Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the current study is to investigate the efficacy, safety and tolerability of several doses of BI 1356 BS (0.5, 2.5 and 5 mg daily) compared to placebo over 12 weeks of treatment in patients with Type 2 diabetes and insufficient glycemic control. In addition, there will be an open-label treatment arm with metformin for sensitivity measurement with this patient population. Population pharmacokinetics of BI 1356 BS will also be assessed in this study.
Interventions
DRUGPlacebo
Placebo matching BI 1356
DRUGBI 1356 dose 3 once daily
BI 1356 dose 3 once daily
DRUGBI 1356 dose 2 once daily
BI 1356 dose 2 once daily
DRUGBI 1356 dose 1 once daily
BI 1356 dose 1 once daily
DRUGMetformin
Metformin
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
21 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Male and female patients with a diagnosis of Type 2 diabetes treated only with diet and exercise (drug naïve) or with one or two oral hypoglycemic agents (as single treatment or in combination) other than rosiglitazone or pioglitazone -treatment. Antidiabetic therapy has to be stable for at least 10 weeks prior to screening. 2. Diagnosis of Type 2 diabetes with duration of at least 3 months 3. Glycosylated haemoglobin A1 (HbA1c) of: 7.5-10.0% at screening for drug naïve patients (no wash-out needed) 7.0-9.0% at screening for patients treated with only one oral antidiabetic agent (wash-out required) 6.5-8.0% at screening for patients treated with two oral antidiabetic agents (wash-out required) 4. HbA1c of 7.5%-10.0% at Visit 3 (beginning of the 2-week placebo run-in period). 5. Age \>=21 and \<=75 years. 6. BMI (Body Mass Index) \>=25.0 and \<=40 kg/m2. 7. Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
1. Clinically relevant cardiovascular disease (e.g., myocardial infarction, stroke or transient ischemic attack within six months before enrollment) 2. Impaired hepatic function defined by serum levels of either alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase above 3-fold upper limit of normal 3. Renal insufficiency or impaired renal function defined by serum creatinine above upper limit of normal at screening 4. Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or clinically relevant neurologic disorders (including cerebrovascular but with the exception of polyneuropathy) that would interfere with participation in the trial 5. Chronic or clinically relevant acute infections (e.g., Human immunodeficiency virus, Hepatitis) 6. History of relevant allergy/hypersensitivity that would interfere with trial participation (including allergy to investigational product or its excipients) 7. Treatment with rosiglitazone or pioglitazone within 6 months prior to screening 8. Treatment with insulin within 3 months prior to screening 9. Alcohol or drug abuse within the last 3 months that would interfere with trial participation) 10. Participation in another trial with an investigational drug within two months prior to administration or during the trial 11. Fasting plasma glucose \>240 mg/dl (= 13.3 mmol/L) at Visit 2, 3 or 4 any visit and confirmed by a second measurement (not on the same day) 12. Pre-menopausal women (last menstruation \<=1 year prior to signing informed consent) who: 1. are not surgically sterile, 2. or are nursing or pregnant; 3. or are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include transdermal patch, intra-uterine devices, oral, implantable or injectable contraceptives and vasectomised partner. No exception will be made. 13. Intolerance of metformin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 12 | Baseline, week 12 | The change from baseline reflects the Week 12 HbA1c minus the Week 0 HbA1c. Means are adjusted for baseline HbA1c. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | Baseline, week 12 | Change from baseline reflects the Week 12 FPG minus the Week 0 FPG. Means are adjusted for baseline FPG. |
| Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | Baseline, week 12 | An absolute efficacy response is defined as HbA1c \<= 7.0% at 12 weeks. A non-response is defined as HbA1c \> 7.0% at 12 weeks. |
Countries
Australia, Canada, Czechia, Russia, Ukraine, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients randomized to receive treatment with matching placebo | 67 |
| Linagliptin (BI 1356) 0.5 mg Patients randomized to receive treatment with linagliptin 0.5 mg | 58 |
| Linagliptin (BI 1356) 2.5 mg Patients randomized to receive treatment with linagliptin 2.5 mg | 57 |
| Linagliptin (BI 1356) 5.0 mg Patients randomized to receive treatment with linagliptin 5.0 mg | 55 |
| Metformin Patients randomized to receive treatment with metformin | 65 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 | 1 | 2 | 1 |
| Overall Study | Lack of Efficacy | 14 | 9 | 4 | 4 | 3 |
| Overall Study | Lost to Follow-up | 1 | 1 | 2 | 1 | 1 |
| Overall Study | Other reason (not specified) | 3 | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 1 | 6 | 0 |
Baseline characteristics
| Characteristic | Placebo | Linagliptin (BI 1356) 0.5 mg | Linagliptin (BI 1356) 2.5 mg | Linagliptin (BI 1356) 5.0 mg | Metformin | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 8.9 | 58.0 years STANDARD_DEVIATION 9.4 | 59.8 years STANDARD_DEVIATION 10.3 | 56.6 years STANDARD_DEVIATION 9.6 | 53.7 years STANDARD_DEVIATION 10.7 | 57.3 years STANDARD_DEVIATION 9.9 |
| Baseline glycosylated hemoglobin (HbA1c) | 8.3 percentage STANDARD_DEVIATION 0.63 | 8.2 percentage STANDARD_DEVIATION 0.62 | 8.4 percentage STANDARD_DEVIATION 0.8 | 8.4 percentage STANDARD_DEVIATION 0.8 | 8.3 percentage STANDARD_DEVIATION 0.64 | 8.3 percentage STANDARD_DEVIATION 0.69 |
| Body Mass Index (BMI) | 30.8 kilogram/square meter STANDARD_DEVIATION 4.1 | 30.9 kilogram/square meter STANDARD_DEVIATION 3.8 | 31.5 kilogram/square meter STANDARD_DEVIATION 4.5 | 31.2 kilogram/square meter STANDARD_DEVIATION 4.3 | 31.2 kilogram/square meter STANDARD_DEVIATION 4.8 | 31.1 kilogram/square meter STANDARD_DEVIATION 4.3 |
| Fasting blood plasma glucose (FPG) | 183.0 milligram/deciliter (mg/dL) STANDARD_DEVIATION 34.9 | 185.2 milligram/deciliter (mg/dL) STANDARD_DEVIATION 34 | 191.9 milligram/deciliter (mg/dL) STANDARD_DEVIATION 37.8 | 188.7 milligram/deciliter (mg/dL) STANDARD_DEVIATION 40.1 | 193.9 milligram/deciliter (mg/dL) STANDARD_DEVIATION 45.9 | 188.4 milligram/deciliter (mg/dL) STANDARD_DEVIATION 38.8 |
| Race/Ethnicity, Customized Asian | 3 participants | 3 participants | 1 participants | 2 participants | 2 participants | 11 participants |
| Race/Ethnicity, Customized Black | 6 participants | 3 participants | 3 participants | 1 participants | 5 participants | 18 participants |
| Race/Ethnicity, Customized Hispanic | 4 participants | 4 participants | 6 participants | 6 participants | 4 participants | 24 participants |
| Race/Ethnicity, Customized Missing | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic | 63 participants | 54 participants | 51 participants | 49 participants | 61 participants | 278 participants |
| Race/Ethnicity, Customized White | 58 participants | 52 participants | 53 participants | 52 participants | 57 participants | 272 participants |
| Sex: Female, Male Female | 34 Participants | 13 Participants | 30 Participants | 24 Participants | 26 Participants | 127 Participants |
| Sex: Female, Male Male | 33 Participants | 45 Participants | 27 Participants | 31 Participants | 39 Participants | 175 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 67 | 15 / 58 | 9 / 57 | 8 / 55 | 13 / 65 |
| serious Total, serious adverse events | 1 / 67 | 1 / 58 | 2 / 57 | 0 / 55 | 1 / 65 |
Outcome results
Primary
Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 12
The change from baseline reflects the Week 12 HbA1c minus the Week 0 HbA1c. Means are adjusted for baseline HbA1c.
