Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial compare the use of two different doses of Empagliflozin to placebo, in T2DM patients on 16 wks linagliptin treatment and metformin background therapy.
Interventions
DRUGLinagliptin
tablet
Fixed dose combination.
DRUGEmpagliflozin placebo + Linagliptin placebo
Matching Empagliflozin + Linagliptin low dose
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. 2. Male and female patients on diet and exercise regimen, pre-treated with immediate release metformin for at least 12 weeks, and patients should be on a dose higher or equal to 1500 mg/day of metformin, or maximum tolerated dose, or maximum dose as per local label. 3. HbA1c higher or equal to 8.0% and lower or equal to 10.5% at screening visit. 4. Age 18 years or more at screening. 5. Body Mass Index lower or equal to 45 kg/m2 at screening visit. 6. Signed and dated written informed consent.
Exclusion criteria
1. Uncontrolled hyperglycemia with glucose level above 270 mg/dl (above 15 mmol/dl) after an overnight fast. 2. Use of any other antidiabetic drug (except metformin background therapy). 3. Acute coronary syndrome, stroke or TIA within 3 months prior to informed consent. 4. Indication of liver disease. 5. Impaired renal function. 6. Gastrointestinal surgery. 7. Treatment with anti-obesity drugs within 3 months prior to screening, or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight. 8. Current treatment with systemic steroids at time of informed consent or uncontrolled endocrine disorder except type 2 diabetes mellitus.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment | Baseline and 24 weeks | Change from baseline in Glycated haemoglobin (HbA1c) \[%\] after 24 weeks of treatment with double-blind trial medication. Baseline was defined as the last observation before the first intake of any double-blind randomised trial medication. The term 'baseline' was not used to refer to measurements before the administration of open-label medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Plasma Glucose (FPG) Change From Baseline After 24 Weeks of Double-blind Treatment. | Baseline and 24 weeks | Change from baseline FPG (mmol/L) after 24 weeks of treatment with double-blind trial medication. |
| Body Weight Change From Baseline After 24 Weeks of Double-blind Treatment | Baseline and 24 weeks | Change from baseline Body weight after 24 weeks of treatment with double-blind trial medication. |
Countries
Australia, Brazil, Canada, El Salvador, France, New Zealand, Norway, South Korea, Spain, Taiwan, United States
Participant flow
Pre-assignment details
16-week open-label (OL) lina 5 period followed by a 1-week OL period with additional placebo administration preceded randomisation to double-blind treatment. Patients were randomised to double blind treatment only when they had not met glycaemic control criteria after the 16-week OL period. All treatments were administered in addition to metformin.
Participants by arm
| Arm | Count |
|---|---|
| Empagliflozin 25 mg Patients received 1 FDC Empagliflozin (empa) 25/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period. | 110 |
| Empagliflozin 10 mg Patients received 1 FDC empa 10/lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to lina 5 and 1 matching placebo tablet to FDC empa 25/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period. | 112 |
| Placebo Patients received 1 lina 5 mg tablet and two placebo tablet (1 matching placebo tablet to FDC empa 25/lina 5 and 1 matching placebo tablet to FDC empa 10/lina 5), administered orally, once every day for 24 weeks during the double blind treatment period. | 110 |
| Total | 332 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Period | Adverse Event | 0 | 3 | 2 | 0 |
| Double-Blind Period | Lack of Efficacy | 0 | 1 | 0 | 0 |
| Double-Blind Period | Lost to Follow-up | 2 | 4 | 2 | 0 |
| Double-Blind Period | Not treated | 1 | 0 | 0 | 0 |
| Double-Blind Period | Protocol Violation | 0 | 1 | 1 | 0 |
| Double-Blind Period | Withdrawal by Subject | 2 | 0 | 0 | 0 |
| Open-Label Period | Adverse Event | 0 | 0 | 0 | 9 |
| Open-Label Period | Lack of Efficacy | 0 | 0 | 0 | 1 |
| Open-Label Period | Lost to Follow-up | 0 | 0 | 0 | 14 |
| Open-Label Period | Other Reasons | 0 | 0 | 0 | 224 |
| Open-Label Period | Protocol Violation | 0 | 0 | 0 | 13 |
| Open-Label Period | Withdrawal by Subject | 0 | 0 | 0 | 12 |
Baseline characteristics
| Characteristic | Empagliflozin 25 mg | Empagliflozin 10 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 55.4 Years STANDARD_DEVIATION 9.9 | 54.3 Years STANDARD_DEVIATION 9.5 | 55.9 Years STANDARD_DEVIATION 9.6 | 55.2 Years STANDARD_DEVIATION 9.7 |
| Sex: Female, Male Female | 39 Participants | 46 Participants | 49 Participants | 134 Participants |
| Sex: Female, Male Male | 71 Participants | 66 Participants | 61 Participants | 198 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 110 | 19 / 112 | 34 / 110 | 78 / 606 |
| serious Total, serious adverse events | 4 / 110 | 5 / 112 | 10 / 110 | 18 / 606 |
Outcome results
Primary
HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment
Change from baseline in Glycated haemoglobin (HbA1c) \[%\] after 24 weeks of treatment with double-blind trial medication. Baseline was defined as the last observation before the first intake of any double-blind randomised trial medication. The term 'baseline' was not used to refer to measurements before the administration of open-label medication.
