Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the randomised part of the study is to investigate the efficacy and safety of BI 1356 plus metformin compared to BI 1356 or metformin alone given for 24 weeks to drug naive or previously treated (4 weeks wash-out, 2 weeks placebo run-in) type 2 diabetic patients with insufficient glycaemic control. For the open-label part of the study the objective is to estimate the efficacy and safety of BI 1356 and metformin in type 2 diabetic patients with very poor glycaemic control for 24 weeks
Interventions
DRUGBI 1356
BI 1356 high dose tablet, once daily
DRUGBI 1356 + metformin
BI 1356 low dose tablet + Metformin 500 mg tablet, twice daily
DRUGBi 1356 + metformin
BI 1356 low dose tablet + Metformin 1000 mg tablet, twice daily
DRUGMetformin
Metformin 500 mg tablet, twice daily
DRUGmetformin
metformin 1000 mg tablet, twice daily
DRUGmatching placebo
matching placebo
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
Patients with type 2 diabetes (drug naive or pre-treated) with insufficient glycaemic control (HbA1c higher or equal than 7.5 to less than 11.0 %), with very poor glycaemic control (HbA1c higher or equal than 11.0 %) who are not eligible for randomisation to be included in the open-label arm
Exclusion criteria
Myocardial infarction, stroke or transient ischemic attack (TIA), unstable or acute congestive heart failure, impaired hepatic function, treatment with rosiglitazone or pioglitazone, with a GLP1 analogue, with insulin, with anti-obesity drugs, with systemic steroids, renal failure or impairment, gastric bypass
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 2 | Baseline and week 2 | This change from baseline reflects the Week 2 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. |
| Percentage of Patients With HbA1c <7.0% at Week 24 | Baseline and Week 24 | The percentage of patients with an HbA1c value below 7% 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 above 7%. |
| 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 <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 above 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 above 6.5% |
| Percentage of Patients With HbA1c Lowering by 0.5% at Week 24 | Baseline and week 24 | The percentage of patients with an HbA1c reduction from baseline greater than 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 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 2h PPG and previous anti-diabetic medication. |
| HbA1c Change From Baseline at Week 24 for Open-label Patients | 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 percentage. Mean is unadjusted. |
| FPG Change From Baseline at Week 24 for Open-label Patients | Baseline and week 24 | This change from baseline reflects the Week 24 FPG minus the baseline FPG. Mean is unadjusted. |
| Use of Rescue Therapy | 24 weeks | The use of rescue therapy (SUs, thiazolidinediones \[TZDs\], or insulin) was permitted only during the randomised treatment period of the trial (i.e. Visits 3 to 7), and was to be administered only if a patient had a 'confirmed' glucose level after an overnight fast. |
| Percentage of Patients With HbA1c<7.0 at Week 24 | Baseline and Week 24 | The percentage of patients with an HbA1c value below 7% 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 above 7%. |
Countries
Canada, Croatia, Estonia, France, Germany, India, Lithuania, Mexico, Netherlands, Romania, Russia, Sweden, Tunisia, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients treated with matching placebo | 72 |
| M500BID Patients treated with Metformin 500mg BID | 144 |
| M1000BID Patients treated with Metformin 1000mg BID | 147 |
| Lina5 Patients treated with Linagliptin 5mg OD | 142 |
