Diabetes Mellitus, Type 2
Conditions
Brief summary
This study will investigate the efficacy and safety of BI 10773 in type 2 diabetic patients in order to provide these data for approval for BI 10773 by regulatory authorities as an antidiabetic agent as add-on therapy to pioglitazone alone or in combination with metformin.
Interventions
DRUGPlacebo
Placebo tablets matching BI 10773 low dose
DRUGBI 10773
BI 10773 tablets 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 pre-treated with pioglitazone alone or in combination with metformin. The treatment regimen should be unchanged for 12 weeks prior to randomisation. 3. HbA1c of \>/= 7.0% and \</= 10.0% at Visit 1 (screening). 4. Age \>/= 18. 5. BMI \</= 45 kg/m2 (Body Mass Index) at Visit 1 (screening). 6. Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation.
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. Any other antidiabetic medication within 12 weeks prior to randomisation, except those defined as the permitted background therapy via inclusion criteria no. 2. 3. Myocardial infarction, stroke or transient ischaemic attack (TIA) within 3 months prior to informed consent. 4. Indication of liver disease, defined by serum levels of either alanine transaminase (ALT/SGPT), aspartate transaminase (AST/SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during screening or during the placebo run-in period (i.e. at a visit prior to the randomisation visit, Visit 3). 5. Impaired renal function, defined as eGFR (estimated Glomerular Filtration Rate) \< 30 ml/min (severe renal impairment, MDRD \[Modification of Diet in Renal Disease\] formula) as determined during screening or during the placebo run-in period (i.e. at a visit prior to the randomisation visit, Visit 3). 6. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption. 7. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years . 8. Blood dyscrasias or any disorders causing haemolysis or unstable red blood cells (e.g. malaria, babesiosis, haemolytic anaemia). 9. Contraindications to pioglitazone according to the local label. 10. Contraindication to pioglitazone and/or metformin (relevant only for those patients who enter the study with both these background therapies) according to the local labels. 11. 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. 12. 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 T2D. 13. 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 trial 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 (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if acceptable to local authorities), double barrier method and vasectomised partner. 14. 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. 15. Participation in another trial with an investigational drug within 30 days prior to informed consent. 16. Any other clinical condition that would jeopardise patient safety while participating in this clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline | Baseline and 24 weeks | Change From Baseline in HbA1c after 24 weeks. Note that adjusted means are provided. |
| HbA1c Change From Baseline for Pio and Met Background Medication Patients | Baseline and 24 weeks | Change From Baseline in HbA1c after 24 weeks for patients with pioglitazone (pio) and metformin (met) background medication only. Note that adjusted means are provided. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Plasma Glucose (FPG) Change From Baseline | Baseline and 24 weeks | Change from baseline in fasting plasma glucose (FPG) after 24 weeks of treatment. Note that adjusted means are provided. |
| Body Weight Change From Baseline | Baseline and 24 weeks | Change from baseline in body weight after 24 weeks. Note that adjusted means are provided. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Hypoglycaemic Events | From first drug administration until 7 days after last intake of study drug, up to 256 days | Number of patients with hypoglycaemic events, as reported as adverse events. |
Countries
Canada, Greece, India, Philippines, Thailand, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo A placebo tablet, matching the empagliflozin 10mg and 25mg tablets, taken once daily for 24 weeks | 165 |
| Empa 10mg Single oral dose of empagliflozin (empa) 10mg taken once daily for 24 weeks | 165 |
| Empa 25mg Single oral dose of empagliflozin (empa) 25mg taken once daily for 24 weeks | 168 |
| Total | 498 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 | 5 |
| Overall Study | Lost to Follow-up | 4 | 3 | 2 |
| Overall Study | Non compliant with protocol | 2 | 2 | 3 |
| Overall Study | Not treated | 1 | 0 | 0 |
| Overall Study | Other reason not defined above | 2 | 2 | 1 |
| Overall Study | Patient refusal to continue,not due toAE | 6 | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | Empa 10mg | Empa 25mg | Total |
|---|---|---|---|---|
| Age, Continuous | 54.6 years STANDARD_DEVIATION 10.5 | 54.7 years STANDARD_DEVIATION 9.9 | 54.2 years STANDARD_DEVIATION 8.9 | 54.5 years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 92 Participants | 82 Participants | 83 Participants | 257 Participants |
| Sex: Female, Male Male | 73 Participants | 83 Participants | 85 Participants | 241 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 | 56 / 165 | 50 / 165 | 34 / 168 |
| serious Total, serious adverse events | 7 / 165 | 7 / 165 | 6 / 168 |
Outcome results
Primary
HbA1c Change From Baseline
Change From Baseline in HbA1c after 24 weeks. Note that adjusted means are provided.
