Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the study is to investigate the efficacy and safety of linagliptin 2.5 mg twice daily compared to 5 mg once daily compared to placebo given orally for 12 weeks as add-on therapy to metformin in patients with type 2 diabetes mellitus with insufficient glycaemic control. It is planned to show non-inferiority of linagliptin 2.5 mg twice daily compared to 5 mg once daily and each treatment's superiority over placebo.
Interventions
DRUGlinagliptin low dose
patient to receive tablets containing low dose linagliptin twice daily
DRUGplacebo
patient to receive placebo tablet(s) matching linagliptin
DRUGlinagliptin medium dose
patient to receive a tablet containing medium dose linagliptin 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. Diagnosis of type 2 diabetes mellitus. 2. Current treatment with metformin alone (\>/= 1500 mg or maximally tolerated dose) or metformin plus 1 other antidiabetic drug. Metformin must be administered in twice daily dosing regimen. Patients taking metformin three times daily can be included if posology is switched to twice daily and total daily dose is maintained. 3. Glycosylated haemoglobin (HbA1c) is between 7.0% - 10.0%. 4. Body Mass Index (BMI) \</=45 kg/m2.
Exclusion criteria
1. Treatment with extended release metformin. 2. Uncontrolled hyperglycaemia (fasting plasma glucose \> 240 mg/dL or 13.3 mmol/L). 3. Myocardial infarction (MI), stroke or transient ischaemic attack (TIA) within 6 months prior to informed consent. 4. Impaired hepatic or renal function, or gastric bypass surgery. 5. Treatment with glitazones, glucagon like peptide-1 (GLP-1) analogues/mimetics, antiobesity agents, or insulin within 3 months of informed consent. 6. Current treatment with systemic steroids or change in dosage of thyroid hormones. 7. Alcohol or drug abuse within 3 months of informed consent. 8. Participation in another trial with investigational drug within 2 months prior to informed consent. 9. Pre-menopausal women who are nursing, pregnant or not practicing an acceptable method of birth control.
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 baseline HbA1c percent. Treatment means are adjusted for baseline HbA1c and use of prior oral antidiabetics (OADs) in addition to background metformin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis | Baseline and week 12 | Mixed model includes treatment, baseline HbA1c, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction. |
| FPG Change From Baseline at Week 12 | Baseline and week 12 | Change from baseline reflects the Week 12 FPG minus the baseline FPG. Treatment means are adjusted for baseline HbA1c, baseline fasting plasma glucose and use of prior oral antidiabetics (OADs) in addition to background metformin. |
| FPG Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis | Baseline and week 6 | Mixed model includes treatment, baseline HbA1c, baseline FPG, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction. |
| FPG Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis | Baseline and week 12 | Mixed model includes treatment, baseline HbA1c, baseline FPG, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction. |
| HbA1c Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis | Baseline and week 6 | Mixed model includes treatment, baseline HbA1c, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction. |
| Percentage of Patients With Rescue Therapy | 12 weeks | Percentage of patients with rescue therapy at Week 12. The analysis was performed on the full analysis set (FAS) using OC. |
