Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the study is to investigate the efficacy, safety and tolerability of linagliptin 5 mg qd compared to placebo given for 24 weeks in inadequately controlled T2DM patients on empagliflozin 10 mg or 25 mg and maximum tolerated dose of metformin. The primary objective of efficacy evaluation is planned after 24 weeks of treatment. The study is designed to show superiority of the combination of empagliflozin and linagliptin over empagliflozin alone.
Interventions
DRUGBI 10773
Empagliflozin active
DRUGBI 10773 Placebo
Empagliflozin placebo
DRUGBI 10773 / BI 1356
Empagliflozin / Linagliptin 25/5 mg Dose FDC active
DRUGBI 10773 / BI 1356 Placebo
Empagliflozin / Linagliptin 10/5 mg Dose placebo FDC
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. Signed and dated ICF (Informed Consent Form) 2. Male or female on diet and exercise regime and on stable background metformin \> or equal to 1500 mg or maximun dose according to local label 3. HBA1c (Glicoslated Hemoglobin) \> or equal to 8% and \< or equal to 10.5 % at Visit 1 4. HbA1c \> or equal to 7 and \< or equal to 10.5 at Visit 4 5. Age \> or equal to 18 years 6. BMI (Body Mass Index) \< or equal to 45
Exclusion criteria
1. Uncontrolled hyperglycemia during open label period and placebo add on run-in period 2. Use of any other antidiabetic 3. Renal function below 60 ml/min/1.73 m2 4. Antiobesity drugs or aggresive diets 5. Gastorintestinal surgeries 6. Current systemic steroids or uncontrolled endocrine disorders other than Diabetes Type 2 7. Acute coronary syndrome and stroke within 3 months of informed consent 8. Known allergies to DPP-IV (Dypeptidil Peptidase IV) or SGLT-2 (Sodium Glucose Transporter 2) inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of HbA1c After 24 Weeks of Treatment. | Baseline and 24 weeks | Change from baseline in Glycated haemoglobin (HbA1c) \[%\] after 24 weeks of treatment with double-blind trial medication, i.e. HbA1c change from baseline at Week 24. The term baseline was not used to refer to measurements prior to the administration of open-label medication. Such measurements were referred to as pre-treatment. Analyses of change from pre-treatment used the last value before first administration of open-label medication as point of reference. Observed Case (OC): This method analyse only available data that were observed while patients were on treatment, i.e., excluding the missing data. All values measured after rescue medication taken were set to missing. Full Analysis Set (FAS): Includes all patients in the Treated set who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the double-blind part of the trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Plasma Glucose (FPG) Change From Baseline at 24 Weeks. | Baseline and 24 weeks | Change from baseline FPG (mmol/L) after 24 weeks of treatment with double-blind trial medication, i.e. FPG change from baseline at Week 24. |
Countries
Argentina, Australia, Canada, El Salvador, Germany, Italy, Portugal, Russia, Spain, Ukraine, United States
Participant flow
Recruitment details
Subjects randomised to 16 week(wk) open-label (OL) treatment with either empagliflozin (empa) 25 or empa 10 treatment, thereafter subjects entered to 1 wk open label placebo (Plc) add-on period in order to complete further eligibility evaluations before being randomised into 1 of the 24 wk double-blind treatment groups.
Pre-assignment details
This was a randomised, double-blind, multi-national, parallel group trial. In this trial the treatment effects of linagliptin (lina) 5 compared with Plc were analysed as add-on to either empa 25 or empa 10. All trial treatments were administered in addition to metformin background treatment.
Participants by arm
| Arm | Count |
|---|---|
| Empa 10 mg OL Subjects were orally administered once daily empa 10 mg film-coated tablet for 16 wk during OL treatment period, thereafter patients received once daily fixed dose combination (FDC) placebo tablet matching to FDC empa 10 mg/lina 5 mg in addition to empa 10 mg for 1 week during open label placebo add-on treatment period. | 352 |
| Empa 25 mg OL Subjects were orally administered once daily empa 25 mg film-coated tablet for 16 week during OL treatment period, thereafter patients received once daily FDC Plc tablet matching to FDC empa 25 mg/lina 5 mg in addition to empa 25 mg for 1 wk during open label placebo add-on treatment period. | 354 |
| Total | 706 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Double Blind Treatment Period | Adverse Event | 0 | 0 | 4 | 5 | 3 | 2 |
| Double Blind Treatment Period | Lack of Efficacy | 0 | 0 | 0 | 0 | 0 | 1 |
| Double Blind Treatment Period | Lost to Follow-up | 0 | 0 | 4 | 1 | 5 | 2 |
| Double Blind Treatment Period | Not treated | 0 | 0 | 0 | 2 | 2 | 0 |
| Double Blind Treatment Period | Other reason not defined above | 0 | 0 | 4 | 2 | 2 | 1 |
| Double Blind Treatment Period | Protocol Violation | 0 | 0 | 2 | 0 | 0 | 0 |
| Double Blind Treatment Period | Withdrawal by Subject | 0 | 0 | 1 | 2 | 0 | 1 |
| Open Label Treatment Period | Adverse Event | 5 | 15 | 0 | 0 | 0 | 0 |
| Open Label Treatment Period | Lack of Efficacy | 1 | 1 | 0 | 0 | 0 | 0 |
| Open Label Treatment Period | Lost to Follow-up | 4 | 3 | 0 | 0 | 0 | 0 |
| Open Label Treatment Period | Not treated | 2 | 1 | 0 | 0 | 0 | 0 |
| Open Label Treatment Period | Other reason not defined above | 77 | 94 | 0 | 0 | 0 | 0 |
| Open Label Treatment Period | Protocol Violation | 5 | 5 | 0 | 0 | 0 | 0 |
| Open Label Treatment Period | Withdrawal by Subject | 4 | 10 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Empa 10 mg OL | Empa 25 mg OL | Total |
|---|---|---|---|
| Age, Continuous | 57.0 Years STANDARD_DEVIATION 9.6 | 56.7 Years STANDARD_DEVIATION 9.9 | 56.8 Years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 145 Participants | 161 Participants | 306 Participants |
| Sex: Female, Male Male | 207 Participants | 193 Participants | 400 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 47 / 352 | 38 / 354 | 22 / 126 | 10 / 128 | 18 / 112 | 21 / 112 |
| serious Total, serious adverse events | 12 / 352 | 12 / 354 | 4 / 126 | 5 / 128 | 3 / 112 | 4 / 112 |
Outcome results
Primary
Change From Baseline of HbA1c After 24 Weeks of Treatment.