| L2.5+M500BID Patients treated with Linagliptin 2.5mg+ Metformin 500mg BID | 143 |
| L2.5+M1000BID Patients treated with Linagliptin 2.5mg+ Metformin 1000mg BID | 143 |
| L2.5+M1000BID (Open Label) Open label set: Linagliptin 2.5mg + Metformin 1000mg BID | 66 |
| Total | 857 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 | 6 | 6 | 5 | 2 | 4 |
| Overall Study | Lost to Follow-up | 1 | 3 | 4 | 3 | 4 | 0 | 0 |
| Overall Study | Other reason (incl. lack of efficacy) | 7 | 5 | 3 | 5 | 2 | 4 | 5 |
| Overall Study | Protocol Violation | 2 | 1 | 3 | 3 | 3 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 4 | 5 | 4 | 2 | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | M500BID | M1000BID | Lina5 | L2.5+M500BID | L2.5+M1000BID | L2.5+M1000BID (Open Label) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 55.7 Years STANDARD_DEVIATION 11 | 52.9 Years STANDARD_DEVIATION 10.4 | 55.2 Years STANDARD_DEVIATION 10.6 | 56.2 Years STANDARD_DEVIATION 10.8 | 55.6 Years STANDARD_DEVIATION 11.2 | 56.4 Years STANDARD_DEVIATION 10.7 | 53.5 Years STANDARD_DEVIATION 11.1 | 55.2 Years STANDARD_DEVIATION 10.8 |
| Body Mass Index (BMI) continuous | 28.62 kg/m^2 STANDARD_DEVIATION 5.17 | 28.92 kg/m^2 STANDARD_DEVIATION 4.83 | 29.52 kg/m^2 STANDARD_DEVIATION 5.31 | 28.95 kg/m^2 STANDARD_DEVIATION 4.67 | 29.66 kg/m^2 STANDARD_DEVIATION 5.31 | 28.55 kg/m^2 STANDARD_DEVIATION 4.8 | 28.81 kg/m^2 STANDARD_DEVIATION 4.93 | 29.07 kg/m^2 STANDARD_DEVIATION 4.97 |
| Fasting plasma glucose (FPG) | 203.7 mg/dL STANDARD_DEVIATION 51.2 | 191.2 mg/dL STANDARD_DEVIATION 46.9 | 192.3 mg/dL STANDARD_DEVIATION 52.8 | 195.3 mg/dL STANDARD_DEVIATION 50.2 | 198.6 mg/dL STANDARD_DEVIATION 60.2 | 196.9 mg/dL STANDARD_DEVIATION 51.2 | 261.8 mg/dL STANDARD_DEVIATION 80.9 | 200.2 mg/dL STANDARD_DEVIATION 57.3 |
| Glycosylated Hemoglobin A1 (HbA1C) | 8.67 Percent STANDARD_DEVIATION 0.95 | 8.66 Percent STANDARD_DEVIATION 0.9 | 8.52 Percent STANDARD_DEVIATION 0.87 | 8.70 Percent STANDARD_DEVIATION 0.97 | 8.71 Percent STANDARD_DEVIATION 0.95 | 8.68 Percent STANDARD_DEVIATION 1.03 | 11.84 Percent STANDARD_DEVIATION 1.42 | 8.91 Percent STANDARD_DEVIATION 1.31 |
| Sex: Female, Male Female | 36 Participants | 62 Participants | 69 Participants | 62 Participants | 70 Participants | 66 Participants | 40 Participants | 405 Participants |
| Sex: Female, Male Male | 36 Participants | 82 Participants | 78 Participants | 80 Participants | 73 Participants | 77 Participants | 26 Participants | 452 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 | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 20 / 72 | 27 / 144 | 27 / 147 | 31 / 142 | 31 / 143 | 36 / 143 | 18 / 66 |
| serious Total, serious adverse events | 1 / 72 | 3 / 144 | 6 / 147 | 3 / 142 | 2 / 143 | 2 / 143 | 1 / 66 |
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 | 0.13 Percent | Standard Error 0.11 |
| M500BID | HbA1c Change From Baseline at Week 24 | -0.64 Percent | Standard Error 0.08 |
| M1000BID | HbA1c Change From Baseline at Week 24 | -1.07 Percent | Standard Error 0.08 |
| Lina5 | HbA1c Change From Baseline at Week 24 | -0.45 Percent | Standard Error 0.08 |
| L2.5+M500BID | HbA1c Change From Baseline at Week 24 | -1.22 Percent | Standard Error 0.08 |
| L2.5+M1000BID | HbA1c Change From Baseline at Week 24 | -1.59 Percent | Standard Error 0.08 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-0.79, -0.36]ANCOVA
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-0.73, -0.3]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-0.99, -0.55]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-1.36, -0.92]ANCOVA
Secondary
Adjusted Means for 2h Post-Prandial 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 2h PPG and previous anti-diabetic medication.
