Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the current study is to investigate the safety and efficacy of linagliptin (5mg / once daily) given for 52 weeks as add-on therapy to patients with type 2 diabetes mellitus and insufficient glycaemic control despite diet, exercise, and treatment with one approved antidiabetic drug.
Interventions
DRUGLinagliptin
Linagliptin once daily
DRUGMetformin
Metformin twice or three time per day
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of type 2 diabetes mellitus 2. Male and female patients on diet and exercise regimen who are treated with one antidiabetic drug
Exclusion criteria
1. Myocardial infarction, stroke, transient ischemic attack, or pulmonary embolism 2. Impaired hepatic function 3. Glitazone, glinide, and sulfonylurea group: renal failure or renal impairment defined as estimated glomerular filtration rate \<30 ml/min (severe renal impairment) at Visit 1, Biguanide group: renal failure or renal impairment defined as estimated glomerular filtration rate \<60 ml/min (moderate renal impairment) at Visit 1 4. Treatment with anti-obesity drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) | The first drug administration through 7 days after the last drug administration, up to 382 days | The number of patient with any AEs, patients with severe AE, patients with AEs leading to discontinuation of trial drug, and patients with Hypoglycaemic events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glycosylated Haemoglobin A1c (HbA1c) | Baseline and 52 weeks | The change from baseline in HbA1c after 52 weeks of treatment. When the HbA1c after 52 weeks treatment was missing, the value from the measurements at the closest preceding visit replaced the missing value. |
Countries
Japan
Participant flow
Recruitment details
A total of 618 patients were enrolled in the trial at 43 trial sites, and 37 patients were withdrawn from the trial because of screening failure. 581 patients were entered into the 2-week placebo run-in period, and 7 patients were withdrawn. 574 patients completed the 2-week placebo run-in period and took linagliptin 5 mg or metformin.
Participants by arm
| Arm | Count |
|---|---|
| Bigu+Lina biguanide plus linagliptin | 82 |
| Glin+Lina glinide plus linagliptin | 66 |
| Glit+Lina glitazone plus linagliptin | 74 |
| SU+Lina sulfonylurea plus linagliptin | 143 |
| A-GI+Lina alpha-glucosidase inhibitor plus linagliptin | 85 |
| SU+Met sulfonylurea plus metformin | 63 |
| A-GI+Met alpha-glucosidase inhibitor plus metformin | 61 |
| Total | 574 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 6 | 0 | 7 | 1 | 4 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 2 | 0 | 0 | 0 |
| Overall Study | Other (house moving) | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 2 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 | 2 | 1 | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Bigu+Lina | Glin+Lina | Glit+Lina | SU+Lina | A-GI+Lina | SU+Met | A-GI+Met | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Customized | 58.4 years STANDARD_DEVIATION 9.9 | 62.6 years STANDARD_DEVIATION 8.8 | 60.4 years STANDARD_DEVIATION 9.4 | 61.8 years STANDARD_DEVIATION 10.8 | 62.0 years STANDARD_DEVIATION 10.4 | 61.2 years STANDARD_DEVIATION 10.6 | 59.3 years STANDARD_DEVIATION 10.3 | 60.9 years STANDARD_DEVIATION 10.2 |
| Sex: Female, Male Female | 33 Participants | 18 Participants | 16 Participants | 38 Participants | 30 Participants | 19 Participants | 19 Participants | 173 Participants |
| Sex: Female, Male Male | 49 Participants | 48 Participants | 58 Participants | 105 Participants | 55 Participants | 44 Participants | 42 Participants | 401 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 | 55 / 82 | 41 / 66 | 37 / 74 | 83 / 143 | 54 / 85 | 31 / 63 | 33 / 61 |
| serious Total, serious adverse events | 8 / 82 | 5 / 66 | 2 / 74 | 7 / 143 | 7 / 85 | 5 / 63 | 3 / 61 |
Outcome results
Primary
Incidence of Adverse Events (AEs)
The number of patient with any AEs, patients with severe AE, patients with AEs leading to discontinuation of trial drug, and patients with Hypoglycaemic events
Time frame: The first drug administration through 7 days after the last drug administration, up to 382 days
Population: The treated set (TS) comprised all patients who received at least one dose of randomised study medication in the 52-week treatment period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bigu+Lina | Incidence of Adverse Events (AEs) | Patients with severe AE | 1 Patients |
| Bigu+Lina | Incidence of Adverse Events (AEs) | Patients with any AE | 69 Patients |
| Bigu+Lina | Incidence of Adverse Events (AEs) | Patients with Hypoglycaemic events | 1 Patients |
| Bigu+Lina | Incidence of Adverse Events (AEs) | Patients with AEs leading to discontinuation | 2 Patients |
| Glin+Lina | Incidence of Adverse Events (AEs) | Patients with Hypoglycaemic events | 0 Patients |
| Glin+Lina | Incidence of Adverse Events (AEs) | Patients with severe AE | 1 Patients |
