Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the study is to test the efficacy, safety and tolerability of several doses of BI 1356 BS (1, 5, or 10 mg taken once daily) compared to placebo given for 12 weeks together with metformin in patients with type 2 diabetes mellitus who are not at goal with their HbA1c levels. In addition, there will be an unblinded treatment arm with glimepiride as add-on therapy to metformin for comparison. The influence of several factors (gender, age, weight, race, etc.) on the bioavailability and efficacy of BI 1356 BS will also be tested in this study.
Interventions
DRUGLinagliptin
Linagliptin medium dose tablet once daily
DRUGPlacebo
Placebo tablets once daily
DRUGGlimepiride
Glimepiride tablets once daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Inclusion\_Criteria: * Male and female patients with a diagnosis of type 2 diabetes mellitus and previo usly treated with metformin alone or with metformin and one other oral antidiabetic d rug * HbA1c 7.0 9.0% at screening for patients treated with metformin and one other oral antidiabetic drug * HbA1c 7.5 10.0% at screening for patients treated with metformin alone * HbA1c 7.5 10.0% at beginning of the placebo run-in phase * Age \> 21 and \< 75 years * MI \> 25 and \< 40 kg/m2 (Body Mass Index)
Exclusion criteria
Exclusion\_Criteria: * Clinically relevant cardiovascular disease * Impaired hepatic function * Renal insufficiency or impaired renal function * Treatment with rosiglitazone or pioglitazone within 6 months prior to screening * Treatment with insulin within 3 months prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline at Week 12 | Baseline and week 12 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 12 HbA1c percent minus the HbA1c percent baseline value. Means are treatment adjusted for baseline HbA1c. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With HbA1c<=7.0% at Week 12 | week 12 | Descriptive calculation of Patients with HbA1c \<= 7.0% at Week 12. |
| Fasting Blood Plasma Glucose Level (FPG) Change From Baseline at Week 12 | Baseline and week 12 | This change from baseline reflects the Week 12 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. |
Countries
France, Germany, Slovakia, Sweden, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients randomized to receive treatment with matching placebo | 71 |
| Linagliptin 1 mg Patients randomized to receive treatment with Linagliptin 1 mg | 65 |
| Linagliptin 5 mg Patients randomized to receive treatment with Linagliptin 5 mg | 66 |
| Linagliptin 10 mg Patients randomized to receive treatment with Linagliptin 10 mg | 66 |
| Glimepiride Patients randomized to receive treatment with Glimepiride | 65 |
| Total | 333 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 5 | 3 | 2 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 | 0 | 1 |
| Overall Study | Other incl. Lack of efficacy | 10 | 4 | 3 | 4 | 0 |
| Overall Study | Protocol Violation | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 4 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Linagliptin 1 mg | Linagliptin 5 mg | Linagliptin 10 mg | Glimepiride | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 60.1 Years STANDARD_DEVIATION 8.1 | 59.2 Years STANDARD_DEVIATION 8.4 | 59.6 Years STANDARD_DEVIATION 9.8 | 61.8 Years STANDARD_DEVIATION 8.8 | 59.4 Years STANDARD_DEVIATION 9.9 | 60.0 Years STANDARD_DEVIATION 9 |
| Body Mass Index (BMI) continuous | 32.2 kg/m^2 STANDARD_DEVIATION 4.2 | 32.3 kg/m^2 STANDARD_DEVIATION 4.3 | 31.7 kg/m^2 STANDARD_DEVIATION 4.5 | 31.7 kg/m^2 STANDARD_DEVIATION 4.5 | 31.5 kg/m^2 STANDARD_DEVIATION 4.2 | 31.9 kg/m^2 STANDARD_DEVIATION 4.3 |
| Fasting plasma glucose (FPG) continuous | 185.5 mg/dL STANDARD_DEVIATION 38.8 | 182.3 mg/dL STANDARD_DEVIATION 42 | 189.3 mg/dL STANDARD_DEVIATION 42.4 | 188.7 mg/dL STANDARD_DEVIATION 42.4 | 179.9 mg/dL STANDARD_DEVIATION 40.4 | 185.1 mg/dL STANDARD_DEVIATION 41 |
| Glycosylated Hemoglobin A1 (HbA1C) continuous | 8.37 Percent STANDARD_DEVIATION 0.74 | 8.24 Percent STANDARD_DEVIATION 0.74 | 8.46 Percent STANDARD_DEVIATION 0.85 | 8.35 Percent STANDARD_DEVIATION 0.73 | 8.22 Percent STANDARD_DEVIATION 0.7 | 8.33 Percent STANDARD_DEVIATION 0.75 |
| Sex: Female, Male Female | 27 Participants | 29 Participants | 29 Participants | 31 Participants | 24 Participants | 140 Participants |
| Sex: Female, Male Male | 44 Participants | 36 Participants | 37 Participants | 35 Participants | 41 Participants | 193 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 | 10 / 71 | 4 / 65 | 8 / 66 | 8 / 66 | 4 / 65 |
| serious Total, serious adverse events | 1 / 71 | 3 / 65 | 1 / 66 | 4 / 66 | 1 / 65 |
Outcome results
Primary
HbA1c Change From Baseline at Week 12
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 12 HbA1c percent minus the HbA1c percent baseline value. Means are treatment adjusted for baseline HbA1c.