Time frame: Baseline and week 24
Population: Meal tolerance test (MTT) set (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 Glucose (PPG) Change From Baseline at Week 24 | -35.4 mg/dL | Standard Error 23.2 |
| M500BID | Adjusted Means for 2h Post-Prandial Glucose (PPG) Change From Baseline at Week 24 | -82.9 mg/dL | Standard Error 14.4 |
| M1000BID | Adjusted Means for 2h Post-Prandial Glucose (PPG) Change From Baseline at Week 24 | -87.2 mg/dL | Standard Error 14.8 |
| Lina5 | Adjusted Means for 2h Post-Prandial Glucose (PPG) Change From Baseline at Week 24 | -35.3 mg/dL | Standard Error 16.1 |
| L2.5+M500BID | Adjusted Means for 2h Post-Prandial Glucose (PPG) Change From Baseline at Week 24 | -86.0 mg/dL | Standard Error 17.5 |
| L2.5+M1000BID | Adjusted Means for 2h Post-Prandial Glucose (PPG) Change From Baseline at Week 24 | -109.2 mg/dL | Standard Error 16.2 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: 0.889395% CI: [-48.5, 42.2]ANCOVA
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: 0.323495% CI: [-66.2, 22.2]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: 0.037395% CI: [-98.5, -3.1]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: 0.001895% CI: [-119.3, -28.6]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 | 8.9 mg/dL | Standard Error 5 |
| M500BID | FPG Change From Baseline at Week 12 | -21.8 mg/dL | Standard Error 3.3 |
| M1000BID | FPG Change From Baseline at Week 12 | -31.9 mg/dL | Standard Error 3.4 |
| Lina5 | FPG Change From Baseline at Week 12 | -8.4 mg/dL | Standard Error 3.4 |
| L2.5+M500BID | FPG Change From Baseline at Week 12 | -36.2 mg/dL | Standard Error 3.4 |
| L2.5+M1000BID | FPG Change From Baseline at Week 12 | -49.9 mg/dL | Standard Error 3.3 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: 0.002495% CI: [-23.7, -5.1]ANCOVA
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: 0.000295% CI: [-27.4, -8.7]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-37.1, -18.5]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-50.8, -32.2]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 | 7.3 mg/dL | Standard Error 5.1 |
| M500BID | FPG Change From Baseline at Week 18 | -13.7 mg/dL | Standard Error 3.4 |
| M1000BID | FPG Change From Baseline at Week 18 | -30.3 mg/dL | Standard Error 3.5 |
| Lina5 | FPG Change From Baseline at Week 18 | -9.2 mg/dL | Standard Error 3.4 |
| L2.5+M500BID | FPG Change From Baseline at Week 18 | -34.6 mg/dL | Standard Error 3.4 |
| L2.5+M1000BID | FPG Change From Baseline at Week 18 | -48.1 mg/dL | Standard Error 3.4 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-30.4, -11.4]ANCOVA
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: 0.000395% CI: [-27.4, -8.3]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-35, -15.9]ANCOVA
Comparison: Linagliptin 5 mg vs. Linagliptin 2.5 mg with Metformin 1000 mgp-value: <0.000195% CI: [-48.5, -29.4]ANCOVA
Secondary
FPG Change From Baseline at Week 2
This change from baseline reflects the Week 2 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and week 2
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 2 | 5.3 mg/dL | Standard Error 4.3 |
| M500BID | FPG Change From Baseline at Week 2 | -19.6 mg/dL | Standard Error 2.9 |
| M1000BID | FPG Change From Baseline at Week 2 | -21.8 mg/dL | Standard Error 2.9 |
| Lina5 | FPG Change From Baseline at Week 2 | -13.0 mg/dL | Standard Error 2.9 |
| L2.5+M500BID | FPG Change From Baseline at Week 2 | -34.5 mg/dL | Standard Error 2.9 |
| L2.5+M1000BID | FPG Change From Baseline at Week 2 | -38.6 mg/dL | Standard Error 2.9 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: 0.000395% CI: [-22.9, -6.8]ANCOVA
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-24.9, -8.8]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-29.5, -13.4]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-33.6, -17.6]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 | 10.2 mg/dL | Standard Error 5.3 |
