Diabetes Mellitus, Type 2
Conditions
Brief summary
Efficacy of BI 1356 compared to placebo in patients for whom metformin therapy is inappropriate (intolerability, contraindication). The second part of the study looks at the safety of BI 1356 in this patient population with longer term treatment in comparison to a sulfonylurea drug (glimepiride)
Interventions
DRUGLinagliptin
5mg once daily
0 mg placebo comparator for part 1 of study (to 18 weeks)
DRUGGlimepiride
1-4mg for part 2 of study (weeks 19-52)
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 between 18 and 80 years old with type 2 diabetes and insufficient glycemic control (HbA1c 7% to 10%) for whom metformin therapy is inappropriate (intolerability or contraindication)
Exclusion criteria
Myocardial infarction, stroke or Transient ischaemic attack in last 6 months Treatment with rosiglitazone or pioglitazone, GLP-1 analogues, insulin or anti-obesity drugs in past 3 months Impaired hepatic function Severe renal impairment current treatment with systemic steroids change in dosage of thyroid hormones hereditary galactose intolerance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline at Week 18 (Interim Analysis) | Baseline and week 18 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the Week 0 HbA1c percent. Means are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance. |
| HbA1c Change From Baseline at Week 18 (Final Analysis) | Baseline and week 18 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the Week 0 HbA1c percent. Means are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance. HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the Week 0 HbA1c percent. Means are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance. The primary analysis was re-run at the completion of the study in the final study report. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With HbA1c<6.5 at Week 18 (Interim Analysis) | Week 18 | Odds ratios are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance. |
| Percentage of Patients With HbA1c Lowering by 0.5% at Week 18 (Interim Analysis) | Week 18 | Odds ratios are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance. |
| Fasting Plasma Glucose (FPG) Change From Baseline at Week 18 (Interim Analysis) | Baseline and week 18 | This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. Means are adjusted for baseline FPG, baseline HbA1c, prior OADs and reason for metformin intolerance (Interim Analysis). |
| The Change in FPG From Baseline by Visit Over Time | Baseline and weeks 6,12,18, 22, 26, 30, 34, 40, 46, 52 | This change from baseline reflects the FPG (at weeks 6, 12, 18, 22, 26, 30, 34, 40, 46, 52) minus the Week 0 FPG. |
| The Change in HbA1c From Baseline by Visit Over Time | Baseline and weeks 6,12, 18, 22, 26, 30, 34, 40, 46, 52 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the HbA1c percent (at weeks 6, 12, 18, 22, 26, 30, 34, 40, 46, 52) minus the Week 0 HbA1c percent. |
| Percentage of Patients With HbA1c<7.0 at Week 18 (Interim Analysis) | Week 18 | Odds ratios are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance. |
Countries
Canada, Mexico, Philippines, Romania, Russia, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Glimepiride Patients treated with matching placebo (up to 18 weeks) followed by Glimepiride (after 18 weeks to 52 weeks) | 76 |
| Linagliptin Patients treated with Linagliptin 5mg once daily (up to 52 weeks) | 151 |
| Total | 227 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 |
| Overall Study | Lack of Efficacy | 2 | 5 |
| Overall Study | Lost to Follow-up | 3 | 8 |
| Overall Study | Other reason (not specified) | 4 | 1 |
| Overall Study | Protocol Violation | 2 | 6 |
| Overall Study | Withdrawal by Subject | 6 | 8 |
Baseline characteristics
| Characteristic | Placebo/Glimepiride | Linagliptin | Total |
|---|---|---|---|
| Age, Continuous | 56.7 Years STANDARD_DEVIATION 9.7 | 56.4 Years STANDARD_DEVIATION 10.6 | 56.5 Years STANDARD_DEVIATION 10.3 |
| Body Mass Index (BMI) continuous | 30.19 kg/m^2 STANDARD_DEVIATION 4.97 | 29.09 kg/m^2 STANDARD_DEVIATION 5.62 | 29.46 kg/m^2 STANDARD_DEVIATION 5.42 |
| Fasting blood plasma (FPG) glucose | 180.5 mg/dL STANDARD_DEVIATION 44.7 | 183.3 mg/dL STANDARD_DEVIATION 46.4 | 182.4 mg/dL STANDARD_DEVIATION 45.8 |
| Glycosylated hemoglobin (HbA1c) - Interim Analysis | 8.06 percent STANDARD_DEVIATION 0.89 | 8.11 percent STANDARD_DEVIATION 0.95 | 8.09 percent STANDARD_DEVIATION 0.93 |
| Sex: Female, Male Female | 43 Participants | 96 Participants | 139 Participants |
| Sex: Female, Male Male | 33 Participants | 55 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 40 / 76 | 59 / 151 |
| serious Total, serious adverse events | 3 / 76 | 1 / 151 |
Outcome results
Primary
HbA1c Change From Baseline at Week 18 (Final Analysis)
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the Week 0 HbA1c percent. Means are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance. HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the Week 0 HbA1c percent. Means are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance. The primary analysis was re-run at the completion of the study in the final study report.
