Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the current study is to investigate the efficacy, safety and tolerability of BI 1356 (Linagliptin) (5 mg / once daily) compared to placebo given for 24 weeks as initial combination therapy with pioglitazone 30 mg in patients with type 2 diabetes mellitus with insufficient glycaemic control.
Interventions
DRUGplacebo + pioglitazone (30 mg)
placebo + overcapsulated 30 mg tablet, once daily
DRUGLinagliptin + pioglitazone (30 mg)
5 mg tablet + overcapsulated 30 mg tablet, 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. Signed and dated written Informed Consent (IC) by date of Visit 1a in accordance with Good Clinical Practice (GCP) and local legislation 2. Patients with a diagnosis of type 2 diabetes mellitus and treatment naive or previously treated with any oral hypoglycaemic agent; antidiabetic therapy has to be unchanged for ten weeks prior to informed consent. 3. Glycosylated haemoglobin A1 (HbA1c) 7.5-11% at Visit 2 (Start of Run-in). 4. Male and female patients aged \> or = 18 and \< or = to 80 years at Visit 1a (Screening). 5. Body Mass Index (BMI) \< or = 40 kg/m2 at Visit 1a (Screening) 6. Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation.
Exclusion criteria
1. Myocardial infarction, stroke or Transient Isquemic Atack (TIA) within 6 months prior to Inform Consent (IC) 2. Impaired hepatic function, defined by serum levels of either Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), or alkaline phosphatase above 3 x upper limit of normal (ULN) determined at Visit 1a. 3. Known hypersensitivity or allergy to the investigational product or its excipients and/or to hydrochloride of pioglitazone or its excipients 4. Treatment with Glucagon-like peptide-1 (GLP-1) analogue / agonist within 3 months prior to IC. 5. Treatment with insulin within 3 months prior to IC 6. Treatment with anti-obesity drugs 3 months prior to IC. 7. Alcohol abuse within the 3 months prior to IC that would interfere with trial participation or drug abuse. 8. Participation in another trial with an investigational drug within 2 months prior to IC. 9. Fasting blood glucose \> 240 mg/dl (=13.3 mmol/L) at screening (Visit 1). 10. Pre-menopausal women (last menstruation \< or =1 year prior to signing IC) 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 submit to periodic pregnancy testing during 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. 11. Treatment with systemic steroids or change in the dosage of thyroid hormone within six weeks prior to IC 12. Heart failure New York Heart Asociation (NYHA) class I-IV, or history of heart failure. 13. Diabetic ketoacidosis within 6 months prior to IC. 14. Hemodialyzed patients due to limited experience with Thiazolidinediones (TZDs) 15. Any other clinical condition wich, in the opinion of the investigator, would not alow safe completion of the protocol and safe administration of BI1356 and pioglitazone.
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 an HbA1c Lowering by 0.5% at Week 24 | Baseline and Week 24 | The percentage of patients with an HbA1c reduction from baseline greater than 0.5% 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 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 baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetes medication. |
Countries
Austria, Greece, Hungary, Japan, Portugal, Romania, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Pioglitazone Patients randomized to receive treatment with matching placebo (to Linagliptin 5 mg) and Pioglitazone 30 mg | 130 |
| Linagliptin + Pioglitazone Patients randomized to receive treatment with Linagliptin 5 mg and Pioglitazone 30 mg | 259 |
| Total | 389 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 4 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Other incl. lack of efficacy | 4 | 2 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Placebo + Pioglitazone | Linagliptin + Pioglitazone | Total |
|---|---|---|---|
| Age, Continuous | 57.1 Years STANDARD_DEVIATION 10.1 | 57.7 Years STANDARD_DEVIATION 9.6 | 57.5 Years STANDARD_DEVIATION 9.8 |
| Body mass index continuous | 29.72 kg/m^2 STANDARD_DEVIATION 4.84 | 28.68 kg/m^2 STANDARD_DEVIATION 4.82 | 29.02 kg/m^2 STANDARD_DEVIATION 4.85 |
| Fasting Plasma Glucose (FPG) | 190.3 mg/dL STANDARD_DEVIATION 43.8 | 189.8 mg/dL STANDARD_DEVIATION 42.7 | 189.9 mg/dL STANDARD_DEVIATION 43 |
| Glycosylated haemoglobin A1 (HbA1c) | 8.58 Percent STANDARD_DEVIATION 0.87 | 8.60 Percent STANDARD_DEVIATION 0.79 | 8.59 Percent STANDARD_DEVIATION 0.82 |
| Sex: Female, Male Female | 45 Participants | 107 Participants | 152 Participants |