| M500BID | FPG Change From Baseline at Week 24 | -15.8 mg/dL | Standard Error 3.5 |
| M1000BID | FPG Change From Baseline at Week 24 | -32.2 mg/dL | Standard Error 3.6 |
| Lina5 | FPG Change From Baseline at Week 24 | -8.6 mg/dL | Standard Error 3.6 |
| L2.5+M500BID | FPG Change From Baseline at Week 24 | -33.2 mg/dL | Standard Error 3.5 |
| L2.5+M1000BID | FPG Change From Baseline at Week 24 | -49.4 mg/dL | Standard Error 3.5 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: 0.000595% CI: [-27.2, -7.6]ANCOVA
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: 0.000695% CI: [-27.1, -7.3]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-34.4, -14.8]ANCOVA
Comparison: Linagliptin 5mg vs. linagliptin 2.5mg with metformin 1000mgp-value: <0.000195% CI: [-50.6, -31]ANCOVA
Secondary
FPG Change From Baseline at Week 24 for Open-label Patients
This change from baseline reflects the Week 24 FPG minus the baseline FPG. Mean is unadjusted.
Time frame: Baseline and week 24
Population: The open label set (OLS) included all patients with baseline HbA1c too high to be randomised and were assigned open-label medication, also with a baseline on treatment HbA1c value. The Open label Set (OLS) included all patients treated with at least one dose on open-label L2.5+M1000 medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline at Week 24 for Open-label Patients | -73.58 mg/dL | Standard Deviation 70.94 |
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 | 6.2 mg/dL | Standard Error 4.7 |
| M500BID | FPG Change From Baseline at Week 6 | -20.8 mg/dL | Standard Error 3.2 |
| M1000BID | FPG Change From Baseline at Week 6 | -31.6 mg/dL | Standard Error 3.2 |
| Lina5 | FPG Change From Baseline at Week 6 | -10.8 mg/dL | Standard Error 3.2 |
| L2.5+M500BID | FPG Change From Baseline at Week 6 | -38.7 mg/dL | Standard Error 3.2 |
| L2.5+M1000BID | FPG Change From Baseline at Week 6 | -48.3 mg/dL | Standard Error 3.2 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-26.7, -9.1]ANCOVA
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: 0.000295% CI: [-25.6, -7.9]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-36.7, -19.1]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-46.4, -28.8]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 | 0.16 Percent | Standard Error 0.11 |
| M500BID | HbA1c Change From Baseline at Week 12 | -0.61 Percent | Standard Error 0.07 |
| M1000BID | HbA1c Change From Baseline at Week 12 | -0.95 Percent | Standard Error 0.07 |
| Lina5 | HbA1c Change From Baseline at Week 12 | -0.42 Percent | Standard Error 0.07 |
| L2.5+M500BID | HbA1c Change From Baseline at Week 12 | -1.13 Percent | Standard Error 0.07 |
| L2.5+M1000BID | HbA1c Change From Baseline at Week 12 | -1.37 Percent | Standard Error 0.07 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-0.72, -0.31]ANCOVA
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-0.63, -0.22]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-0.92, -0.51]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-1.16, -0.75]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 | 0.16 Percent | Standard Error 0.12 |
| M500BID | HbA1c Change From Baseline at Week 18 | -0.66 Percent | Standard Error 0.08 |
| M1000BID | HbA1c Change From Baseline at Week 18 | -1.06 Percent | Standard Error 0.08 |
| Lina5 | HbA1c Change From Baseline at Week 18 | -0.45 Percent | Standard Error 0.08 |
| L2.5+M500BID | HbA1c Change From Baseline at Week 18 | -1.17 Percent | Standard Error 0.08 |
| L2.5+M1000BID | HbA1c Change From Baseline at Week 18 | -1.54 Percent | Standard Error 0.08 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-0.73, -0.29]ANCOVA
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-0.69, -0.26]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-0.94, -0.49]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-1.3, -0.86]ANCOVA
Secondary
HbA1c Change From Baseline at Week 24 for Open-label Patients
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percentage. Mean is unadjusted.
