Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the current study is to investigate the efficacy, safety and tolerability of Linagliptin (BI 1356) (5 mg or 10 mg / once daily) compared to placebo given for 12 weeks and voglibose for 26 weeks as mono therapy in patients with type 2 diabetes mellitus with insufficient glycaemic control. Furthermore, long-term safety is evaluated with an extension treatment to 52 weeks.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Japanese patients with a diagnosis of type 2 diabetes mellitus. Antidiabetic therapy has to be stable for at least 10 weeks before Visit 1. 2. Glycosylated haemoglobin A1 (HbA1c) 7.0 - 10.0% at Visit 3 (beginning of the 2-week placebo run-in phase) 3. Age: \>= 20 and \<= 80 4. Body Mass Index (BMI) \<= 40 kg/m2
Exclusion criteria
1. Myocardial infarction, stroke or transient ischemic attack (TIA) within 6 months before Visit 1 2. Impaired hepatic function 3. History of severe allergy/hypersensitivity 4. Treatment with anti-diabetic, anti obesity drugs, etc 3 months before Visit 1 5. Fasting blood glucose \>240 mg/dl (=13.3 mmol/L) at Visits 2 or 3
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c at Week 12 | 12 weeks | Change from the baseline measurement, where the baseline measurement was obtained at randomization (0 week) before receiving study medication |
| Change From Baseline in HbA1c at Week 26 | 26 weeks | Change from the baseline measurement, where the baseline measurement was obtained at randomization (0 week) before receiving study medication |
| Examination of Long-term Safety of Linagliptin (52-week Treatment) | 52 weeks | The incidence of AEs (Preferred Terms) with a frequency of 5% or more in the patients with type 2 diabetes mellitus who received linagliptin (5 mg or 10 mg) once daily for 52 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | 12 weeks | Change from the baseline measurement, where the baseline measurement was obtained at randomization (0 week) before receiving study medication |
| Relative Efficacy Response of HbA1c at Week 12 | 12 weeks | HbA1c value decreased below 7.0%, below 6.5% and reduction from baseline ≥0.5% at Week 12 |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 52 | 52 weeks | Change from the baseline measurement, where the baseline measurement was obtained at randomization (0 week) before receiving study medication |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | 26 weeks | Change from the baseline measurement, where the baseline measurement was obtained at randomization (0 week) before receiving study medication |
| Relative Efficacy Response of HbA1c at Week 26 | 26 weeks | HbA1c value decreased below 7.0%, below 6.5% and reduction from baseline ≥0.5% at Week 26 |
| Relative Efficacy Response of HbA1c at Week 52 | 52 weeks | HbA1c value decreased below 7.0%, below 6.5% and reduction from baseline ≥0.5% at Week 52 |
Countries
Japan
Participant flow
Recruitment details
Total 6 groups (including sub-groups in placebo and voglibose groups)
Pre-assignment details
Placebo group has 2 sub-groups, placebo-linagliptin 5mg (from 2nd stage) and placebo-linagliptin 10mg (from 2nd stage). Both Linagliptin 5 mg and 10 mg groups don't have sub-group. Voglibose group has 2 sub-groups, voglibose-linagliptin 5mg (from 3rd stage) and voglibose-linagliptin 10mg (from 3rd stage).
Participants by arm
| Arm | Count |
|---|---|
| Placebo The patients with placebo at the start of randomised study medication | 80 |
| Linagliptin 5mg The patients with linagliptin 5 mg at the start of randomised study medication | 159 |
| Linagliptin 10 mg The patients with linagliptin 10 mg at the start of randomised study medication | 160 |
| Voglibose The patients with voglibose at the start of randomised study medication | 162 |
| Total | 561 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| 1st Stage | Adverse Event | 3 | 3 | 3 | 3 | 2 | 1 |
| 1st Stage | Investigator's decision | 0 | 0 | 0 | 1 | 0 | 0 |
| 1st Stage | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 1 |
| 2nd Stage | Adverse Event | 2 | 0 | 2 | 3 | 7 | 2 |
| 2nd Stage | Investigator's decision | 0 | 0 | 1 | 1 | 0 | 0 |
| 2nd Stage | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 1 |
| Extension Stage | Adverse Event | 1 | 2 | 9 | 7 | 1 | 1 |
| Extension Stage | Closure of the trial site | 0 | 0 | 0 | 0 | 1 | 1 |
| Extension Stage | Lack of Efficacy | 0 | 0 | 1 | 0 | 0 | 0 |
| Extension Stage | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 |
| Extension Stage | Withdrawal by Subject | 0 | 0 | 1 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Linagliptin 5mg | Linagliptin 10 mg | Voglibose | Total |
|---|---|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 8.9 | 60.3 years STANDARD_DEVIATION 9.4 | 61.3 years STANDARD_DEVIATION 10 | 58.5 years STANDARD_DEVIATION 9.9 | 60.0 years STANDARD_DEVIATION 9.7 |