Time frame: Baseline, week 12
Population: Full Analysis Set includes all randomized patients with baseline and on-treatment value of HbA1c. Last observation carried forward (LOCF) was used as the imputation rule.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 12 | 0.18 percent | Standard Error 0.1 |
| Linagliptin (BI 1356) 0.5 mg | Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 12 | 0.04 percent | Standard Error 0.1 |
| Linagliptin (BI 1356) 2.5 mg | Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 12 | -0.24 percent | Standard Error 0.1 |
| Linagliptin (BI 1356) 5.0 mg | Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 12 | -0.28 percent | Standard Error 0.1 |
| Metformin | Change From Baseline in HbA1c (Glycosylated Haemoglobin) at Week 12 | -0.68 percent | Standard Error 0.09 |
Comparison: Linagliptin 0.5 mg versus placebop-value: 0.327195% CI: [-0.41, 0.14]ANCOVA
Comparison: Linagliptin 2.5 mg versus placebop-value: 0.003295% CI: [-0.69, -0.14]ANCOVA
Comparison: Linagliptin 5.0 mg versus placebop-value: 0.001295% CI: [-0.74, -0.18]ANCOVA
Comparison: Metformin versus placebop-value: <0.000195% CI: [-1.1, -0.59]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12
Change from baseline reflects the Week 12 FPG minus the Week 0 FPG. Means are adjusted for baseline FPG.
Time frame: Baseline, week 12
Population: Full Analysis Set includes all randomized patients with baseline and on-treatment value of HbA1c. Last observation carried forward (LOCF) was used as the imputation rule.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | 4.24 mg/dL | Standard Error 4.4 |
| Linagliptin (BI 1356) 0.5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | 6.69 mg/dL | Standard Error 4.6 |
| Linagliptin (BI 1356) 2.5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | -15.2 mg/dL | Standard Error 4.7 |
| Linagliptin (BI 1356) 5.0 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | -9.09 mg/dL | Standard Error 4.8 |
| Metformin | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 | -30.1 mg/dL | Standard Error 4.3 |
Comparison: Linagliptin 0.5 mg versus placebop-value: 0.702795% CI: [-10, 15.1]ANCOVA
Comparison: Linagliptin 2.5 mg versus placebop-value: 0.00395% CI: [-32, -6.6]ANCOVA
Comparison: Linagliptin 5.0 mg versus placebop-value: 0.041895% CI: [-26, -0.5]ANCOVA
p-value: <0.000195% CI: [-47, -22]ANCOVA
Secondary
Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks
An absolute efficacy response is defined as HbA1c \<= 7.0% at 12 weeks. A non-response is defined as HbA1c \> 7.0% at 12 weeks.
Time frame: Baseline, week 12
Population: FAS patients with baseline HbA1c \> 7.0%. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | HbA1c <= 7% | 6.3 participants |
| Placebo | Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | HbA1c > 7% | 93.7 participants |
| Linagliptin (BI 1356) 0.5 mg | Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | HbA1c <= 7% | 10.5 participants |
| Linagliptin (BI 1356) 0.5 mg | Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | HbA1c > 7% | 89.5 participants |
| Linagliptin (BI 1356) 2.5 mg | Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | HbA1c <= 7% | 7.3 participants |
| Linagliptin (BI 1356) 2.5 mg | Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | HbA1c > 7% | 92.7 participants |
| Linagliptin (BI 1356) 5.0 mg | Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | HbA1c > 7% | 88.9 participants |
| Linagliptin (BI 1356) 5.0 mg | Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | HbA1c <= 7% | 11.1 participants |
| Metformin | Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | HbA1c <= 7% | 26.2 participants |
| Metformin | Percentage of Patients With Absolute Efficacy Response (HbA1c <= 7.0%) at 12 Weeks | HbA1c > 7% | 73.8 participants |
Comparison: Linagliptin 0.5 mg versus placebop-value: 0.41395% CI: [0.464, 6.492]Regression, Logistic
Comparison: Linagliptin 2.5 mg versus placebop-value: 0.84295% CI: [0.275, 4.861]Regression, Logistic
Comparison: Linagliptin 5.0 mg versus placebop-value: 0.36495% CI: [0.492, 6.91]Regression, Logistic
Comparison: Metformin versus placebop-value: 0.00595% CI: [1.648, 16.562]Regression, Logistic