| The Occurrence of a Treat to Target Efficacy Response (HbA1c <7.0%) After 12 Weeks of Treatment | 12 weeks | Percentage of those patients with baseline HbA1c \>= 7.0% who had HbA1c \< 7% at Week 12. The analysis was performed on the full analysis set (FAS) using NCF. |
| The Occurrence of a Treat to Target Efficacy Response (HbA1c <6.5 %) After 12 Weeks of Treatment | 12 weeks | Percentage of those patients with baseline HbA1c \>= 6.5% who had HbA1c \< 6.5% at Week 12. The analysis was performed on the full analysis set (FAS) using NCF. |
| Percentage of Patients With HbA1c Lowering by 0.5% or More at Week 12 | Week 12 | Percentage of patients with HbA1c lowering by at least 0.5% after 12 weeks. The analysis was performed on the full analysis set (FAS) using NCF. |
Countries
Belgium, Canada, France, India, Italy, Malaysia, Netherlands, South Korea, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients treated with matching placebo | 44 |
| Lina 2.5 Twice Daily (Bid) Patients treated with Linagliptin 2.5mg bid | 223 |
| Lina 5 Once Daily (qd) Patients treated with Linagliptin 5mg qd | 224 |
| Total | 491 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 8 | 3 |
| Overall Study | Other reason (not specified) | 1 | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 3 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 4 | 1 |
Baseline characteristics
| Characteristic | Placebo | Lina 2.5 Twice Daily (Bid) | Lina 5 Once Daily (qd) | Total |
|---|---|---|---|---|
| Age, Continuous | 59.9 Years STANDARD_DEVIATION 10.7 | 58.7 Years STANDARD_DEVIATION 9.9 | 58.4 Years STANDARD_DEVIATION 10.6 | 58.6 Years STANDARD_DEVIATION 10.3 |
| Body Mass Index (BMI) continuous | 28.65 kg/m^2 STANDARD_DEVIATION 5.53 | 29.77 kg/m^2 STANDARD_DEVIATION 5.23 | 29.55 kg/m^2 STANDARD_DEVIATION 4.95 | 29.57 kg/m^2 STANDARD_DEVIATION 5.13 |
| Fasting blood plasma glucose (FPG) | 166.2 mg/dL STANDARD_DEVIATION 40.3 | 164.1 mg/dL STANDARD_DEVIATION 41.8 | 165.8 mg/dL STANDARD_DEVIATION 35.1 | 165.1 mg/dL STANDARD_DEVIATION 38.6 |
| Glycosylated hemoglobin (HbA1c) | 7.92 percent STANDARD_DEVIATION 0.74 | 7.96 percent STANDARD_DEVIATION 0.78 | 7.98 percent STANDARD_DEVIATION 0.72 | 7.97 percent STANDARD_DEVIATION 0.75 |
| Sex: Female, Male Female | 23 Participants | 85 Participants | 103 Participants | 211 Participants |
| Sex: Female, Male Male | 21 Participants | 138 Participants | 121 Participants | 280 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 44 | 0 / 223 | 0 / 224 |
| serious Total, serious adverse events | 0 / 44 | 9 / 223 | 5 / 224 |
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 baseline HbA1c percent. Treatment means are adjusted for baseline HbA1c and use of prior oral antidiabetics (OADs) in addition to background metformin.
Time frame: Baseline and week 12
Population: The Full Analysis Set (FAS) included all treated 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 | 0.28 percent | Standard Error 0.11 |
| Lina 2.5 Twice Daily (Bid) | HbA1c Change From Baseline at Week 12 | -0.46 percent | Standard Error 0.05 |
| Lina 5 Once Daily (qd) | HbA1c Change From Baseline at Week 12 | -0.52 percent | Standard Error 0.05 |
Comparison: Linagliptin 2.5mg bid versus Placebop-value: <0.000195% CI: [-0.97, -0.52]ANCOVA
Comparison: Linagliptin 5mg qd versus Placebop-value: <0.000195% CI: [-1.02, -0.58]ANCOVA
Comparison: Linagliptin 2.5mg bid versus Linagliptin 5mg qd95% CI: [-0.07, 0.19]ANCOVA
Secondary
FPG Change From Baseline at Week 12
Change from baseline reflects the Week 12 FPG minus the baseline FPG. Treatment means are adjusted for baseline HbA1c, baseline fasting plasma glucose and use of prior oral antidiabetics (OADs) in addition to background metformin.
