Diabetes Mellitus, Type 2
Conditions
Brief summary
The aim of this study is to investigate the efficacy, safety and tolerability of BI 10773 compared to placebo and sitagliptin given for 24 weeks as monotherapy in patients with T2DM with insufficient glycaemic control. For the open-label part of the study the objective is to estimate the efficacy and safety of BI 10773 when given for 24 weeks in patients with T2DM with very poor glycaemic control.
Interventions
DRUGPlacebo identical to BI10773 high dose
placebo tablets once daily
DRUGBI 10773
BI 10773 low dose tablet once daily
DRUGBI 10773 open label
Patients receive BI 10773 high dose tablets open label once daily
DRUGPlacebo identical to BI10773 low dose
placebo tablets once daily
DRUGPlacebo identical to Sitagliptin 100mg
placebo tablets once daily
DRUGBI10773
BI 10773 high dose tablets once daily
DRUGSitagliptin
Sitagliptin tablets 100 mg once 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-naïve; 3. HbA1c \>= 7.0% and \<= 10.0% at Visit 1 (screening) for randomised treatment; HbA1c \> 10.0% at visit 1 (screening) for the open-label BI 10773 arm; 4. Age \>= 20 (Japan); Age \>= 18 (countries other than Japan); 5. BMI \<= 45 kg/m2 at Visit 1 (screening); 6. Signed and dated written informed consent by date of Visit 1
Exclusion criteria
1. Uncontrolled hyperglycaemia; 2. Acute coronary syndrome (non-STEMI, STEMI and unstable angina pectoris), stroke or TIA within 3 months prior to informed consent; 3. Indication of liver disease, either ALT, AST, or alkaline phosphatase above 3 x ULN; 4. Impaired renal function (eGFR\<50 ml/min); 5. Bariatric surgery within the past two years or other GI surgeries; 6. Medical history of cancer; 7. Contraindications to sitagliptin; 8. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cell; 9. Treatment with any anti-diabetes drug within 12 weeks prior to randomisation; 10. Treatment with anti-obesity drugs or any other treatment leading to unstable body weight; 11. Current treatment with systemic steroids or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except T2DM; 12. Pre-menopausal women who are nursing or pregnant or are of child-bearing potential and not practicing an acceptable method of birth control; 13. Alcohol or drug abuse; 14. Intake of an investigational drug in another trial within 30 days prior to intake of study medication in this trial; 15. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 24 Weeks | Baseline and day 169 | The term baseline refers to the last observation before the start of randomised trial treatment (or of open-label treatment for the open-label arm). In this endpoint, the measured values show unadjusted values, whereas the statistical analyses show adjusted values. Statistics for open-label group are descriptive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 in Body Weight | Baseline and day 169 | The term baseline refers to the last observation before the start of randomised trial treatment (or of open-label treatment for the open-label arm). In this endpoint, the measured values show unadjusted values, whereas the statistical analyses show adjusted values. Statistics for open-label group are descriptive. |
| Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Baseline and week 24 | The term baseline refers to the last observation before the start of randomised trial treatment (or of open-label treatment for the open-label arm). In this endpoint, the measured values show unadjusted values, whereas the statistical analyses show adjusted values. Statistics for open-label group are descriptive. For blood pressure, data following changes in antihypertensive therapy is censored, in the same way that data following initiation of rescue medication is censored. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Hypoglycaemic Adverse Events | From first drug intake until 7 days after last medication intake, up to 219 days | Confirmed hypoglycaemic events refer to all hypoglycaemic events, that had a glucose value \<= 70 ml/dL or where assistance was required. Symptomatic hypoglycaemic events were to be reported as adverse events. Patients can be counted in more than one category. |
Countries
Belgium, Canada, China, Germany, India, Ireland, Japan, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients receive tablets identical to those containing 10 mg and 25 mg Empagliflozin and to Sitagliptin 100 mg once daily in the morning. | 228 |
| Empagliflozin10 mg Patients receive 10 mg Empagliflozin in tablets once daily in the morning. | 224 |
| Empagliflozin 25 mg Patients receive 25 mg Empagliflozin in tablets once daily in the morning. | 224 |
| Sitagliptin 100 Patients receive 100 mg Sitagliptin in tablets once daily in the morning. | 223 |
| Empagliflozin 25 mg OL Patients receive 25 mg Empagliflozin in tablets open label once daily in the morning. | 87 |
