Diabetes Mellitus, Type 2
Conditions
Brief summary
The aim of the present study is to investigate the safety of BI 10773 treatment in patients with Type 2 Diabetes Mellitus and high cardiovascular risk.
Interventions
BI 10773 tablets once daily
DRUGPlacebo BI 10773 high dose
Placebo tablets identical to BI 10773
BI 10773 tablets once daily
DRUGPlacebo BI 10773 low dose
Placebo tablets identical to 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
1. Diagnosis of type 2 diabetes mellitus prior to informed consent 2. Male or female patients on diet and exercise regimen who are drug naive or pre treated with any background therapy. Antidiabetic therapy has to be unchanged for 12 weeks prior to randomization. 3. Glycosylated haemoglobin (HbA1c) of \>= 7.0% and \<=10% for patients on background therapy or HbA1c \>= 7.0% and \<= 9.0% for drug naive patients 4. Age \>= 18 years 5. Body Mass index \<= 45 at Visit 1 6. Signed and dated informed consent 7. High cardiovascular risk
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. Indication of liver disease, defined by serum levels of either alanine aminotransferase (ALT), aspartate aminotransferase ALT or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at screening and/or run in. 3. Planned cardiac surgery or angioplasty within 3 months 4. Impaired renal function, defined as Glomerular Filtration Rate \<30 ml/min (severe renal impairment, Modification of Diet in Renal Disease formula) during screening or run in. 5. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption 6. Blood dyscrasias or any disorders causing haemolysis or unstable Red Blood Cell (e.g. malaria, babesiosis, haemolytic anemia) 7. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years 8. Contraindications to background therapy according to the local label 9. 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 10. 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 type 2 diabetes mellitus 11. 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, oral, implantable or injectable contraceptives, sexual abstinence, double barrier method and vasectomised partner 12. 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 13. Participation in another trial with an investigational drug within 30 days prior to informed consent 14. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial 15. Acute coronary syndrome, stroke or TIA within 2 months prior to informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First Occurrence of Any of the Following Adjudicated Components of the Primary Composite Endpoint (3-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), and Non-fatal Stroke. | From randomisation to individual end of observation, up to 4.6 years | Time to the first occurrence of any of the following adjudicated components of the primary composite endpoint (3-point major adverse cardiovascular events (MACE)): cardiovascular (CV) death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), and non-fatal stroke. Percentage of patients with the event are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Silent MI | From randomisation to individual end of observation, up to 4.6 years | Silent MI; defined as presence in the ECG of: * Any Q-wave in leads V2-V3 ≥0.02 seconds or QS complex in leads V2 and V3 * Q-wave ≥0.03 seconds and ≥0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6; V4-V6; II, III, and aVF) * R-wave ≥0.04 seconds in V1-V2 and R/S ≥1 with a concordant positive T-wave in the absence of a conduction defect. It was also required that there had been no adjudicated and confirmed event of either acute MI, hospitalisation for unstable angina, coronary revascularisation procedures or stent thrombosis following randomisation up to and including the date of the specified ECG measurement. Percentage of patients with the event are presented. |
| Percentage of Participants With Heart Failure Requiring Hospitalisation (Adjudicated) | From randomisation to individual end of observation, up to 4.6 years | Heart failure requiring hospitalisation (adjudicated). Percentage of patients with the event are presented. |
| Percentage of Participants With the Composite of All Events Adjudicated (4-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), Non-fatal Stroke and Hospitalization for Unstable Angina Pectoris | From randomisation to individual end of observation, up to 4.6 years | The composite of all events adjudicated (4-point MACE): cardiovascular death (including fatal stroke and fatal myocardial infarction), non-fatal myocardial infarction (excluding silent MI), non-fatal stroke and hospitalization for unstable angina pectoris.This is a key secondary endpoint of the trial. Percentage of patients with the event are presented. |
| Percentage of Participants With New Onset Macroalbuminuria | From randomisation to individual end of observation, up to 4.6 years | New onset macroalbuminuria defined as UACR \>300 mg/g. Percentage of patients with the event are presented. |
| Percentage of Participants With the Composite Microvascular Outcome | From randomisation to individual end of observation, up to 4.6 years | Composite microvascular outcome defined as: * Initiation of retinal photocoagulation * Vitreous haemorrhage * Diabetes-related blindness, or * New or worsening nephropathy defined as: * New onset of macroalbuminuria; or * Doubling of serum creatinine level accompanied by an eGFR (based on modification of diet in renal disease (MDRD) formula) ≤45 mL/min/1.73m2; or * Initiation of continuous renal replacement therapy, or * Death due to renal disease. Percentage of patients with the event are presented. |
| Percentage of Participants With New Onset Albuminuria | From randomisation to individual end of observation, up to 4.6 years | New onset albuminuria defined as urine albumin / creatinine ratio (UACR) ≥30 mg/g. Percentage of patients with the event are presented. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Colombia, Croatia, Czechia, Denmark, Estonia, France, Georgia, Greece, Hong Kong, Hungary, India, Indonesia, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, New Zealand, Norway, Peru, Philippines, Poland, Portugal, Romania, Russia, Singapore, South Africa, South Korea, Spain, Sri Lanka, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Patients randomised to treatments in 1:1:1 ratio.
