Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the current study is to investigate the efficacy, safety and tolerability of BI 1356 (5 mg once daily) compared to placebo given for 24 weeks as add-on therapy to metformin in patients with type 2 diabetes mellitus with insufficient glycaemic control
Interventions
DRUGlinagliptin
Patients receive linagliptin 5 mg tablets once daily
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Male and female patients with a diagnosis of type 2 diabetes mellitus and previously treated with metformin alone, or with metformin and not more than one other oral antidiabetic drug 2. Diagnosis of type 2 diabetes prior to informed consent 3. Glycosylated haemoglobin A1 (HbA1c)at screening: For patients undergoing wash out of previous medication: HbA1c 6.5 - 9.0% For patients not undergoing wash-out of previous medication: HbA1c 7.0 - 10.0% 4. Glycosylated haemoglobin A1 (HbA1c) 7.0 - 10.0% at the beginning of Placebo Run-in 5. Age 18 -80 years 6. BMI (Body Mass Index) less than 40 kg/m2 7. Signed and dated written informed consent by date of Visit 1a in accordance with GCP and local legislation
Exclusion criteria
1. Myocardial infarction, stroke or transient ischemic attack (TIA) within 6 months prior to informed consent 2. Impaired hepatic function 3. Known hypersensitivity or allergy to the investigational product or its excipients or metformin or placebo 4. Treatment with rosiglitazone or pioglitazone within 3 months prior to informed consent 5. Treatment with an injectable GLP-1 analogue (e.g. exenatide) within 3 months prior to informed consent 6. Treatment with insulin within 3 months prior to informed consent 7. Treatment with anti-obesity drugs (e.g. sibutramine, orlistat, rimonabant) within 3 months prior to informed consent 8. Alcohol abuse within the 3 months prior to informed consent that would interfere with trial participation or drug abuse 9. Participation in another trial with an investigational drug within 2 months prior to informed consent 10. Pre-menopausal women 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. 11. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent. 12. Renal failure or renal impairment 13. Unstable or acute congestive heart failure 14. Acute or chronic metabolic acidosis (present in patient history) 15. Hereditary galactose intolerance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline at Week 24 | Baseline and week 24 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
Secondary
| 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 baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
| HbA1c Change From Baseline at Week 18 | Baseline and week 18 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
| FPG Change From Baseline at Week 24 | Baseline and week 24 | This change from baseline reflects the Week 24 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. |
| FPG Change From Baseline at Week 6 | Baseline and week 6 | This change from baseline reflects the Week 6 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. |
| 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. |
| FPG Change From Baseline at Week 18 | Baseline and week 18 | This change from baseline reflects the Week 18 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. |
| HbA1c Change From Baseline at Week 6 | Baseline and week 6 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
| Percentage of Patients With HbA1c < 7.0% at Week 24 | Baseline and week 24 | The percentage of patients with an HbA1c value below 7.0% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c \>= 7.0%. |
| Percentage of Patients With HbA1c <6.5% at Week 24 | Baseline and week 24 | The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c \>= 6.5%. Only patients with baseline HbA1c \>= 6.5% |
| Percentage of Patients With HbA1c<6.5% at Week 24 | Baseline and week 24 | The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c \>= 6.5%. |
| Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24 | Baseline and week 24 | The percentage of patients with an HbA1c reduction from baseline \>= 0.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c reduction less than 0.5%. |