Time frame: Baseline and week 18
Population: The Full Analysis Set (FAS) included all treated patients with a baseline and at least one on-treatment HbA1c measurement available during the first phase of the study. Last observation carried forward (LOCF) was used as the imputation rule.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 18 (Final Analysis) | 0.21 percent | Standard Error 0.16 |
| Linagliptin | HbA1c Change From Baseline at Week 18 (Final Analysis) | -0.39 percent | Standard Error 0.14 |
Comparison: Linagliptin versus Placebo. The primary analysis performed at the interim was re-run at the end of the study to accommodate changes made to the final study database.p-value: <0.000195% CI: [-0.88, -0.32]ANCOVA
Primary
HbA1c Change From Baseline at Week 18 (Interim Analysis)
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the Week 0 HbA1c percent. Means are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance.
Time frame: Baseline and week 18
Population: The Full Analysis Set (FAS) included all treated patients with a baseline and at least one on-treatment HbA1c measurement available during the first phase of the study. Last Observation Carried Forward (LOCF) was used as the imputation rule.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 18 (Interim Analysis) | 0.14 percent | Standard Error 0.16 |
| Linagliptin | HbA1c Change From Baseline at Week 18 (Interim Analysis) | -0.44 percent | Standard Error 0.14 |
Comparison: Linagliptin versus Placebop-value: <0.000195% CI: [-0.86, -0.29]ANCOVA
Secondary
Fasting Plasma Glucose (FPG) Change From Baseline at Week 18 (Interim Analysis)
This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. Means are adjusted for baseline FPG, baseline HbA1c, prior OADs and reason for metformin intolerance (Interim Analysis).
Time frame: Baseline and week 18
Population: All patients in FAS with values for FPG at baseline and at week 18. Last Observation Carried Forward (LOCF) was used as the imputation rule (Interim Analysis).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline at Week 18 (Interim Analysis) | 7.2 mg/dl | Standard Error 6 |
| Linagliptin | Fasting Plasma Glucose (FPG) Change From Baseline at Week 18 (Interim Analysis) | -13.3 mg/dl | Standard Error 5.2 |
Comparison: Linagliptin versus Placebop-value: 0.000295% CI: [-31.1, -9.9]ANCOVA
Secondary
Percentage of Patients With HbA1c<6.5 at Week 18 (Interim Analysis)
Odds ratios are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance.
Time frame: Week 18
Population: FAS patients with baseline HbA1c \>= 6.5%. Patients without a value at Week 18 were analysed as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c<6.5 at Week 18 (Interim Analysis) | 2.9 percent of patients |
| Linagliptin | Percentage of Patients With HbA1c<6.5 at Week 18 (Interim Analysis) | 8.9 percent of patients |
Comparison: Linagliptin vs. Placebop-value: 0.128195% CI: [0.71, 15.196]Regression, Logistic
Secondary
Percentage of Patients With HbA1c<7.0 at Week 18 (Interim Analysis)
Odds ratios are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance.
Time frame: Week 18
Population: Full Analysis Set (FAS) patients with baseline HbA1c \>= 7.0%. Patients without a value at week 18 were analysed as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c<7.0 at Week 18 (Interim Analysis) | 11.8 percent of patients |
| Linagliptin | Percentage of Patients With HbA1c<7.0 at Week 18 (Interim Analysis) | 23.5 percent of patients |
Comparison: Linagliptin versus Placebop-value: 0.037495% CI: [1.057, 6.279]Regression, Logistic
Secondary
Percentage of Patients With HbA1c Lowering by 0.5% at Week 18 (Interim Analysis)
Odds ratios are adjusted for baseline HbA1c, prior OADs and reason for metformin intolerance.
Time frame: Week 18
Population: The Full Analysis Set (FAS) included all treated patients with a baseline and at least one on-treatment HbA1c measurement available during the first phase of the study. Patients without a value at week 18 were analysed as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c Lowering by 0.5% at Week 18 (Interim Analysis) | 17.8 percent of patients |
| Linagliptin | Percentage of Patients With HbA1c Lowering by 0.5% at Week 18 (Interim Analysis) | 36.1 percent of patients |
Comparison: Linagliptin versus Placebop-value: 0.004695% CI: [1.374, 5.711]Regression, Logistic
Secondary
The Change in FPG From Baseline by Visit Over Time
This change from baseline reflects the FPG (at weeks 6, 12, 18, 22, 26, 30, 34, 40, 46, 52) minus the Week 0 FPG.