Time frame: Baseline and week 24
Population: The open label set (OLS) included all patients with baseline HbA1c too high to be randomised and were assigned open-label medication, also with an on treatment HbA1c value. The Open label Set (OLS) included all patients treated with at least one dose on open-label L2.5+M1000 medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 24 for Open-label Patients | -3.19 Percent | Standard Deviation 2.04 |
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 | 0.03 Percent | Standard Error 0.08 |
| M500BID | HbA1c Change From Baseline at Week 6 | -0.45 Percent | Standard Error 0.05 |
| M1000BID | HbA1c Change From Baseline at Week 6 | -0.61 Percent | Standard Error 0.05 |
| Lina5 | HbA1c Change From Baseline at Week 6 | -0.36 Percent | Standard Error 0.06 |
| L2.5+M500BID | HbA1c Change From Baseline at Week 6 | -0.86 Percent | Standard Error 0.05 |
| L2.5+M1000BID | HbA1c Change From Baseline at Week 6 | -1.00 Percent | Standard Error 0.05 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [-0.56, -0.26]ANCOVA
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-0.53, -0.23]ANCOVA
Comparison: Linagliptin 5mg vs Linagliptin 2.5mg with metformin 500mgp-value: <0.000195% CI: [-0.65, -0.35]ANCOVA
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [-0.79, -0.48]ANCOVA
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 above 6.5%
Time frame: Baseline and Week 24
Population: The FAS included all treated and randomised 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) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c < 6.5% at Week 24 | 3.1 percentage of patients |
| M500BID | Percentage of Patients With HbA1c < 6.5% at Week 24 | 5.0 percentage of patients |
| M1000BID | Percentage of Patients With HbA1c < 6.5% at Week 24 | 12.3 percentage of patients |
| Lina5 | Percentage of Patients With HbA1c < 6.5% at Week 24 | 3.7 percentage of patients |
| L2.5+M500BID | Percentage of Patients With HbA1c < 6.5% at Week 24 | 13.1 percentage of patients |
| L2.5+M1000BID | Percentage of Patients With HbA1c < 6.5% at Week 24 | 27.1 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 above 6.5%. Only patients with baseline HbA1c =\< 6.5%
Time frame: Baseline and Week 24
Population: FAS treated and randomised patients 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 | 3.1 percentage of patients | 0 |
| M500BID | Percentage of Patients With HbA1c <6.5% at Week 24 | 5.0 percentage of patients | 0 |
| M1000BID | Percentage of Patients With HbA1c <6.5% at Week 24 | 12.3 percentage of patients | 0 |
| Lina5 | Percentage of Patients With HbA1c <6.5% at Week 24 | 3.7 percentage of patients | 0 |
| L2.5+M500BID | Percentage of Patients With HbA1c <6.5% at Week 24 | 13.1 percentage of patients | 0 |
| L2.5+M1000BID | Percentage of Patients With HbA1c <6.5% at Week 24 | 27.1 percentage of patients | 0 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: 0.010295% CI: [1.342, 8.943]Regression, Logistic
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: 0.000495% CI: [1.747, 7.094]Regression, Logistic
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: 0.005395% CI: [1.564, 13.069]Regression, Logistic
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [4.314, 33.08]Regression, Logistic
Secondary
Percentage of Patients With HbA1c<7.0 at Week 24
The percentage of patients with an HbA1c value below 7% 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 above 7%.
Time frame: Baseline and Week 24
Population: The FAS included all treated and randomised 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) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c<7.0 at Week 24 | 10.8 percentage of patients |
| M500BID | Percentage of Patients With HbA1c<7.0 at Week 24 | 19.1 percentage of patients |
| M1000BID | Percentage of Patients With HbA1c<7.0 at Week 24 | 31.2 percentage of patients |
| Lina5 | Percentage of Patients With HbA1c<7.0 at Week 24 | 10.4 percentage of patients |
| L2.5+M500BID | Percentage of Patients With HbA1c<7.0 at Week 24 | 30.7 percentage of patients |
| L2.5+M1000BID | Percentage of Patients With HbA1c<7.0 at Week 24 | 54.3 percentage of patients |
Secondary
Percentage of Patients With HbA1c <7.0% at Week 24
The percentage of patients with an HbA1c value below 7% 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 above 7%.