| Glin+Lina | Incidence of Adverse Events (AEs) | Patients with any AE | 55 Patients |
| Glin+Lina | Incidence of Adverse Events (AEs) | Patients with AEs leading to discontinuation | 5 Patients |
| Glit+Lina | Incidence of Adverse Events (AEs) | Patients with severe AE | 0 Patients |
| Glit+Lina | Incidence of Adverse Events (AEs) | Patients with any AE | 62 Patients |
| Glit+Lina | Incidence of Adverse Events (AEs) | Patients with AEs leading to discontinuation | 0 Patients |
| Glit+Lina | Incidence of Adverse Events (AEs) | Patients with Hypoglycaemic events | 2 Patients |
| SU+Lina | Incidence of Adverse Events (AEs) | Patients with severe AE | 2 Patients |
| SU+Lina | Incidence of Adverse Events (AEs) | Patients with AEs leading to discontinuation | 8 Patients |
| SU+Lina | Incidence of Adverse Events (AEs) | Patients with any AE | 114 Patients |
| SU+Lina | Incidence of Adverse Events (AEs) | Patients with Hypoglycaemic events | 21 Patients |
| A-GI+Lina | Incidence of Adverse Events (AEs) | Patients with severe AE | 1 Patients |
| A-GI+Lina | Incidence of Adverse Events (AEs) | Patients with any AE | 71 Patients |
| A-GI+Lina | Incidence of Adverse Events (AEs) | Patients with AEs leading to discontinuation | 1 Patients |
| A-GI+Lina | Incidence of Adverse Events (AEs) | Patients with Hypoglycaemic events | 2 Patients |
| SU+Met | Incidence of Adverse Events (AEs) | Patients with severe AE | 1 Patients |
| SU+Met | Incidence of Adverse Events (AEs) | Patients with any AE | 44 Patients |
| SU+Met | Incidence of Adverse Events (AEs) | Patients with Hypoglycaemic events | 10 Patients |
| SU+Met | Incidence of Adverse Events (AEs) | Patients with AEs leading to discontinuation | 4 Patients |
| A-GI+Met | Incidence of Adverse Events (AEs) | Patients with Hypoglycaemic events | 2 Patients |
| A-GI+Met | Incidence of Adverse Events (AEs) | Patients with AEs leading to discontinuation | 0 Patients |
| A-GI+Met | Incidence of Adverse Events (AEs) | Patients with any AE | 52 Patients |
| A-GI+Met | Incidence of Adverse Events (AEs) | Patients with severe AE | 0 Patients |
Secondary
Glycosylated Haemoglobin A1c (HbA1c)
The change from baseline in HbA1c after 52 weeks of treatment. When the HbA1c after 52 weeks treatment was missing, the value from the measurements at the closest preceding visit replaced the missing value.
Time frame: Baseline and 52 weeks
Population: The full analysis set (FAS) comprised all treated patients who had baseline HbA1c measurement and at least one on-treatment HbA1c measurement available
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bigu+Lina | Glycosylated Haemoglobin A1c (HbA1c) | Change from baseline to 52 weeks | -0.88 Percentage | Standard Deviation 0.64 |
| Bigu+Lina | Glycosylated Haemoglobin A1c (HbA1c) | At 52 weeks | 7.10 Percentage | Standard Deviation 0.82 |
| Bigu+Lina | Glycosylated Haemoglobin A1c (HbA1c) | Baseline | 7.98 Percentage | Standard Deviation 0.75 |
| Glin+Lina | Glycosylated Haemoglobin A1c (HbA1c) | At 52 weeks | 7.19 Percentage | Standard Deviation 0.75 |
| Glin+Lina | Glycosylated Haemoglobin A1c (HbA1c) | Baseline | 7.92 Percentage | Standard Deviation 0.82 |
| Glin+Lina | Glycosylated Haemoglobin A1c (HbA1c) | Change from baseline to 52 weeks | -0.73 Percentage | Standard Deviation 0.65 |
| Glit+Lina | Glycosylated Haemoglobin A1c (HbA1c) | Change from baseline to 52 weeks | -0.79 Percentage | Standard Deviation 0.5 |
| Glit+Lina | Glycosylated Haemoglobin A1c (HbA1c) | Baseline | 7.86 Percentage | Standard Deviation 0.83 |
| Glit+Lina | Glycosylated Haemoglobin A1c (HbA1c) | At 52 weeks | 7.07 Percentage | Standard Deviation 0.74 |
| SU+Lina | Glycosylated Haemoglobin A1c (HbA1c) | At 52 weeks | 7.42 Percentage | Standard Deviation 0.91 |
| SU+Lina | Glycosylated Haemoglobin A1c (HbA1c) | Baseline | 8.12 Percentage | Standard Deviation 0.78 |
| SU+Lina | Glycosylated Haemoglobin A1c (HbA1c) | Change from baseline to 52 weeks | -0.70 Percentage | Standard Deviation 0.7 |
| A-GI+Lina | Glycosylated Haemoglobin A1c (HbA1c) | At 52 weeks | 6.96 Percentage | Standard Deviation 0.75 |
| A-GI+Lina | Glycosylated Haemoglobin A1c (HbA1c) | Baseline | 7.87 Percentage | Standard Deviation 0.75 |
| A-GI+Lina | Glycosylated Haemoglobin A1c (HbA1c) | Change from baseline to 52 weeks | -0.91 Percentage | Standard Deviation 0.61 |
| SU+Met | Glycosylated Haemoglobin A1c (HbA1c) | Baseline | 8.01 Percentage | Standard Deviation 0.64 |
| SU+Met | Glycosylated Haemoglobin A1c (HbA1c) | Change from baseline to 52 weeks | -0.82 Percentage | Standard Deviation 0.78 |
| SU+Met | Glycosylated Haemoglobin A1c (HbA1c) | At 52 weeks | 7.19 Percentage | Standard Deviation 0.72 |
| A-GI+Met | Glycosylated Haemoglobin A1c (HbA1c) | Change from baseline to 52 weeks | -1.09 Percentage | Standard Deviation 0.87 |
| A-GI+Met | Glycosylated Haemoglobin A1c (HbA1c) | At 52 weeks | 6.98 Percentage | Standard Deviation 0.75 |
| A-GI+Met | Glycosylated Haemoglobin A1c (HbA1c) | Baseline | 8.07 Percentage | Standard Deviation 1.04 |