Pre-assignment details
Randomisation stratified by:BMI at randomisation(\<30/≥30 kg/m2),HbA1c at screening (\<8.5%/ ≥8.5%);geographical region(North America including Australia and New Zealand,Latin America,Europe,Africa,Asia);renal function at screening (normal:eGFR ≥90 mL/min, mild impairment:60 mL/min ≤ eGFR ≤89 mL/min, moderate impairment:30 mL/min ≤ eGFR≤59 mL/min).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Oral administration of Placebo matching empagliflozin 10 mg or 25 mg (1 tablet once daily) | 2,333 |
| Empagliflozin 10 mg Oral administration of Empagliflozin 10 mg (BI 10773) film coated tablets (1 tablet once daily) | 2,345 |
| Empagliflozin 25 mg Oral administration of Empagliflozin 25 mg (BI 10773) film coated tablets (1 tablet once daily) | 2,342 |
| Total | 7,020 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Discontinuation From Study (Treated Set) | Consent withdrawn: Final VS available | 23 | 35 | 25 |
| Discontinuation From Study (Treated Set) | Consent withdrawn:Final VS not available | 8 | 6 | 5 |
| Discontinuation From Study (Treated Set) | Lost to FU for 3PMACE:Final VS available | 7 | 6 | 5 |
| Discontinuation From Study (Treated Set) | Lost to FU for 3P-MACE:Final VS NA | 4 | 4 | 2 |
| Discontinuation From Study (Treated Set) | Site closure: Final VS available | 20 | 21 | 19 |
| Discontinuation From Study (Treated Set) | Site closure:Final VS not available (NA) | 5 | 9 | 7 |
| Discontinuation From Treatment | Adverse Event | 303 | 267 | 273 |
| Discontinuation From Treatment | Lack of Efficacy | 11 | 1 | 0 |
| Discontinuation From Treatment | Lost to Follow-up | 15 | 9 | 6 |
| Discontinuation From Treatment | Non compliant with protocol | 15 | 15 | 12 |
| Discontinuation From Treatment | Not treated | 4 | 2 | 2 |
| Discontinuation From Treatment | Other than those specified | 162 | 142 | 125 |
| Discontinuation From Treatment | Refusal to continue, not due to AE | 172 | 118 | 122 |
| Discontinuation From Treatment | Study drug stopped, reason missing | 5 | 3 | 4 |
Baseline characteristics
| Characteristic | Placebo | Empagliflozin 10 mg | Empagliflozin 25 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 8.8 | 63.0 years STANDARD_DEVIATION 8.6 | 63.2 years STANDARD_DEVIATION 8.6 | 63.1 years STANDARD_DEVIATION 8.6 |
| Sex: Female, Male Female | 653 Participants | 692 Participants | 659 Participants | 2004 Participants |
| Sex: Female, Male Male | 1680 Participants | 1653 Participants | 1683 Participants | 5016 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1,690 / 2,333 | 1,556 / 2,345 | 1,551 / 2,342 |
| serious Total, serious adverse events | 988 / 2,333 | 876 / 2,345 | 913 / 2,342 |
Outcome results
Primary
Time to the First Occurrence of Any of the Following Adjudicated Components of the Primary Composite Endpoint (3-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), and Non-fatal Stroke.