| Sex: Female, Male Female | 23 Participants | 48 Participants | 48 Participants | 47 Participants | 166 Participants |
| Sex: Female, Male Male | 57 Participants | 111 Participants | 112 Participants | 115 Participants | 395 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 | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 80 | 19 / 36 | 21 / 38 | 101 / 159 | 107 / 160 | 83 / 162 | 28 / 71 | 31 / 76 |
| serious Total, serious adverse events | 1 / 80 | 3 / 36 | 1 / 38 | 14 / 159 | 10 / 160 | 7 / 162 | 3 / 71 | 3 / 76 |
Outcome results
Primary
Change From Baseline in HbA1c at Week 12
Change from the baseline measurement, where the baseline measurement was obtained at randomization (0 week) before receiving study medication
Time frame: 12 weeks
Population: For the 12-week analysis, it was planed the comparison between Linagliptin and placebo. Then the patients with voglibose were excluded in this analysis.Full analysis set for 12-week treatment period with Last Observation Carried Forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c at Week 12 | 0.63 Percent | Standard Error 0.08 |
| Linagliptin 5mg | Change From Baseline in HbA1c at Week 12 | -0.24 Percent | Standard Error 0.06 |
| Linagliptin 10 mg | Change From Baseline in HbA1c at Week 12 | -0.25 Percent | Standard Error 0.06 |
Comparison: Linagliptin 5 mg vs placebo at week 12p-value: <0.000195% CI: [-1.04, -0.7]ANCOVA
Comparison: Linagliptin 10 mg vs placebo at week 12p-value: <0.000195% CI: [-1.05, -0.71]ANCOVA
Primary
Change From Baseline in HbA1c at Week 26
Change from the baseline measurement, where the baseline measurement was obtained at randomization (0 week) before receiving study medication
Time frame: 26 weeks
Population: For the 26-week analysis, it was planed the comparison between Linagliptin and Voglibose. Then the patients with placebo were excluded in this analysis.Full analysis set for 26-week treatment period with Last Observation Carried Forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c at Week 26 | -0.13 Percent | Standard Error 0.07 |
| Linagliptin 5mg | Change From Baseline in HbA1c at Week 26 | -0.19 Percent | Standard Error 0.07 |
| Linagliptin 10 mg | Change From Baseline in HbA1c at Week 26 | 0.19 Percent | Standard Error 0.07 |
p-value: 0.000395% CI: [-0.49, -0.15]ANCOVA
Comparison: Linagliptin 10 mg vs voglibose at week 26p-value: <0.000195% CI: [-0.56, -0.21]ANCOVA
Primary
Examination of Long-term Safety of Linagliptin (52-week Treatment)
The incidence of AEs (Preferred Terms) with a frequency of 5% or more in the patients with type 2 diabetes mellitus who received linagliptin (5 mg or 10 mg) once daily for 52 weeks
Time frame: 52 weeks
Population: The patients who received at least one dose of linagliptin 5 mg or linagliptin 10 mg during the randomised treatment period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Examination of Long-term Safety of Linagliptin (52-week Treatment) | Nasopharyngitis | 84 participants |
| Placebo | Examination of Long-term Safety of Linagliptin (52-week Treatment) | Back pain | 15 participants |
| Placebo | Examination of Long-term Safety of Linagliptin (52-week Treatment) | Constipation | 12 participants |
| Linagliptin 5mg | Examination of Long-term Safety of Linagliptin (52-week Treatment) | Nasopharyngitis | 81 participants |
| Linagliptin 5mg | Examination of Long-term Safety of Linagliptin (52-week Treatment) | Back pain | 21 participants |
| Linagliptin 5mg | Examination of Long-term Safety of Linagliptin (52-week Treatment) | Constipation | 19 participants |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12
Change from the baseline measurement, where the baseline measurement was obtained at randomization (0 week) before receiving study medication
Time frame: 12 weeks
Population: For the 12-week analysis, it was planed the comparison between Linagliptin and placebo. Then the patients with voglibose were excluded in this analysis.Full analysis set for 12-week treatment period with Last Observation Carried Forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | 7.4 mg/dL | Standard Error 2.5 |
| Linagliptin 5mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | -12.3 mg/dL | Standard Error 1.9 |
| Linagliptin 10 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | -13.0 mg/dL | Standard Error 1.9 |
Comparison: Linagliptin 5 mg vs placebo at week 12p-value: <0.000195% CI: [-25.4, -14]ANCOVA
Comparison: Linagliptin 10 mg vs placebo at week 12p-value: <0.000195% CI: [-26.2, -14.7]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
Change from the baseline measurement, where the baseline measurement was obtained at randomization (0 week) before receiving study medication
Time frame: 26 weeks
Population: For the 26-week analysis, it was planed the comparison between Linagliptin and Voglibose. Then the patients with placebo were excluded in this analysis.Full analysis set for 26-week treatment period with Last Observation Carried Forward