| Total | 986 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 2 | 4 | 6 | 3 |
| Overall Study | Lack of Efficacy | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 12 | 5 | 6 | 3 | 0 |
| Overall Study | Other reason not defined above | 5 | 2 | 2 | 3 | 2 |
| Overall Study | Protocol Violation | 3 | 2 | 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 12 | 7 | 6 | 5 | 3 |
Baseline characteristics
| Characteristic | Placebo | Empagliflozin10 mg | Empagliflozin 25 mg | Sitagliptin 100 | Empagliflozin 25 mg OL | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 54.9 years STANDARD_DEVIATION 10.9 | 56.2 years STANDARD_DEVIATION 11.6 | 53.8 years STANDARD_DEVIATION 11.6 | 55.1 years STANDARD_DEVIATION 9.9 | 50.2 years STANDARD_DEVIATION 11.3 | 55.0 years STANDARD_DEVIATION 11 |
| Sex: Female, Male Female | 105 Participants | 82 Participants | 79 Participants | 82 Participants | 23 Participants | 371 Participants |
| Sex: Female, Male Male | 123 Participants | 142 Participants | 145 Participants | 141 Participants | 64 Participants | 615 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 | 63 / 229 | 45 / 224 | 36 / 223 | 44 / 223 | 27 / 87 |
| serious Total, serious adverse events | 6 / 229 | 8 / 224 | 5 / 223 | 6 / 223 | 3 / 87 |
Outcome results
Primary
Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 24 Weeks
The term baseline refers to the last observation before the start of randomised trial treatment (or of open-label treatment for the open-label arm). In this endpoint, the measured values show unadjusted values, whereas the statistical analyses show adjusted values. Statistics for open-label group are descriptive.
Time frame: Baseline and day 169
Population: FAS and open-label set, last observation carried forward (LOCF) was used as the imputation rule for both sets
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 24 Weeks | 0.06 percent of HbA1c | Standard Error 0.05 |
| Empagliflozin10 mg | Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 24 Weeks | -0.66 percent of HbA1c | Standard Error 0.06 |
| Empagliflozin 25 mg | Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 24 Weeks | -0.77 percent of HbA1c | Standard Error 0.06 |
| Sitagliptin 100 mg | Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 24 Weeks | -0.65 percent of HbA1c | Standard Error 0.05 |
| Empagliflozin 25 mg OL | Change From Baseline in Glycosylated Haemoglobin (HbA1c) After 24 Weeks | -3.10 percent of HbA1c | Standard Error 0.22 |
Comparison: Model was adjusted for treatment,geographical region, and renal function at baseline as fixed effects, and baseline HbA1c as linear covariatep-value: <0.000197.5% CI: [-0.9, -0.57]ANCOVA
Comparison: Model was adjusted for treatment,geographical region, and renal function at baseline as fixed effects, and baseline HbA1c as linear covariatep-value: <0.000197.5% CI: [-1.01, -0.69]ANCOVA
Secondary
Change From Baseline to Week 24 in Body Weight
The term baseline refers to the last observation before the start of randomised trial treatment (or of open-label treatment for the open-label arm). In this endpoint, the measured values show unadjusted values, whereas the statistical analyses show adjusted values. Statistics for open-label group are descriptive.
Time frame: Baseline and day 169
Population: FAS (LOCF) and open-label set (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 24 in Body Weight | -0.33 kg | Standard Error 0.15 |
| Empagliflozin10 mg | Change From Baseline to Week 24 in Body Weight | -2.26 kg | Standard Error 0.19 |
| Empagliflozin 25 mg | Change From Baseline to Week 24 in Body Weight | -2.48 kg | Standard Error 0.18 |
| Sitagliptin 100 mg | Change From Baseline to Week 24 in Body Weight | 0.17 kg | Standard Error 0.18 |
| Empagliflozin 25 mg OL | Change From Baseline to Week 24 in Body Weight | -1.93 kg | Standard Error 0.44 |
Comparison: Model was adjusted for treatment,geographical region,and renal function at baseline as fixed effects,baseline body weight and baseline HbA1c as linear covariatep-value: <0.000197.5% CI: [-2.48, -1.38]ANCOVA
Comparison: Model was adjusted for treatment,geographical region,and renal function at baseline as fixed effects,baseline body weight and baseline HbA1c as linear covariatep-value: <0.000195% CI: [-2.7, -1.6]ANCOVA
Secondary
Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP)
The term baseline refers to the last observation before the start of randomised trial treatment (or of open-label treatment for the open-label arm). In this endpoint, the measured values show unadjusted values, whereas the statistical analyses show adjusted values. Statistics for open-label group are descriptive. For blood pressure, data following changes in antihypertensive therapy is censored, in the same way that data following initiation of rescue medication is censored.