Time frame: Baseline and 24 weeks
Population: The full analysis set (FAS) consisted of all patients in the treated set (TS) who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the double-blind part of the trial. Observed Case (OC): In the OC analysis, values after the use of rescue medication were set to missing.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 25 mg | HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment | -0.56 Percentage of HbA1c | Standard Error 0.08 |
| Empagliflozin 10 mg | HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment | -0.65 Percentage of HbA1c | Standard Error 0.08 |
| Placebo | HbA1c Change From Baseline After 24 Weeks Double-blind Randomized Treatment | 0.14 Percentage of HbA1c | Standard Error 0.09 |
Comparison: Superiority of Empagliflozin 25 mg vs. placebo: change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c as linear covariate(s) \& baseline Estimated glomerula filtration rate (eGFR), geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).p-value: <0.000195% CI: [-0.93, -0.46]Mixed Models Analysis
Comparison: Superiority of Empagliflozin 10 mg vs. placebo: change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline HbA1c as linear covariate(s) \& baseline Estimated glomerula filtration rate (eGFR), geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).p-value: <0.000195% CI: [-1.02, -0.55]Mixed Models Analysis
Secondary
Body Weight Change From Baseline After 24 Weeks of Double-blind Treatment
Change from baseline Body weight after 24 weeks of treatment with double-blind trial medication.
Time frame: Baseline and 24 weeks
Population: FAS (OC)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 25 mg | Body Weight Change From Baseline After 24 Weeks of Double-blind Treatment | -2.52 kg | Standard Error 0.25 |
| Empagliflozin 10 mg | Body Weight Change From Baseline After 24 Weeks of Double-blind Treatment | -3.06 kg | Standard Error 0.25 |
| Placebo | Body Weight Change From Baseline After 24 Weeks of Double-blind Treatment | -0.30 kg | Standard Error 0.26 |
Comparison: Superiority of Empagliflozin 25 mg vs. placebo: change in body weight using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline weight, baseline HbA1c as linear covariate(s) \& baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).p-value: <0.000195% CI: [-2.92, -1.52]Mixed Models Analysis
Comparison: Superiority of Empagliflozin 10 mg vs. placebo:change in body weight using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline weight, baseline HbA1c as linear covariate(s) \& baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).p-value: <0.000195% CI: [-3.47, -2.07]Mixed Models Analysis
Secondary
Fasting Plasma Glucose (FPG) Change From Baseline After 24 Weeks of Double-blind Treatment.
Change from baseline FPG (mmol/L) after 24 weeks of treatment with double-blind trial medication.
Time frame: Baseline and 24 weeks
Population: FAS (OC)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin 25 mg | Fasting Plasma Glucose (FPG) Change From Baseline After 24 Weeks of Double-blind Treatment. | -1.75 mmol/L | Standard Error 0.18 |
| Empagliflozin 10 mg | Fasting Plasma Glucose (FPG) Change From Baseline After 24 Weeks of Double-blind Treatment. | -1.46 mmol/L | Standard Error 0.18 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline After 24 Weeks of Double-blind Treatment. | 0.34 mmol/L | Standard Error 0.19 |
Comparison: Superiority of Empagliflozin 25 mg vs. placebo: change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline FPG, baseline HbA1c as linear covariate(s) \& baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).p-value: <0.000195% CI: [-2.61, -1.57]Mixed Models Analysis
Comparison: Superiority of Empagliflozin 10 mg vs. placebo: change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. Model includes baseline FPG, baseline HbA1c as linear covariate(s) \& baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effect(s).p-value: <0.000195% CI: [-2.31, -1.28]Mixed Models Analysis