Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the current study is to investigate the efficacy, safety and tolerability of BI 1356 (5 mg once daily) compared to placebo given for 24 weeks as add-on therapy to metformin in combination with a sulphonylurea in patients with type 2 diabetes mellitus with insufficient glycaemic control.
Interventions
DRUGlinagliptin
active
DRUGplacebo
placebo to linagliptin 5 mg
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. Male and female patients with a diagnosis of type 2 diabetes mellitus, currently treated only with a stable total daily dose of preferably\* \>/= 1500 mg metformin and a dose of a sulphonylurea drug that has been documented, by the Investigator, to be the individual maximum tolerated dose of that sulphonylurea drug. Both the dose and dosing regimen of metformin and the sulphonylurea must be stable (i.e. unchanged) for 10 weeks prior to informed consent, and must not be changed for the duration of the trial 2. Glycosylated haemoglobin A1 (HbA1c) \>/= 7.0 and \</= 10.0% at the screening Visit 1a and at Visit 2 (start of placebo run-in phase) 3. Age \>/= 18 and \</= 80 years at Visit 1a (screening) 4. BMI (Body Mass Index) \</= 40 kg/m2 at Visit 1a (screening) 5. Signed and dated written informed consent, at the latest by the date of Visit 1a, in accordance with GCP and local legislation \*Patients currently treated with a total daily dose of less than 1500 mg metformin can be included in the trial if the Investigator has documented that the dose is the maximum tolerated dose of metformin for that patient.
Exclusion criteria
1. Myocardial infarction, stroke or TIA (transient ischaemic attack) within 6 months prior to the date of informed consent 2. Impaired hepatic function, defined by serum levels of either alanine transaminase (ALT/SGPT), aspartase transaminase (AST/SGOT), or alkaline phosphatase (ALP) above 3 times the upper limit of normal (ULN), as determined at Visit 1a 3. Renal failure or renal impairment (serum creatinine \>/= 1.5 mg/dl) as determined at Visit 1a 4. Treatment with rosiglitazone or pioglitazone within 3 months prior to the date of informed consent 5. Treatment with GLP-1 analogues (e.g. exenatide) within 3 months prior to the date of informed consent 6. Treatment with insulin within 3 months prior to the date of informed consent 7. Treatment with anti-obesity drugs (e.g. sibutramine, rimonabant, orlistat) within 3 months prior to the date of informed consent 8. Current treatment with systemic steroids (i.e. at the time of informed consent) or a change in the dosage of thyroid hormones within 6 weeks prior to the date of informed consent 9. Pre-menopausal women (last menstruation \</= 1 year prior to the date of informed consent) who: * are nursing or pregnant * 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 periodic pregnancy testing during their participation in the trial. Acceptable methods of birth control include transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence and vasectomised partner. No exception will be made. 10. Known hypersensitivity or allergy to the investigational product or its excipients or to the trial background therapy (i.e. metformin in combination with a sulphonylurea) or sulphonamides 11. Dehydration (as confirmed by the Investigators clinical opinion) 12. Current acute or chronic metabolic acidosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline to Week 24 | Baseline and week 24 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HbA1c Change From Baseline to 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. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
| HbA1c Change From Baseline to Week 18 | Baseline and week 18 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
| FPG Change From Baseline to Week 24 | Baseline and week 24 | This change from baseline reflects the Week 24 FPG minus the baseline FPG. Means are treatment-adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. |
| FPG Change From Baseline to Week 6 | Baseline and week 6 | This change from baseline reflects the Week 6 FPG minus the baseline FPG. Means are treatment-adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. |
| FPG Change From Baseline to Week 12 | Baseline and week 12 | This change from baseline reflects the Week 12 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication. |
| HbA1c Change From Baseline to Week 6 | Baseline and week 6 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication. |
| Percentage of Patients With HbA1c <7.0% at Week 24 | Baseline and week 24 | The percentage of patients with an HbA1c value below 7% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 7%. Only patients with baseline HbA1c \>= 7% |