Change from baseline in Glycated haemoglobin (HbA1c) \[%\] after 24 weeks of treatment with double-blind trial medication, i.e. HbA1c change from baseline at Week 24. The term baseline was not used to refer to measurements prior to the administration of open-label medication. Such measurements were referred to as pre-treatment. Analyses of change from pre-treatment used the last value before first administration of open-label medication as point of reference. Observed Case (OC): This method analyse only available data that were observed while patients were on treatment, i.e., excluding the missing data. All values measured after rescue medication taken were set to missing. Full Analysis Set (FAS): Includes all patients in the Treated set who had a baseline HbA1c assessment and at least 1 on-treatment HbA1c assessment during the double-blind part of the trial.
Time frame: Baseline and 24 weeks
Population: FAS (OC)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lina5 (E10) | Change From Baseline of HbA1c After 24 Weeks of Treatment. | -0.53 Percentage of HbA1c | Standard Error 0.07 |
| Plc (E10) | Change From Baseline of HbA1c After 24 Weeks of Treatment. | -0.21 Percentage of HbA1c | Standard Error 0.07 |
| Lina5 (E25) | Change From Baseline of HbA1c After 24 Weeks of Treatment. | -0.58 Percentage of HbA1c | Standard Error 0.07 |
| Plc (E25) | Change From Baseline of HbA1c After 24 Weeks of Treatment. | -0.10 Percentage of HbA1c | Standard Error 0.07 |
Comparison: Superiority of lina5 (E10) vs. Plc (E10): change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c as linear covariates \& baseline estimated glomerula filtration rate (eGFR), geographical region, treatment, visit, visit by treatment interaction as fixed effects.p-value: 0.001395% CI: [-0.52, -0.13]Mixed Model Repeated Measure (MMRM)
Comparison: Superiority of lina5 (E25) vs. Plc (E25): change in HbA1c using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c as linear covariates \& baseline eGFR, geographical region, treatment, visit, visit by treatment interaction as fixed effects.p-value: <0.000195% CI: [-0.66, -0.28]MMRM
Secondary
Fasting Plasma Glucose (FPG) Change From Baseline at 24 Weeks.
Change from baseline FPG (mmol/L) after 24 weeks of treatment with double-blind trial medication, i.e. FPG change from baseline at Week 24.
Time frame: Baseline and 24 weeks
Population: FAS (OC)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lina5 (E10) | Fasting Plasma Glucose (FPG) Change From Baseline at 24 Weeks. | -0.44 mmol/L | Standard Error 0.18 |
| Plc (E10) | Fasting Plasma Glucose (FPG) Change From Baseline at 24 Weeks. | 0.21 mmol/L | Standard Error 0.18 |
| Lina5 (E25) | Fasting Plasma Glucose (FPG) Change From Baseline at 24 Weeks. | -0.68 mmol/L | Standard Error 0.15 |
| Plc (E25) | Fasting Plasma Glucose (FPG) Change From Baseline at 24 Weeks. | -0.24 mmol/L | Standard Error 0.15 |
Comparison: Superiority of lina5 (E10) vs. Plc (E10): change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c \& baseline eGFR as linear covariates, geographical region, treatment, visit, visit by treatment interaction as fixed effects.p-value: 0.010395% CI: [-1.15, -0.16]MMRM
Comparison: Superiority of lina5 (E25) vs. Plc (E25): change in FPG using a restricted maximum likelihood (REML)- based mixed model repeated measures (MMRM) approach. The model includes baseline HbA1c \& baseline eGFR as linear covariates, geographical region, treatment, visit, visit by treatment interaction as fixed effects.p-value: 0.045295% CI: [-0.87, -0.01]MMRM