Time to the first occurrence of any of the following adjudicated components of the primary composite endpoint (3-point major adverse cardiovascular events (MACE)): cardiovascular (CV) death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), and non-fatal stroke. Percentage of patients with the event are presented.
Time frame: From randomisation to individual end of observation, up to 4.6 years
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to the First Occurrence of Any of the Following Adjudicated Components of the Primary Composite Endpoint (3-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), and Non-fatal Stroke. | 12.1 percentage of participants |
| Empagliflozin 10 mg | Time to the First Occurrence of Any of the Following Adjudicated Components of the Primary Composite Endpoint (3-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), and Non-fatal Stroke. | 10.4 percentage of participants |
| Empagliflozin 25 mg | Time to the First Occurrence of Any of the Following Adjudicated Components of the Primary Composite Endpoint (3-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), and Non-fatal Stroke. | 10.5 percentage of participants |
| All Empagliflozin | Time to the First Occurrence of Any of the Following Adjudicated Components of the Primary Composite Endpoint (3-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), and Non-fatal Stroke. | 10.5 percentage of participants |
Comparison: Primary objective was to establish the non-inferiority of All empagliflozin relative to placebo for time to first 3-point MACE. A 4-step hierarchical testing strategy was followed for the non-inferiority test of the primary endpoint and then the key secondary endpoint, each at a margin of 1.3, followed by test of superiority of primary and key secondary endpoints.p-value: <0.000195.02% CI: [0.74, 0.99]Cox proportional hazards model
p-value: 0.038295.02% CI: [0.74, 0.99]Cox proportional hazards model
Secondary
Percentage of Participants With Heart Failure Requiring Hospitalisation (Adjudicated)
Heart failure requiring hospitalisation (adjudicated). Percentage of patients with the event are presented.
Time frame: From randomisation to individual end of observation, up to 4.6 years
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Heart Failure Requiring Hospitalisation (Adjudicated) | 4.1 percentage of participants |
| Empagliflozin 10 mg | Percentage of Participants With Heart Failure Requiring Hospitalisation (Adjudicated) | 2.6 percentage of participants |
| Empagliflozin 25 mg | Percentage of Participants With Heart Failure Requiring Hospitalisation (Adjudicated) | 2.8 percentage of participants |
| All Empagliflozin | Percentage of Participants With Heart Failure Requiring Hospitalisation (Adjudicated) | 2.7 percentage of participants |
p-value: 0.001795% CI: [0.5, 0.85]Cox proportional hazards model
Secondary
Percentage of Participants With New Onset Albuminuria
New onset albuminuria defined as urine albumin / creatinine ratio (UACR) ≥30 mg/g. Percentage of patients with the event are presented.
Time frame: From randomisation to individual end of observation, up to 4.6 years
Population: TS (evaluable cases)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With New Onset Albuminuria | 51.2 percentage of participants |
| Empagliflozin 10 mg | Percentage of Participants With New Onset Albuminuria | 51.5 percentage of participants |
| Empagliflozin 25 mg | Percentage of Participants With New Onset Albuminuria | 51.5 percentage of participants |
| All Empagliflozin | Percentage of Participants With New Onset Albuminuria | 51.5 percentage of participants |
p-value: 0.254795% CI: [0.87, 1.04]Cox proportional hazards model
Secondary
Percentage of Participants With New Onset Macroalbuminuria
New onset macroalbuminuria defined as UACR \>300 mg/g. Percentage of patients with the event are presented.
Time frame: From randomisation to individual end of observation, up to 4.6 years
Population: TS (evaluable cases)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With New Onset Macroalbuminuria | 16.2 percentage of participants |
| Empagliflozin 10 mg | Percentage of Participants With New Onset Macroalbuminuria | 10.9 percentage of participants |
| Empagliflozin 25 mg | Percentage of Participants With New Onset Macroalbuminuria | 11.5 percentage of participants |
| All Empagliflozin | Percentage of Participants With New Onset Macroalbuminuria | 11.2 percentage of participants |
p-value: <0.000195% CI: [0.54, 0.72]Cox proportional hazards model
Secondary
Percentage of Participants With Silent MI
Silent MI; defined as presence in the ECG of: * Any Q-wave in leads V2-V3 ≥0.02 seconds or QS complex in leads V2 and V3 * Q-wave ≥0.03 seconds and ≥0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6; V4-V6; II, III, and aVF) * R-wave ≥0.04 seconds in V1-V2 and R/S ≥1 with a concordant positive T-wave in the absence of a conduction defect. It was also required that there had been no adjudicated and confirmed event of either acute MI, hospitalisation for unstable angina, coronary revascularisation procedures or stent thrombosis following randomisation up to and including the date of the specified ECG measurement. Percentage of patients with the event are presented.