| Percentage of Patients With HbA1c < 7.0% at Week 24 | Baseline and week 24 | The percentage of patients with an HbA1c value below 7% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 7%. |
| Percentage of Patients With HbA1c <6.5% at Week 24 | Baseline and week 24 | The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 6.5%. Only patients with baseline HbA1c \>= 6.5% |
| Percentage of Patients With HbA1c<6.5% at Week 24 | Baseline and week 24 | The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 6.5% |
| Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24 | Baseline and week 24 | The percentage of patients with an HbA1c reduction greater than 0.5% at week 24 from baseline was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c reduction less than 0.5% |
| FPG Change From Baseline to Week 18 | Baseline and week 18 | This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. Means are treatment-adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication |
Countries
Argentina, Belgium, Canada, China, Germany, Philippines, Russia, South Korea, Taiwan, Turkey (Türkiye), United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients randomized to receive treatment with matching placebo | 263 |
| Linagliptin Patients randomized to receive treatment with Linagliptin 5mg | 792 |
| Total | 1,055 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 23 |
| Overall Study | Other incl. lack of efficacy | 4 | 2 |
| Overall Study | Protocol Violation | 4 | 19 |
| Overall Study | Withdrawal by Subject | 8 | 14 |
Baseline characteristics
| Characteristic | Placebo | Linagliptin | Total |
|---|---|---|---|
| Age, Continuous | 57.6 Years STANDARD_DEVIATION 9.7 | 58.3 Years STANDARD_DEVIATION 9.9 | 58.1 Years STANDARD_DEVIATION 9.8 |
| Body mass index (BMI) continuous | 28.16 kg/m^2 STANDARD_DEVIATION 4.52 | 28.38 kg/m^2 STANDARD_DEVIATION 4.79 | 28.33 kg/m^2 STANDARD_DEVIATION 4.72 |
| Fasting Plasma Glucose (FPG) | 162.6 mg/dL STANDARD_DEVIATION 37.1 | 159.3 mg/dL STANDARD_DEVIATION 36.5 | 160.1 mg/dL STANDARD_DEVIATION 36.6 |
| Glycosylated Hemoglobin A1 (HbA1c) | 8.14 Percent STANDARD_DEVIATION 0.84 | 8.15 Percent STANDARD_DEVIATION 0.8 | 8.14 Percent STANDARD_DEVIATION 0.81 |
| Sex: Female, Male Female | 136 Participants | 421 Participants | 557 Participants |
| Sex: Female, Male Male | 127 Participants | 371 Participants | 498 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 94 / 263 | 273 / 792 |
| serious Total, serious adverse events | 10 / 263 | 25 / 792 |
Outcome results
Primary
HbA1c Change From Baseline to Week 24
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and week 24
Population: The Full Analysis Set (FAS) included all treated and randomised 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 to Week 24 | -0.10 Percent | Standard Error 0.05 |
| Linagliptin | HbA1c Change From Baseline to Week 24 | -0.72 Percent | Standard Error 0.03 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.73, -0.5]ANCOVA
Secondary
FPG Change From Baseline to Week 12
This change from baseline reflects the Week 12 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and week 12
Population: This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline to Week 12 | 6.2 mg/dL | Standard Error 2 |
| Linagliptin | FPG Change From Baseline to Week 12 | -9.5 mg/dL | Standard Error 1.2 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-20.3, -11.1]ANCOVA
Secondary
FPG Change From Baseline to Week 18
This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. Means are treatment-adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication
Time frame: Baseline and week 18
Population: This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline to Week 18 | 7.4 mg/dL | Standard Error 2.2 |
| Linagliptin | FPG Change From Baseline to Week 18 | -4.7 mg/dL | Standard Error 1.3 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-17.2, -7.1]ANCOVA
Secondary
FPG Change From Baseline to Week 24
This change from baseline reflects the Week 24 FPG minus the baseline FPG. Means are treatment-adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and week 24
Population: This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline to Week 24 | 8.1 mg/dL | Standard Error 2.4 |
| Linagliptin | FPG Change From Baseline to Week 24 | -4.6 mg/dL | Standard Error 1.4 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-18.1, -7.3]ANCOVA
Secondary
FPG Change From Baseline to Week 6
This change from baseline reflects the Week 6 FPG minus the baseline FPG. Means are treatment-adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.