Time frame: Baseline and 24 weeks
Population: Full analysis set (FAS) which included all randomised and treated patients who had a baseline HbA1c value. 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 |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline | -0.11 percentage of HbA1c | Standard Error 0.07 |
| Empa 10mg | HbA1c Change From Baseline | -0.59 percentage of HbA1c | Standard Error 0.07 |
| Empa 25mg | HbA1c Change From Baseline | -0.72 percentage of HbA1c | Standard Error 0.07 |
p-value: <0.000197.5% CI: [-0.69, -0.27]ANCOVA
p-value: <0.000197.5% CI: [-0.82, -0.4]ANCOVA
Primary
HbA1c Change From Baseline for Pio and Met Background Medication Patients
Change From Baseline in HbA1c after 24 weeks for patients with pioglitazone (pio) and metformin (met) background medication only. Note that adjusted means are provided.
Time frame: Baseline and 24 weeks
Population: Full analysis set (FAS) which included all randomised and treated patients who had a baseline HbA1c value for patients on pioglitazone and metformin background medication. 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 |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline for Pio and Met Background Medication Patients | -0.11 percentage of HbA1c | Standard Error 0.08 |
| Empa 10mg | HbA1c Change From Baseline for Pio and Met Background Medication Patients | -0.55 percentage of HbA1c | Standard Error 0.08 |
| Empa 25mg | HbA1c Change From Baseline for Pio and Met Background Medication Patients | -0.70 percentage of HbA1c | Standard Error 0.07 |
p-value: <0.000197.5% CI: [-0.69, -0.21]ANCOVA
p-value: <0.000197.5% CI: [-0.83, -0.36]ANCOVA
Secondary
Body Weight Change From Baseline
Change from baseline in body weight after 24 weeks. Note that adjusted means are provided.
Time frame: Baseline and 24 weeks
Population: Full analysis set (FAS) which included all randomised and treated patients who had a baseline HbA1c value. 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 |
|---|---|---|---|
| Placebo | Body Weight Change From Baseline | 0.34 kg | Standard Error 0.21 |
| Empa 10mg | Body Weight Change From Baseline | -1.62 kg | Standard Error 0.21 |
| Empa 25mg | Body Weight Change From Baseline | -1.47 kg | Standard Error 0.21 |
p-value: <0.000197.5% CI: [-2.64, -1.27]ANCOVA
p-value: <0.000197.5% CI: [-2.49, -1.13]ANCOVA
Secondary
Fasting Plasma Glucose (FPG) Change From Baseline
Change from baseline in fasting plasma glucose (FPG) after 24 weeks of treatment. Note that adjusted means are provided.
Time frame: Baseline and 24 weeks
Population: Full analysis set (FAS) which included all randomised and treated patients who had a baseline HbA1c value. 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 |
|---|---|---|---|
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline | 6.47 mg/dL | Standard Error 2.61 |
| Empa 10mg | Fasting Plasma Glucose (FPG) Change From Baseline | -17.00 mg/dL | Standard Error 2.63 |
| Empa 25mg | Fasting Plasma Glucose (FPG) Change From Baseline | -21.99 mg/dL | Standard Error 2.59 |
p-value: <0.000197.5% CI: [-31.81, -15.15]ANCOVA
p-value: <0.000197.5% CI: [-36.73, -20.19]ANCOVA
Other Pre-specified
Hypoglycaemic Events
Number of patients with hypoglycaemic events, as reported as adverse events.
Time frame: From first drug administration until 7 days after last intake of study drug, up to 256 days
Population: Treated set which included all patients treated with at least one dose of randomised study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Hypoglycaemic Events | 1.8 percentage of participants |
| Empa 10mg | Hypoglycaemic Events | 1.2 percentage of participants |
| Empa 25mg | Hypoglycaemic Events | 2.4 percentage of participants |