Time frame: Baseline and weeks 6,12,18, 22, 26, 30, 34, 40, 46, 52
Population: Treated set (OC)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 6 (N=63, 134) | 9.7 mg/dL | Standard Deviation 30.7 |
| Placebo | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 12 (N=55,92) | 5.4 mg/dL | Standard Deviation 33 |
| Placebo | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 18 (N=47, 115) | 5.0 mg/dL | Standard Deviation 32.4 |
| Placebo | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 22 (N=46, 110) | -19.3 mg/dL | Standard Deviation 33.3 |
| Placebo | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 26 (N=50, 108) | -22.6 mg/dL | Standard Deviation 33.8 |
| Placebo | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 30 (N=48, 95) | -31.4 mg/dL | Standard Deviation 29.5 |
| Placebo | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 34 (N=48, 95) | -25.6 mg/dL | Standard Deviation 35.2 |
| Placebo | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 40 (N=47, 92) | -19.5 mg/dL | Standard Deviation 33.2 |
| Placebo | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 46 (N=47, 92) | -22.8 mg/dL | Standard Deviation 32.3 |
| Placebo | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 52 (N=43, 86) | -19.1 mg/dL | Standard Deviation 30.1 |
| Linagliptin | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 40 (N=47, 92) | -19.0 mg/dL | Standard Deviation 36.9 |
| Linagliptin | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 6 (N=63, 134) | -8.4 mg/dL | Standard Deviation 41 |
| Linagliptin | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 30 (N=48, 95) | -19.1 mg/dL | Standard Deviation 39.1 |
| Linagliptin | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 12 (N=55,92) | -14.3 mg/dL | Standard Deviation 37.3 |
| Linagliptin | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 52 (N=43, 86) | -14.0 mg/dL | Standard Deviation 37.1 |
| Linagliptin | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 18 (N=47, 115) | -12.9 mg/dL | Standard Deviation 35.9 |
| Linagliptin | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 34 (N=48, 95) | -15.8 mg/dL | Standard Deviation 36 |
| Linagliptin | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 22 (N=46, 110) | -14.0 mg/dL | Standard Deviation 41.8 |
| Linagliptin | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 46 (N=47, 92) | -18.1 mg/dL | Standard Deviation 38.8 |
| Linagliptin | The Change in FPG From Baseline by Visit Over Time | Change from baseline at week 26 (N=50, 108) | -17.0 mg/dL | Standard Deviation 37.8 |
Secondary
The Change in HbA1c From Baseline by Visit Over Time
HbA1c is measured as a percentage. Thus, this change from baseline reflects the HbA1c percent (at weeks 6, 12, 18, 22, 26, 30, 34, 40, 46, 52) minus the Week 0 HbA1c percent.
Time frame: Baseline and weeks 6,12, 18, 22, 26, 30, 34, 40, 46, 52
Population: Treated set (OC)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 6 (N=64, 136) | 0.26 percent | Standard Deviation 0.98 |
| Placebo | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 12 (N=57, 129) | 0.26 percent | Standard Deviation 1.08 |
| Placebo | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 18 (N=47, 118) | 0.10 percent | Standard Deviation 1.06 |
| Placebo | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 22 (N=46, 113) | -0.32 percent | Standard Deviation 0.82 |
| Placebo | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 26 (N=50, 110) | -0.53 percent | Standard Deviation 0.93 |
| Placebo | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 30 (N=49, 98) | -0.79 percent | Standard Deviation 1.06 |
| Placebo | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 34 (N=50, 96) | -0.75 percent | Standard Deviation 0.95 |
| Placebo | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 40 (N=49, 94) | -0.73 percent | Standard Deviation 1.11 |
| Placebo | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 46 (N=45, 92) | -0.78 percent | Standard Deviation 1.04 |
| Placebo | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 52 (N=45, 92) | -0.72 percent | Standard Deviation 1.01 |
| Linagliptin | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 40 (N=49, 94) | -0.45 percent | Standard Deviation 0.9 |
| Linagliptin | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 6 (N=64, 136) | -0.21 percent | Standard Deviation 0.77 |
| Linagliptin | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 30 (N=49, 98) | -0.49 percent | Standard Deviation 0.92 |
| Linagliptin | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 12 (N=57, 129) | -0.43 percent | Standard Deviation 0.84 |
| Linagliptin | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 52 (N=45, 92) | -0.44 percent | Standard Deviation 1 |
| Linagliptin | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 18 (N=47, 118) | -0.38 percent | Standard Deviation 0.87 |
| Linagliptin | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 34 (N=50, 96) | -0.49 percent | Standard Deviation 0.88 |
| Linagliptin | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 22 (N=46, 113) | -0.40 percent | Standard Deviation 0.94 |
| Linagliptin | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 46 (N=45, 92) | -0.42 percent | Standard Deviation 0.96 |
| Linagliptin | The Change in HbA1c From Baseline by Visit Over Time | Change from baseline at week 26 (N=50, 110) | -0.48 percent | Standard Deviation 0.92 |