Time frame: Baseline and Week 24
Population: FAS treated and randomised patients 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 | 10.8 percentage of patients | 0 |
| M500BID | Percentage of Patients With HbA1c <7.0% at Week 24 | 18.6 percentage of patients | 0 |
| M1000BID | Percentage of Patients With HbA1c <7.0% at Week 24 | 30.7 percentage of patients | 0 |
| Lina5 | Percentage of Patients With HbA1c <7.0% at Week 24 | 10.4 percentage of patients | 0 |
| L2.5+M500BID | Percentage of Patients With HbA1c <7.0% at Week 24 | 30.1 percentage of patients | 0 |
| L2.5+M1000BID | Percentage of Patients With HbA1c <7.0% at Week 24 | 53.6 percentage of patients | 0 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: 0.006295% CI: [1.278, 4.402]Regression, Logistic
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [2.343, 7.397]Regression, Logistic
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [2.363, 9.973]Regression, Logistic
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [8.238, 35.471]Regression, Logistic
Secondary
Percentage of Patients With HbA1c Lowering by 0.5% at Week 24
The percentage of patients with an HbA1c reduction from baseline greater than 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 FAS included all treated and randomised 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 With HbA1c Lowering by 0.5% at Week 24 | 29.2 percentage of patients | 0 |
| M500BID | Percentage of Patients With HbA1c Lowering by 0.5% at Week 24 | 46.1 percentage of patients | 0 |
| M1000BID | Percentage of Patients With HbA1c Lowering by 0.5% at Week 24 | 65.9 percentage of patients | 0 |
| Lina5 | Percentage of Patients With HbA1c Lowering by 0.5% at Week 24 | 42.2 percentage of patients | 0 |
| L2.5+M500BID | Percentage of Patients With HbA1c Lowering by 0.5% at Week 24 | 71.5 percentage of patients | 0 |
| L2.5+M1000BID | Percentage of Patients With HbA1c Lowering by 0.5% at Week 24 | 81.4 percentage of patients | 0 |
Comparison: Metformin 500mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [1.903, 5.316]Regression, Logistic
Comparison: Metformin 1000mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: 0.002795% CI: [1.352, 4.196]Regression, Logistic
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 500mgp-value: <0.000195% CI: [2.153, 6.093]Regression, Logistic
Comparison: Linagliptin 5mg vs. Linagliptin 2.5mg with Metformin 1000mgp-value: <0.000195% CI: [3.724, 11.445]Regression, Logistic
Secondary
Use of Rescue Therapy
The use of rescue therapy (SUs, thiazolidinediones \[TZDs\], or insulin) was permitted only during the randomised treatment period of the trial (i.e. Visits 3 to 7), and was to be administered only if a patient had a 'confirmed' glucose level after an overnight fast.
Time frame: 24 weeks
Population: Percentage of patients requiring rescue therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Use of Rescue Therapy | 29.2 percentage of participants |
| M500BID | Use of Rescue Therapy | 13.5 percentage of participants |
| M1000BID | Use of Rescue Therapy | 8.0 percentage of participants |
| Lina5 | Use of Rescue Therapy | 11.1 percentage of participants |
| L2.5+M500BID | Use of Rescue Therapy | 7.3 percentage of participants |
| L2.5+M1000BID | Use of Rescue Therapy | 4.3 percentage of participants |
p-value: 0.044595% CI: [0.109, 0.973]Regression, Logistic
p-value: 0.015195% CI: [0.096, 0.779]Regression, Logistic
p-value: 0.04995% CI: [0.177, 0.996]Regression, Logistic
p-value: 0.261795% CI: [0.244, 1.467]Regression, Logistic