Time frame: Baseline and week 6
Population: This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | FPG Change From Baseline to Week 6 | 6.3 mg/dL | Standard Error 2 |
| Linagliptin | FPG Change From Baseline to Week 6 | -11.5 mg/dL | Standard Error 1.2 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-22.4, -13.2]ANCOVA
Secondary
HbA1c Change From Baseline to Week 12
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 12 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and week 12
Population: The Full Analysis Set (FAS) included all treated and randomised 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 to Week 12 | -0.15 Percent | Standard Error 0.04 |
| Linagliptin | HbA1c Change From Baseline to Week 12 | -0.84 Percent | Standard Error 0.03 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.78, -0.58]ANCOVA
Secondary
HbA1c Change From Baseline to Week 18
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and week 18
Population: The Full Analysis Set (FAS) included all treated and randomised 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 to Week 18 | -0.11 Percent | Standard Error 0.05 |
| Linagliptin | HbA1c Change From Baseline to Week 18 | -0.81 Percent | Standard Error 0.03 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.8, -0.59]ANCOVA
Secondary
HbA1c Change From Baseline to Week 6
HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.
Time frame: Baseline and week 6
Population: The Full Analysis Set (FAS) included all treated and randomised 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 to Week 6 | -0.18 Percent | Standard Error 0.03 |
| Linagliptin | HbA1c Change From Baseline to Week 6 | -0.67 Percent | Standard Error 0.02 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.56, -0.41]ANCOVA
Secondary
Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24
The percentage of patients with an HbA1c reduction greater than 0.5% at week 24 from baseline was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c reduction less than 0.5%
Time frame: Baseline and week 24
Population: The Full Analysis Set (FAS) included all patients with a baseline and at least one on treatment HbA1c measurement available. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24 | 30.2 percentage of patients | 0 |
| Linagliptin | Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24 | 58.2 percentage of patients | 0 |
Comparison: Linagliptin vs. Placebo~The odds-ratio is based on a logistic regression model including baseline HbA1c and previous antidiabetes medication.p-value: <0.000195% CI: [2.474, 4.562]Regression, Logistic
Secondary
Percentage of Patients With HbA1c<6.5% at Week 24
The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 6.5%
Time frame: Baseline and week 24
Population: This population includes the Full Analysis Set (FAS). Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c<6.5% at Week 24 | 4.2 percentage of patients |
| Linagliptin | Percentage of Patients With HbA1c<6.5% at Week 24 | 13.1 percentage of patients |
Secondary
Percentage of Patients With HbA1c <6.5% at Week 24
The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 6.5%. Only patients with baseline HbA1c \>= 6.5%
Time frame: Baseline and week 24
Population: This population includes the FAS with baseline HbA1c \>= 6.5%. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Patients With HbA1c <6.5% at Week 24 | 4.2 percentage of patients | 0 |
| Linagliptin | Percentage of Patients With HbA1c <6.5% at Week 24 | 13.1 percentage of patients | 0 |
Comparison: Linagliptin vs. Placebo~The odds-ratio is based on a logistic regression model including baseline HbA1c and previous antidiabetes medication.p-value: <0.000195% CI: [1.989, 7.327]Regression, Logistic
Secondary
Percentage of Patients With HbA1c < 7.0% at Week 24
The percentage of patients with an HbA1c value below 7% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 7%.
Time frame: Baseline and week 24
Population: This population includes the Full Analysis Set (FAS). Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With HbA1c < 7.0% at Week 24 | 9.2 percentage of patients |
| Linagliptin | Percentage of Patients With HbA1c < 7.0% at Week 24 | 31.2 percentage of patients |
Secondary
Percentage of Patients With HbA1c <7.0% at Week 24
The percentage of patients with an HbA1c value below 7% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 7%. Only patients with baseline HbA1c \>= 7%
Time frame: Baseline and week 24
Population: This population includes the FAS with baseline HbA1c \>= 7.0%. Non-completers were considered as failure imputation (NCF).
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Placebo | Percentage of Patients With HbA1c <7.0% at Week 24 | 8.1 percentage of patients | 0 |
| Linagliptin | Percentage of Patients With HbA1c <7.0% at Week 24 | 29.2 percentage of patients | 0 |
Comparison: Linagliptin vs. Placebo~The odds-ratio is based on a logistic regression model including baseline HbA1c and previous antidiabetes medication.p-value: <0.000195% CI: [3.332, 9.111]Regression, Logistic