| Sex: Female, Male Male | 85 Participants | 152 Participants | 237 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 130 | 33 / 259 |
| serious Total, serious adverse events | 3 / 130 | 8 / 259 |
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 + Pioglitazone | HbA1c Change From Baseline to Week 24 | -0.56 Percent | Standard Error 0.09 |
| Linagliptin + Pioglitazone | HbA1c Change From Baseline to Week 24 | -1.06 Percent | Standard Error 0.06 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.71, -0.3]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 + Pioglitazone | FPG Change From Baseline to Week 12 | -20.5 mg/dL | Standard Error 2.7 |
| Linagliptin + Pioglitazone | FPG Change From Baseline to Week 12 | -33.8 mg/dL | Standard Error 2 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-19.5, -7]ANCOVA
Secondary
FPG Change From Baseline to Week 18
This change from baseline reflects the Week 18 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetes 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 + Pioglitazone | FPG Change From Baseline to Week 18 | -19.3 mg/dL | Standard Error 2.9 |
| Linagliptin + Pioglitazone | FPG Change From Baseline to Week 18 | -33.2 mg/dL | Standard Error 2.1 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-20.5, -7.3]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 + Pioglitazone | FPG Change From Baseline to Week 24 | -18.4 mg/dL | Standard Error 3 |
| Linagliptin + Pioglitazone | FPG Change From Baseline to Week 24 | -32.6 mg/dL | Standard Error 2.2 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-21.1, -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 + Pioglitazone | FPG Change From Baseline to Week 6 | -17.0 mg/dL | Standard Error 2.5 |
| Linagliptin + Pioglitazone | FPG Change From Baseline to Week 6 | -33.3 mg/dL | Standard Error 1.9 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-22.3, -10.5]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 randomised and 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 + Pioglitazone | HbA1c Change From Baseline to Week 12 | -0.35 Percent | Standard Error 0.07 |
| Linagliptin + Pioglitazone | HbA1c Change From Baseline to Week 12 | -0.85 Percent | Standard Error 0.05 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.67, -0.32]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 + Pioglitazone | HbA1c Change From Baseline to Week 18 | -0.55 Percent | Standard Error 0.08 |
| Linagliptin + Pioglitazone | HbA1c Change From Baseline to Week 18 | -1.06 Percent | Standard Error 0.06 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.7, -0.32]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 randomised and 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 + Pioglitazone | HbA1c Change From Baseline to Week 6 | -0.03 Percent | Standard Error 0.06 |
| Linagliptin + Pioglitazone | HbA1c Change From Baseline to Week 6 | -0.41 Percent | Standard Error 0.04 |
Comparison: Linagliptin vs. Placebop-value: <0.000195% CI: [-0.52, -0.24]ANCOVA
Secondary
Percentage of Patients Who Have an HbA1c Lowering by 0.5% at Week 24
The percentage of patients with an HbA1c reduction from baseline greater than 0.5% 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 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 + Pioglitazone | Percentage of Patients Who Have an HbA1c Lowering by 0.5% at Week 24 | 50.8 percentage of patients | 0 |
| Linagliptin + Pioglitazone | Percentage of Patients Who Have an HbA1c Lowering by 0.5% at Week 24 | 75.0 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: [2.286, 6.394]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 + Pioglitazone | Percentage of Patients With HbA1c<6.5% at Week 24 | 14.1 percentage of patients |
| Linagliptin + Pioglitazone | Percentage of Patients With HbA1c<6.5% at Week 24 | 17.5 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 + Pioglitazone | Percentage of Patients With HbA1c <6.5% at Week 24 | 14.1 percentage of patients | 0 |
| Linagliptin + Pioglitazone | Percentage of Patients With HbA1c <6.5% at Week 24 | 17.5 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: 0.354795% CI: [0.716, 2.537]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 + Pioglitazone | Percentage of Patients With HbA1c<7.0 at Week 24 | 30.5 percentage of patients |
| Linagliptin + Pioglitazone | Percentage of Patients With HbA1c<7.0 at Week 24 | 42.9 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 + Pioglitazone | Percentage of Patients With HbA1c <7.0% at Week 24 | 30.5 percentage of patients | 0 |
| Linagliptin + Pioglitazone | Percentage of Patients With HbA1c <7.0% at Week 24 | 42.9 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: 0.005195% CI: [1.25, 3.539]Regression, Logistic