| Adjusted Means for 2h Post Prandial Blood Glucose (PPG) Change From Baseline at Week 24 | Baseline and week 24 | This change from baseline reflects the Week 24 2h PPG minus the baseline 2h PPG. Means are treatment adjusted for baseline HbA1c, baseline PPG and previous anti-diabetic medication. |
| 2 Hour Post-Prandial Glucose (PPG) Increment Over Fasting Plasma Glucose (FPG) at Week 24 | Baseline and week 24 | This change from baseline reflects the Week 24 (2h PPG - FPG) minus the baseline (2h PPG - FPG). Means are treatment adjusted for baseline HbA1c, baseline 2h PPG increment over FPG and previous anti-diabetic medication. |
| Percentage of Patients With HbA1c <7.0% at Week 24. | Baseline and week 24 | The percentage of patients with an HbA1c value below 7.0% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c \>= 7.0%. Only patients with baseline HbA1c \>= 7% |
Countries
Czechia, Finland, Greece, India, Israel, Mexico, New Zealand, Russia, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients randomized to receive treatment with matching placebo | 177 |
| Linagliptin Patients randomized to receive treatment with Linagliptin 5 mg | 523 |
| Total | 700 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 9 |
| Overall Study | Lost to Follow-up | 2 | 6 |
| Overall Study | Other incl. lack of efficacy | 2 | 9 |
| Overall Study | Protocol Violation | 3 | 2 |
| Overall Study | Withdrawal by Subject | 4 | 13 |
Baseline characteristics
| Characteristic | Placebo | Linagliptin | Total |
|---|---|---|---|
| Age, Continuous | 56.6 Years STANDARD_DEVIATION 10.9 | 56.5 Years STANDARD_DEVIATION 10.1 | 56.5 Years STANDARD_DEVIATION 10.3 |
| Body Mass Index (BMI) continuous | 30.05 kg/m^2 STANDARD_DEVIATION 5.01 | 29.85 kg/m^2 STANDARD_DEVIATION 4.84 | 29.90 kg/m^2 STANDARD_DEVIATION 4.88 |
| Fasting blood plasma glucose (FPG) | 166.42 mg/dL STANDARD_DEVIATION 41.89 | 169.62 mg/dL STANDARD_DEVIATION 43.51 | 168.81 mg/dL STANDARD_DEVIATION 43.1 |
| Glycosylated haemoglobin A1 (HbA1C) | 8.02 Percent STANDARD_DEVIATION 0.88 | 8.09 Percent STANDARD_DEVIATION 0.86 | 8.08 Percent STANDARD_DEVIATION 0.87 |
| Sex: Female, Male Female | 76 Participants | 245 Participants | 321 Participants |
| Sex: Female, Male Male | 101 Participants | 278 Participants | 379 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 34 / 177 | 54 / 523 |
| serious Total, serious adverse events | 4 / 177 | 18 / 523 |
Outcome results
Primary
HbA1c Change From Baseline at Week 24
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and week 24
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 24 | 0.15 Percent | Standard Error 0.06 |
| Linagliptin | HbA1c Change From Baseline at Week 24 | -0.49 Percent | Standard Error 0.04 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.78, -0.5]ANCOVA
Secondary
2 Hour Post-Prandial Glucose (PPG) Increment Over Fasting Plasma Glucose (FPG) at Week 24
This change from baseline reflects the Week 24 (2h PPG - FPG) minus the baseline (2h PPG - FPG). Means are treatment adjusted for baseline HbA1c, baseline 2h PPG increment over FPG and previous anti-diabetic medication.
Time frame: Baseline and week 24
Population: Meal Tolerance Test (MTT) set (treated and randomised patients with adequate MTT results available at the beginning and end of the randomised treatment period)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 2 Hour Post-Prandial Glucose (PPG) Increment Over Fasting Plasma Glucose (FPG) at Week 24 | 10.90 mg/dL | Standard Error 9.23 |
| Linagliptin | 2 Hour Post-Prandial Glucose (PPG) Increment Over Fasting Plasma Glucose (FPG) at Week 24 | -30.90 mg/dL | Standard Error 5.62 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-61.71, -21.89]ANCOVA
Secondary
Adjusted Means for 2h Post Prandial Blood Glucose (PPG) Change From Baseline at Week 24
This change from baseline reflects the Week 24 2h PPG minus the baseline 2h PPG. Means are treatment adjusted for baseline HbA1c, baseline PPG and previous anti-diabetic medication.