Time frame: Baseline and week 24
Population: FAS and open-label set, last observation carried forward without values following a change in antihypertensive therapy (LOCF- H) was used as the imputation rule
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Diastolic blood pressure | -0.4 mmHg | Standard Error 0.5 |
| Placebo | Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Systolic blood pressure | 0.0 mmHg | Standard Error 0.8 |
| Empagliflozin10 mg | Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Systolic blood pressure | -3.5 mmHg | Standard Error 1 |
| Empagliflozin10 mg | Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Diastolic blood pressure | -1.1 mmHg | Standard Error 0.6 |
| Empagliflozin 25 mg | Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Systolic blood pressure | -3.2 mmHg | Standard Error 0.9 |
| Empagliflozin 25 mg | Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Diastolic blood pressure | -1.7 mmHg | Standard Error 0.5 |
| Sitagliptin 100 mg | Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Diastolic blood pressure | 0.4 mmHg | Standard Error 0.5 |
| Sitagliptin 100 mg | Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Systolic blood pressure | 0.2 mmHg | Standard Error 0.9 |
| Empagliflozin 25 mg OL | Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Systolic blood pressure | -3.8 mmHg | Standard Error 1.2 |
| Empagliflozin 25 mg OL | Change From Baseline to Week 24 in Systolic and Diastolic Blood Pressure (SBP and DBP) | Diastolic blood pressure | -1.5 mmHg | Standard Error 0.8 |
Comparison: Comparison for Systolic Blood Pressure~Model was adjusted for treatment,geographical region, and renal function at baseline as fixed effects, baseline SBP and baseline HbA1c as linear covariatep-value: 0.023197.5% CI: [-5.2, 0]ANCOVA
Comparison: Comparison for Systolic blood pressure~Model was adjusted for treatment,geographical region, and renal function at baseline as fixed effects, baseline SBP and baseline HbA1c as linear covariatep-value: 0.002897.5% CI: [-6, -0.9]ANCOVA
Comparison: Comparison for diastolic blood pressure~Model was adjusted for treatment,geographical region, and renal function at baseline as fixed effects, baseline DBP and baseline HbA1c as linear covariatep-value: 0.398797.5% CI: [-2.1, 0.9]ANCOVA
Comparison: Comparison for diastolic blood pressure~Model was adjusted for treatment,geographical region, and renal function at baseline as fixed effects, baseline DBP and baseline HbA1c as linear covariatep-value: 0.029697.5% CI: [-3, 0]ANCOVA
Other Pre-specified
Confirmed Hypoglycaemic Adverse Events
Confirmed hypoglycaemic events refer to all hypoglycaemic events, that had a glucose value \<= 70 ml/dL or where assistance was required. Symptomatic hypoglycaemic events were to be reported as adverse events. Patients can be counted in more than one category.
Time frame: From first drug intake until 7 days after last medication intake, up to 219 days
Population: Treated set (actual) including all patients treated with at least 1 dose of randomised trial medication with some treatment switchers (1 from Empa25 to placebo; 1 patient got Empa 10 at least with one mis-allocated kit) and open-label set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Confirmed Hypoglycaemic Adverse Events | Asymptomatic hypoglycaemic adverse events | 0 percentage of participants |
| Placebo | Confirmed Hypoglycaemic Adverse Events | Symptomatic hypoglycaemic adverse events | 0.4 percentage of participants |
| Empagliflozin10 mg | Confirmed Hypoglycaemic Adverse Events | Symptomatic hypoglycaemic adverse events | 0.4 percentage of participants |
| Empagliflozin10 mg | Confirmed Hypoglycaemic Adverse Events | Asymptomatic hypoglycaemic adverse events | 0 percentage of participants |
| Empagliflozin 25 mg | Confirmed Hypoglycaemic Adverse Events | Asymptomatic hypoglycaemic adverse events | 0 percentage of participants |
| Empagliflozin 25 mg | Confirmed Hypoglycaemic Adverse Events | Symptomatic hypoglycaemic adverse events | 0.4 percentage of participants |
| Sitagliptin 100 mg | Confirmed Hypoglycaemic Adverse Events | Symptomatic hypoglycaemic adverse events | 0.4 percentage of participants |
| Sitagliptin 100 mg | Confirmed Hypoglycaemic Adverse Events | Asymptomatic hypoglycaemic adverse events | 0 percentage of participants |
| Empagliflozin 25 mg OL | Confirmed Hypoglycaemic Adverse Events | Symptomatic hypoglycaemic adverse events | 0 percentage of participants |
| Empagliflozin 25 mg OL | Confirmed Hypoglycaemic Adverse Events | Asymptomatic hypoglycaemic adverse events | 0 percentage of participants |