Time frame: Baseline and week 12
Population: Patients from FAS with values for FPG at baseline and on-treatment. Last observation carried forward (LOCF) was used as the imputation rule.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline at Week 12 | -3.5 mg/dL | Standard Error 4.2 |
| Lina 2.5 Twice Daily (Bid) | FPG Change From Baseline at Week 12 | -17.2 mg/dL | Standard Error 1.9 |
| Lina 5 Once Daily (qd) | FPG Change From Baseline at Week 12 | -21.3 mg/dL | Standard Error 1.9 |
Comparison: Linagliptin 2.5mg bid versus Placebop-value: 0.002995% CI: [-22.7, -4.7]ANCOVA
Comparison: Linagliptin 5 mg qd versus Placebop-value: 0.000195% CI: [-26.7, -8.8]ANCOVA
Comparison: Linagliptin 2.5mg bid versus Linagliptin 5mg qd95% CI: [-1, 9.2]ANCOVA
Secondary
FPG Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis
Mixed model includes treatment, baseline HbA1c, baseline FPG, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction.
Time frame: Baseline and week 12
Population: Patients from FAS with values for FPG at baseline and on-treatment. No imputation was performed. Patients without a Week 12 value were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis | -8.7 percent | Standard Error 5 |
| Lina 2.5 Twice Daily (Bid) | FPG Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis | -18.7 percent | Standard Error 2.3 |
| Lina 5 Once Daily (qd) | FPG Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis | -23.9 percent | Standard Error 2.2 |
Comparison: Linagliptin 2.5mg bid versus Placebop-value: 0.065395% CI: [-20.6, 0.6]Mixed Models Analysis
Comparison: Linagliptin 5mg qd versus Placebop-value: 0.004795% CI: [-25.8, -4.7]Mixed Models Analysis
Comparison: Linagliptin 2.5mg bid versus Linagliptin 5mg qd95% CI: [-0.7, 11.3]Mixed Models Analysis
Secondary
FPG Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis
Mixed model includes treatment, baseline HbA1c, baseline FPG, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction.
Time frame: Baseline and week 6
Population: Patients from FAS with values for FPG at baseline and on-treatment. No imputation was performed. Patients without a Week 12 value were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis | -1.2 percent | Standard Error 4.1 |
| Lina 2.5 Twice Daily (Bid) | FPG Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis | -17.8 percent | Standard Error 1.9 |
| Lina 5 Once Daily (qd) | FPG Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis | -20.1 percent | Standard Error 1.8 |
Comparison: Linagliptin 2.5mg bid versus Placebop-value: 0.000295% CI: [-25.3, -7.8]Mixed Models Analysis
Comparison: Linagliptin 5mg qd versus Placebop-value: <0.000195% CI: [-27.6, -10.2]Mixed Models Analysis
Comparison: Linagliptin 2.5mg bid versus Linagliptin 5mg qd95% CI: [-2.6, 7.3]Mixed Models Analysis
Secondary
HbA1c Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis
Mixed model includes treatment, baseline HbA1c, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction.
Time frame: Baseline and week 12
Population: The Full Analysis Set (FAS) included all treated patients with a baseline and at least one on-treatment HbA1c measurement available. No imputation was performed. Patients without a Week 12 value were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis | 0.27 percent | Standard Error 0.11 |
| Lina 2.5 Twice Daily (Bid) | HbA1c Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis | -0.51 percent | Standard Error 0.05 |
| Lina 5 Once Daily (qd) | HbA1c Change From Baseline at Week 12 From Mixed Model Repeated Measures (MMRM) Analysis | -0.55 percent | Standard Error 0.05 |
Comparison: Linagliptin 2.5mg bid versus Placebop-value: <0.000195% CI: [-1, -0.54]Mixed Models Analysis
Comparison: Linagliptin 5mg qd versus Placebop-value: <0.000195% CI: [-1.05, -0.59]Mixed Models Analysis
Comparison: Linagliptin 2.5mg bid versus Linagliptin 5mg qd95% CI: [-0.08, 0.18]Mixed Models Analysis
Secondary
HbA1c Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis
Mixed model includes treatment, baseline HbA1c, use of prior oral antidiabetics (OADs) in addition to background metformin, week repeated within patient, week by treatment interaction.