Time frame: Baseline and week 24
Population: Meal Tolerance Test (MTT) set (treated and randomised patients with adequate MTT results available at the beginning and end of the randomised treatment period)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Means for 2h Post Prandial Blood Glucose (PPG) Change From Baseline at Week 24 | 18.27 mg/dL | Standard Error 12.85 |
| Linagliptin | Adjusted Means for 2h Post Prandial Blood Glucose (PPG) Change From Baseline at Week 24 | -48.86 mg/dL | Standard Error 7.35 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-94.69, -39.58]ANCOVA
Secondary
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 | FPG Change From Baseline at Week 12 | 3.86 mg/dL | Standard Error 2.6 |
| Linagliptin | FPG Change From Baseline at Week 12 | -12.86 mg/dL | Standard Error 1.52 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-22.44, -11.01]ANCOVA
Secondary
FPG Change From Baseline at Week 18
This change from baseline reflects the Week 18 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and week 18
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 | FPG Change From Baseline at Week 18 | 10.32 mg/dL | Standard Error 2.72 |
| Linagliptin | FPG Change From Baseline at Week 18 | -10.51 mg/dL | Standard Error 1.6 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-26.81, -14.84]ANCOVA
Secondary
FPG Change From Baseline at Week 24
This change from baseline reflects the Week 24 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and week 24
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 | FPG Change From Baseline at Week 24 | 10.46 mg/dL | Standard Error 2.8 |
| Linagliptin | FPG Change From Baseline at Week 24 | -10.68 mg/dL | Standard Error 1.65 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-27.3, -14.96]ANCOVA
Secondary
FPG Change From Baseline at Week 6
This change from baseline reflects the Week 6 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and week 6
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 | FPG Change From Baseline at Week 6 | 4.58 mg/dL | Standard Error 2.38 |
| Linagliptin | FPG Change From Baseline at Week 6 | -11.94 mg/dL | Standard Error 1.4 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-21.76, -11.29]ANCOVA
Secondary
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 baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
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 | 0.096 Percent | Standard Error 0.056 |
| Linagliptin | HbA1c Change From Baseline at Week 12 | -0.499 Percent | Standard Error 0.034 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.721, -0.471]ANCOVA
Secondary
HbA1c Change From Baseline at Week 18
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and week 18
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 18 | 0.147 Percent | Standard Error 0.061 |
| Linagliptin | HbA1c Change From Baseline at Week 18 | -0.502 Percent | Standard Error 0.037 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.785, -0.512]ANCOVA
Secondary
HbA1c Change From Baseline at Week 6
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and week 6
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 6 | 0.069 Percent | Standard Error 0.044 |
| Linagliptin | HbA1c Change From Baseline at Week 6 | -0.363 Percent | Standard Error 0.027 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.53, -0.333]ANCOVA
Secondary
Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24
The percentage of patients with an HbA1c reduction from baseline \>= 0.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c reduction less than 0.5%.
Time frame: Baseline and week 24
Population: The Full Analysis Set (FAS) included all patients with a baseline and at least one on treatment HbA1c measurement available. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24 | 21.7 percentage of patients | 0 |
| Linagliptin | Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24 | 49.7 percentage of patients | 0 |
Comparison: Linagliptin vs. Placebo~The odds-ratio is based on a logistic regression model including baseline HbA1c and previous antidiabetic medication.p-value: <0.000195% CI: [2.486, 5.669]Regression, Logistic
Secondary
Percentage of Patients With HbA1c<6.5% at Week 24
The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c \>= 6.5%.
Time frame: Baseline and week 24
Population: This population includes the Full Analysis Set (FAS). Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c<6.5% at Week 24 | 3.4 percentage of patients |
| Linagliptin | Percentage of Patients With HbA1c<6.5% at Week 24 | 10.7 percentage of patients |
Secondary
Percentage of Patients With HbA1c <6.5% at Week 24
The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c \>= 6.5%. Only patients with baseline HbA1c \>= 6.5%
Time frame: Baseline and week 24
Population: This population includes the FAS with baseline HbA1c \>= 6.5%. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Patients With HbA1c <6.5% at Week 24 | 2.3 percentage of patients | 0 |
| Linagliptin | Percentage of Patients With HbA1c <6.5% at Week 24 | 10.4 percentage of patients | 0 |
Comparison: Linagliptin vs. Placebo~The odds-ratio is based on a logistic regression model including baseline HbA1c and previous antidiabetic medication.p-value: 0.001695% CI: [1.907, 15.614]Regression, Logistic
Secondary
Percentage of Patients With HbA1c < 7.0% at Week 24
The percentage of patients with an HbA1c value below 7.0% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c \>= 7.0%.
Time frame: Baseline and week 24
Population: This population includes the Full Analysis Set (FAS). Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c < 7.0% at Week 24 | 11.4 percentage of patients |
| Linagliptin | Percentage of Patients With HbA1c < 7.0% at Week 24 | 28.3 percentage of patients |
Secondary
Percentage of Patients With HbA1c <7.0% at Week 24.
The percentage of patients with an HbA1c value below 7.0% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c \>= 7.0%. Only patients with baseline HbA1c \>= 7%
Time frame: Baseline and week 24
Population: This population includes the FAS with baseline HbA1c \>= 7.0%. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Patients With HbA1c <7.0% at Week 24. | 9.2 percentage of patients | 0 |
| Linagliptin | Percentage of Patients With HbA1c <7.0% at Week 24. | 26.2 percentage of patients | 0 |
Comparison: Linagliptin vs. Placebo~The odds-ratio is based on a logistic regression model including baseline HbA1c and previous antidiabetic medication.p-value: <0.000195% CI: [2.41, 8.013]Regression, Logistic