Time frame: Baseline and week 12
Population: The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment HbA1c measurement available. Last observation carried forward (LOCF) was used as the imputation rule.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 12 | 0.25 Percent | Standard Error 0.1 |
| Linagliptin 1 mg | HbA1c Change From Baseline at Week 12 | -0.15 Percent | Standard Error 0.1 |
| Linagliptin 5 mg | HbA1c Change From Baseline at Week 12 | -0.48 Percent | Standard Error 0.11 |
| Linagliptin 10 mg | HbA1c Change From Baseline at Week 12 | -0.42 Percent | Standard Error 0.1 |
| Glimepiride | HbA1c Change From Baseline at Week 12 | -0.59 Percent | Standard Error 0.1 |
Comparison: Linagliptin 10 mg vs. Placebo~Missing endpoints after 12 weeks of treatment were replaced using Last Observation Carried Forward (LOCF)p-value: <0.000195% CI: [-0.95, -0.39]Pairwise comparison based on ANCOVA
Comparison: Linagliptin 5 mg vs. Placebo~missing endpoints after 12 weeks of treatment were replaced using Last Observation Carried Forward (LOCF)p-value: <0.000195% CI: [-1.01, -0.44]Pairwise comparison based on ANCOVA
Comparison: Linagliptin 1 mg vs. Placebo~Missing endpoints after 12 weeks of treatment were replaced using Last Observation Carried Forward (LOCF)p-value: 0.005595% CI: [-0.68, -0.12]Pairwise comparison based on ANCOVA
Comparison: Placebo vs. Linagliptin 10 mg~Analysis additionally adjusted for previous anti-diabetic medication.~Missing endpoints after 12 weeks of treatment were replaced using Last Observation Carried Forward (LOCF).p-value: <0.000195% CI: [-0.99, -0.46]Pairwise comparison based on ANCOVA
Comparison: Linagliptin 5 mg vs. Placebo~Analysis additionally adjusted for previous anti-diabetic medication.~Missing endpoints after 12 weeks of treatment were replaced using last observation carried forward (LOCF).p-value: <0.000195% CI: [-1.02, -0.48]Pairwise comparison based on ANCOVA
Comparison: Linagliptin 1 mg vs. Placebo~Analysis additionally adjusted for previous anti-diabetic medication.~Missing endpoints after 12 weeks of treatment were replaced using last observation carried forward (LOCF).p-value: 0.004995% CI: [-0.66, -0.12]Pairwise comparison based on ANCOVA
Secondary
Fasting Blood Plasma Glucose Level (FPG) Change From Baseline at Week 12
This change from baseline reflects the Week 12 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and week 12
Population: This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Fasting Blood Plasma Glucose Level (FPG) Change From Baseline at Week 12 | 13.63 mg/dL | Standard Error 4.3 |
| Linagliptin 1 mg | Fasting Blood Plasma Glucose Level (FPG) Change From Baseline at Week 12 | -5.32 mg/dL | Standard Error 4.51 |
| Linagliptin 5 mg | Fasting Blood Plasma Glucose Level (FPG) Change From Baseline at Week 12 | -21.29 mg/dL | Standard Error 4.48 |
| Linagliptin 10 mg | Fasting Blood Plasma Glucose Level (FPG) Change From Baseline at Week 12 | -15.87 mg/dL | Standard Error 4.33 |
Comparison: Linagliptin 10mg vs. Placebop-value: <0.000195% CI: [-41.4, -17.5]Pairwise comparison based on ANCOVA
Comparison: Linagliptin 5mg vs. Placebop-value: <0.000195% CI: [-47, -22.8]Pairwise comparison based on ANCOVA
Comparison: Linagliptin 1 mg vs. Placebop-value: 0.002295% CI: [-31, -6.87]Pairwise comparison based on ANCOVA
Secondary
Percentage of Patients With HbA1c<=7.0% at Week 12
Descriptive calculation of Patients with HbA1c \<= 7.0% at Week 12.
Time frame: week 12
Population: This population includes the Full Analysis Set (FAS). Last observation carried forward (LOCF) was used as the imputation rule.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c<=7.0% at Week 12 | 1.4 Percentage of Patients |
| Linagliptin 1 mg | Percentage of Patients With HbA1c<=7.0% at Week 12 | 15.6 Percentage of Patients |
| Linagliptin 5 mg | Percentage of Patients With HbA1c<=7.0% at Week 12 | 14.5 Percentage of Patients |
| Linagliptin 10 mg | Percentage of Patients With HbA1c<=7.0% at Week 12 | 21.2 Percentage of Patients |
| Glimepiride | Percentage of Patients With HbA1c<=7.0% at Week 12 | 31.3 Percentage of Patients |
Comparison: Linagliptin 10 mg vs. Placebop-value: 0.005495% CI: [2.367, 145.781]Regression, Logistic
Comparison: Linagliptin 5 mg vs. Placebop-value: 0.021495% CI: [1.439, 95.351]Regression, Logistic
Comparison: Linagliptin 1 mg vs. Placebop-value: 0.016795% CI: [1.586, 102.895]Regression, Logistic
Comparison: Glimepiride vs. Placebop-value: 0.00195% CI: [4.063, 242.028]Regression, Logistic