Time frame: Baseline and week 6
Population: The Full Analysis Set (FAS) included all treated patients with a baseline and at least one on-treatment HbA1c measurement available. No imputation was performed. Patients without a Week 6 value were handled by the statistical model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis | 0.32 percent | Standard Error 0.08 |
| Lina 2.5 Twice Daily (Bid) | HbA1c Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis | -0.34 percent | Standard Error 0.04 |
| Lina 5 Once Daily (qd) | HbA1c Change From Baseline at Week 6 From Mixed Model Repeated Measures (MMRM) Analysis | -0.34 percent | Standard Error 0.04 |
Comparison: Linagliptin 2.5mg bid versus Placebop-value: <0.000195% CI: [-0.83, -0.48]Mixed Models Analysis
Comparison: Linagliptin 5mg qd versus Placebop-value: <0.000195% CI: [-0.84, -0.49]Mixed Models Analysis
Comparison: Linagliptin 2.5mg bid versus Linagliptin 5mg qd95% CI: [-0.1, 0.1]Mixed Models Analysis
Secondary
Percentage of Patients With HbA1c Lowering by 0.5% or More at Week 12
Percentage of patients with HbA1c lowering by at least 0.5% after 12 weeks. The analysis was performed on the full analysis set (FAS) using NCF.
Time frame: Week 12
Population: The Full Analysis Set (FAS) included all treated patients with a baseline and at least one on-treatment HbA1c measurement available. Patients without a value at Week 12 were analysed as non-responders
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c Lowering by 0.5% or More at Week 12 | 16.3 percent |
| Lina 2.5 Twice Daily (Bid) | Percentage of Patients With HbA1c Lowering by 0.5% or More at Week 12 | 55.1 percent |
| Lina 5 Once Daily (qd) | Percentage of Patients With HbA1c Lowering by 0.5% or More at Week 12 | 59.7 percent |
Secondary
Percentage of Patients With Rescue Therapy
Percentage of patients with rescue therapy at Week 12. The analysis was performed on the full analysis set (FAS) using OC.
Time frame: 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With Rescue Therapy | 7.0 percent |
| Lina 2.5 Twice Daily (Bid) | Percentage of Patients With Rescue Therapy | 3.7 percent |
| Lina 5 Once Daily (qd) | Percentage of Patients With Rescue Therapy | 1.8 percent |
Secondary
The Occurrence of a Treat to Target Efficacy Response (HbA1c <6.5 %) After 12 Weeks of Treatment
Percentage of those patients with baseline HbA1c \>= 6.5% who had HbA1c \< 6.5% at Week 12. The analysis was performed on the full analysis set (FAS) using NCF.
Time frame: 12 weeks
Population: FAS (NCF) with baseline HbA1c \>= 6.5%
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Occurrence of a Treat to Target Efficacy Response (HbA1c <6.5 %) After 12 Weeks of Treatment | 0.0 percentage of participants |
| Lina 2.5 Twice Daily (Bid) | The Occurrence of a Treat to Target Efficacy Response (HbA1c <6.5 %) After 12 Weeks of Treatment | 12.7 percentage of participants |
| Lina 5 Once Daily (qd) | The Occurrence of a Treat to Target Efficacy Response (HbA1c <6.5 %) After 12 Weeks of Treatment | 11.8 percentage of participants |
Secondary
The Occurrence of a Treat to Target Efficacy Response (HbA1c <7.0%) After 12 Weeks of Treatment
Percentage of those patients with baseline HbA1c \>= 7.0% who had HbA1c \< 7% at Week 12. The analysis was performed on the full analysis set (FAS) using NCF.
Time frame: 12 weeks
Population: FAS (NCF) with baseline HbA1c \>= 7.0%
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Occurrence of a Treat to Target Efficacy Response (HbA1c <7.0%) After 12 Weeks of Treatment | 10.0 percentage of participants |
| Lina 2.5 Twice Daily (Bid) | The Occurrence of a Treat to Target Efficacy Response (HbA1c <7.0%) After 12 Weeks of Treatment | 34.0 percentage of participants |
| Lina 5 Once Daily (qd) | The Occurrence of a Treat to Target Efficacy Response (HbA1c <7.0%) After 12 Weeks of Treatment | 33.0 percentage of participants |