Time frame: From randomisation to individual end of observation, up to 4.6 years
Population: TS (evaluable cases)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Silent MI | 1.2 percentage of participants |
| Empagliflozin 10 mg | Percentage of Participants With Silent MI | 1.6 percentage of participants |
| Empagliflozin 25 mg | Percentage of Participants With Silent MI | 1.6 percentage of participants |
| All Empagliflozin | Percentage of Participants With Silent MI | 1.6 percentage of participants |
p-value: 0.417295% CI: [0.7, 2.33]Cox proportional hazards model
Secondary
Percentage of Participants With the Composite Microvascular Outcome
Composite microvascular outcome defined as: * Initiation of retinal photocoagulation * Vitreous haemorrhage * Diabetes-related blindness, or * New or worsening nephropathy defined as: * New onset of macroalbuminuria; or * Doubling of serum creatinine level accompanied by an eGFR (based on modification of diet in renal disease (MDRD) formula) ≤45 mL/min/1.73m2; or * Initiation of continuous renal replacement therapy, or * Death due to renal disease. Percentage of patients with the event are presented.
Time frame: From randomisation to individual end of observation, up to 4.6 years
Population: TS (evaluable cases)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With the Composite Microvascular Outcome | 20.5 percentage of participants |
| Empagliflozin 10 mg | Percentage of Participants With the Composite Microvascular Outcome | 13.9 percentage of participants |
| Empagliflozin 25 mg | Percentage of Participants With the Composite Microvascular Outcome | 14.1 percentage of participants |
| All Empagliflozin | Percentage of Participants With the Composite Microvascular Outcome | 14.0 percentage of participants |
p-value: <0.000195% CI: [0.54, 0.7]Cox proportional hazards model
Secondary
Percentage of Participants With the Composite of All Events Adjudicated (4-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), Non-fatal Stroke and Hospitalization for Unstable Angina Pectoris
The composite of all events adjudicated (4-point MACE): cardiovascular death (including fatal stroke and fatal myocardial infarction), non-fatal myocardial infarction (excluding silent MI), non-fatal stroke and hospitalization for unstable angina pectoris.This is a key secondary endpoint of the trial. Percentage of patients with the event are presented.
Time frame: From randomisation to individual end of observation, up to 4.6 years
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With the Composite of All Events Adjudicated (4-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), Non-fatal Stroke and Hospitalization for Unstable Angina Pectoris | 14.3 percentage of participants |
| Empagliflozin 10 mg | Percentage of Participants With the Composite of All Events Adjudicated (4-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), Non-fatal Stroke and Hospitalization for Unstable Angina Pectoris | 12.8 percentage of participants |
| Empagliflozin 25 mg | Percentage of Participants With the Composite of All Events Adjudicated (4-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), Non-fatal Stroke and Hospitalization for Unstable Angina Pectoris | 12.8 percentage of participants |
| All Empagliflozin | Percentage of Participants With the Composite of All Events Adjudicated (4-point MACE): CV Death (Including Fatal Stroke and Fatal MI), Non-fatal MI (Excluding Silent MI), Non-fatal Stroke and Hospitalization for Unstable Angina Pectoris | 12.8 percentage of participants |
Comparison: A 4-step hierarchical testing strategy was followed for the non-inferiority test of the primary endpoint and then the key secondary endpoint, each at a margin of 1.3, followed by test of superiority of primary and key secondary endpoints.p-value: <0.000195.02% CI: [0.78, 1.01]Cox proportional hazards model
Comparison: A 4-step hierarchical testing strategy was followed for the non-inferiority test of the primary endpoint and then the key secondary endpoint, each at a margin of 1.3, followed by test of superiority of primary and key secondary endpoints.p-value: 0.079595.02% CI: [0.78, 1.01]Cox proportional hazards model