants |
| Glimepiride | The Occurrence of Confirmed Hypoglycaemic Events During 104 Weeks of Treatment. | 189 participants |
Comparison: Testing Hierarchy for main analysis (104 weeks):~1. Non-inferiority in HbA1c change from baseline at 104 weeks,~2. Superiority in body weight change from baseline at 104 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 104 weeks,~4. Superiority in HbA1c change from baseline at 104 weeks,~5. Superiority in systolic blood pressure change from baseline at 104 weeks,~6. Superiority in diastolic blood pressure change from baseline at 104 weeks.p-value: <0.000197.5% CI: [0.06, 0.173]Cochran-Mantel-Haenszel
Secondary
The Occurrence of Confirmed Hypoglycaemic Events During 52 Weeks of Treatment.
Time frame: baseline and 52 weeks
Population: Treated set, all patients treated with at least one dose of randomised study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Empaglifozin 25 mg | The Occurrence of Confirmed Hypoglycaemic Events During 52 Weeks of Treatment. | 12 participants |
| Glimepiride | The Occurrence of Confirmed Hypoglycaemic Events During 52 Weeks of Treatment. | 159 participants |
Comparison: Testing Hierarchy for first interim analysis (52 weeks):~1. Non-inferiority in HbA1c change from baseline at 52 weeks,~2. Superiority in body weight change from baseline at 52 weeks,~3. Superiority in occurrence of confirmed hypoglycaemic adverse events at 52 weeks,~4. Superiority in systolic blood pressure change from baseline at 52 weeks,~5. Superiority in diastolic blood pressure change from baseline at 52 weeks.p-value: <0.000197.5% CI: [0.04, 0.148]Cochran-Mantel-Haenszel