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -5.0 mg/dL | Standard Error 2.4 |
| Linagliptin 5mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -7.8 mg/dL | Standard Error 2.4 |
| Linagliptin 10 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | 2.0 mg/dL | Standard Error 2.4 |
Comparison: Linagliptin 5 mg vs Voglibose at week 26p-value: 0.023995% CI: [-13, -0.9]ANCOVA
Comparison: Linagliptin 10 mg vs voglibose at week 26p-value: 0.001595% CI: [-15.8, -3.8]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 52
Change from the baseline measurement, where the baseline measurement was obtained at randomization (0 week) before receiving study medication
Time frame: 52 weeks
Population: The patients who had at least one available baseline FPG measurement under the treatment with linagliptin
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 52 | -3.2 mg/dL | Standard Error 2.7 |
| Linagliptin 5mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 52 | -5.9 mg/dL | Standard Error 2.7 |
Secondary
Relative Efficacy Response of HbA1c at Week 12
HbA1c value decreased below 7.0%, below 6.5% and reduction from baseline ≥0.5% at Week 12
Time frame: 12 weeks
Population: For the 12-week analysis, it was planed the comparison between Linagliptin and placebo. Then the patients with voglibose were excluded in this analysis.Full analysis set for 12-week treatment period with Last Observation Carried Forward.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Relative Efficacy Response of HbA1c at Week 12 | HbA1c <6.5% | 0 Participants |
| Placebo | Relative Efficacy Response of HbA1c at Week 12 | HbA1c <7.0% | 8 Participants |
| Placebo | Relative Efficacy Response of HbA1c at Week 12 | HbA1c reduction from baseline ≥0.5% | 7 Participants |
| Linagliptin 5mg | Relative Efficacy Response of HbA1c at Week 12 | HbA1c <6.5% | 15 Participants |
| Linagliptin 5mg | Relative Efficacy Response of HbA1c at Week 12 | HbA1c <7.0% | 42 Participants |
| Linagliptin 5mg | Relative Efficacy Response of HbA1c at Week 12 | HbA1c reduction from baseline ≥0.5% | 91 Participants |
| Linagliptin 10 mg | Relative Efficacy Response of HbA1c at Week 12 | HbA1c <7.0% | 56 Participants |
| Linagliptin 10 mg | Relative Efficacy Response of HbA1c at Week 12 | HbA1c reduction from baseline ≥0.5% | 94 Participants |
| Linagliptin 10 mg | Relative Efficacy Response of HbA1c at Week 12 | HbA1c <6.5% | 18 Participants |
Secondary
Relative Efficacy Response of HbA1c at Week 26
HbA1c value decreased below 7.0%, below 6.5% and reduction from baseline ≥0.5% at Week 26
Time frame: 26 weeks
Population: For the 26-week analysis, it was planed the comparison between Linagliptin and Voglibose. Then the patients with placebo were excluded in this analysis.Full analysis set for 26-week treatment period with Last Observation Carried Forward.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Relative Efficacy Response of HbA1c at Week 26 | HbA1c <6.5% | 15 Participants |
| Placebo | Relative Efficacy Response of HbA1c at Week 26 | HbA1c <7.0% | 48 Participants |
| Placebo | Relative Efficacy Response of HbA1c at Week 26 | HbA1c reduction from baseline ≥0.5% | 91 Participants |
| Linagliptin 5mg | Relative Efficacy Response of HbA1c at Week 26 | HbA1c <6.5% | 21 Participants |
| Linagliptin 5mg | Relative Efficacy Response of HbA1c at Week 26 | HbA1c <7.0% | 54 Participants |
| Linagliptin 5mg | Relative Efficacy Response of HbA1c at Week 26 | HbA1c reduction from baseline ≥0.5% | 84 Participants |
| Linagliptin 10 mg | Relative Efficacy Response of HbA1c at Week 26 | HbA1c <7.0% | 36 Participants |
| Linagliptin 10 mg | Relative Efficacy Response of HbA1c at Week 26 | HbA1c reduction from baseline ≥0.5% | 61 Participants |
| Linagliptin 10 mg | Relative Efficacy Response of HbA1c at Week 26 | HbA1c <6.5% | 7 Participants |
Secondary
Relative Efficacy Response of HbA1c at Week 52
HbA1c value decreased below 7.0%, below 6.5% and reduction from baseline ≥0.5% at Week 52
Time frame: 52 weeks
Population: For the 52-week analysis, it was planed to analyse for Linagliptin 5mg and 10mg. Then the patients with placebo and voglibose were excluded in this analysis. Full analysis set for 52-week treatment period with Last Observation Carried Forward
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Relative Efficacy Response of HbA1c at Week 52 | HbA1c <6.5% | 6 Participants |
| Placebo | Relative Efficacy Response of HbA1c at Week 52 | HbA1c reduction from baseline ≥0.5% | 62 Participants |
| Placebo | Relative Efficacy Response of HbA1c at Week 52 | HbA1c <7.0% | 38 Participants |
| Linagliptin 5mg | Relative Efficacy Response of HbA1c at Week 52 | HbA1c <6.5% | 10 Participants |
| Linagliptin 5mg | Relative Efficacy Response of HbA1c at Week 52 | HbA1c reduction from baseline ≥0.5% | 62 Participants |
| Linagliptin 5mg | Relative Efficacy Response of HbA1c at Week 52 | HbA1c <7.0% | 29 Participants |