Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of the current study is to investigate the efficacy, safety and tolerability of Linagliptin (5 mg once daily) compared to placebo given for 24 weeks as add on therapy to metformin in combination with pioglitazone in patients with type 2 diabetes mellitus with insufficient glycaemic control.
Interventions
DRUGPlacebo
Placebo matching linagliptin tablets once daily
DRUGLinagliptin
Linagliptin tablets once daily
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of diabetes mellitus prior to informed consent 2. Patients treated with metformin and pioglitazone (therapy should be unchanged for 12 weeks) 3. Glycosylated haemoglobin A1 \>= 7.5% and \<= 10% 4. Age between 18 and less than 80 5. \- Body Mass index less or equal to 45
Exclusion criteria
1. Uncontrolled hyperglycaemia during run in period 2. Myocardial infarction, stroke or transient ischaemic accident within 3 months prior to informed consent 3. Impaired hepatic function 4. Gastric by pass surgery 5. Treatment with roziglitazone, GLP 1 analogues, DPP-4 inhibitors or insulin within 3 months prior to informed consent 6. Treatment with anti-obesity drugs 7. Current treatment with systemic steroids at the time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent 8. Premenopausal women 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 during the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 24 Weeks | baseline, 24 weeks | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 6 Weeks | baseline, 6 weeks | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin |
| Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 12 Weeks | baseline, 12 weeks | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin |
| Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 18 Weeks | baseline, 18 weeks | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin |
| Occurrence of Absolute Efficacy Response (HbA1c < 7%) After 24 Weeks | 24 weeks | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin |
| Occurrence of Absolute Efficacy Response (HbA1c < 6.5%) After 24 Weeks | 24 weeks | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin |
| Occurrence of Relative Efficacy Response (Reduction in HbA1c >= 0.5%) After 24 Weeks | 24 weeks | Glycosylated hemoglobin is reported as a percentage of the total hemoglobin |
| Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks | baseline, 24 weeks | Adjusted mean change in fasting plasma glucose (FPG) from baseline at week 24 |
| Change From Baseline in Fasting Plasma Glucose (FPG) After 6 Weeks | baseline, 6 weeks | Adjusted mean change in fasting plasma glucose (FPG) from baseline at week 6 |
| Change From Baseline in Fasting Plasma Glucose (FPG) After 12 Weeks | baseline, 12 weeks | Adjusted mean change in fasting plasma glucose (FPG) from baseline at week 12 |
| Change From Baseline in Fasting Plasma Glucose (FPG) After 18 Weeks | baseline, 18 weeks | Adjusted mean change in fasting plasma glucose (FPG) from baseline at week 18 |
Countries
France, India, Philippines, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Tablet | 89 |
| Linagliptin 5 mg Tablet | 183 |
| Total | 272 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 5 |
| Overall Study | Lost to Follow-up | 2 | 5 |
| Overall Study | Non-compliance issues | 3 | 3 |
| Overall Study | Other | 9 | 7 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Tablet | Linagliptin 5 mg Tablet | Total |
|---|---|---|---|
| Age, Continuous | 55.2 years STANDARD_DEVIATION 8.4 | 53.1 years STANDARD_DEVIATION 9.7 | 53.8 years STANDARD_DEVIATION 9.3 |
| Age, Customized 65 to 74 years | 8 participants | 20 participants | 28 participants |
| Age, Customized < 65 years | 79 participants | 162 participants | 241 participants |
| Age, Customized >= 75 years | 2 participants | 1 participants | 3 participants |
| Alcohol status Drinks - investigator opinion/interfere with study | 0 participants | 0 participants | 0 participants |
| Alcohol status Drinks - no interference with study | 10 participants | 27 participants | 37 participants |
| Alcohol status Non drinker | 79 participants | 156 participants | 235 participants |
| Body Mass Index (BMI) | 28.1 kilograms per square meter STANDARD_DEVIATION 5.5 | 28.2 kilograms per square meter STANDARD_DEVIATION 5.2 | 28.2 kilograms per square meter STANDARD_DEVIATION 5.3 |
| Body Mass Index (BMI) categories >= 25 and < 30 kilograms/square meter | 38 participants | 76 participants | 114 participants |
| Body Mass Index (BMI) categories < 25 kilograms/square meter | 29 participants | 51 participants | 80 participants |
| Body Mass Index (BMI) categories >= 30 kilograms/square meter | 22 participants | 56 participants | 78 participants |
| Height | 162.0 centimeters STANDARD_DEVIATION 11 | 161.4 centimeters STANDARD_DEVIATION 11.4 | 161.6 centimeters STANDARD_DEVIATION 11.2 |
| Sex: Female, Male Female | 40 Participants | 100 Participants | 140 Participants |
| Sex: Female, Male Male | 49 Participants | 83 Participants | 132 Participants |
| Smoking status Currently smokes | 2 participants | 16 participants | 18 participants |
| Smoking status Ex-smoker | 12 participants | 16 participants | 28 participants |
| Smoking status Never smoked | 75 participants | 151 participants | 226 participants |
| Waist circumference | 97.7 centimeters STANDARD_DEVIATION 13.5 | 98.1 centimeters STANDARD_DEVIATION 13.1 | 98.0 centimeters STANDARD_DEVIATION 13.2 |
| Weight | 74.4 kilograms STANDARD_DEVIATION 19.8 | 74.4 kilograms STANDARD_DEVIATION 20.4 | 74.4 kilograms STANDARD_DEVIATION 20.2 |
| Weight categories <= 70 kilograms | 46 participants | 97 participants | 143 participants |
| Weight categories > 70 to 80 kilograms | 17 participants | 32 participants | 49 participants |
| Weight categories > 80 to 90 kilograms | 10 participants | 18 participants | 28 participants |
| Weight categories > 90 kilograms | 16 participants | 36 participants | 52 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 89 | 31 / 183 |
| serious Total, serious adverse events | 3 / 89 | 4 / 183 |
Outcome results
Primary
Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 24 Weeks
Glycosylated hemoglobin is reported as a percentage of the total hemoglobin
Time frame: baseline, 24 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication and had both a baseline HbA1c value and an on-treatment HbA1c value. Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Tablet | Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 24 Weeks | -0.27 Percentage | Standard Error 0.13 |
| Linagliptin 5 mg Tablet | Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 24 Weeks | -0.84 Percentage | Standard Error 0.11 |
p-value: <0.000195% CI: [-0.83, -0.31]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) After 12 Weeks
Adjusted mean change in fasting plasma glucose (FPG) from baseline at week 12
Time frame: baseline, 12 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication and had both a baseline FPG value and an on-treatment FPG value. Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Tablet | Change From Baseline in Fasting Plasma Glucose (FPG) After 12 Weeks | 3.8 mg/dL (milligrams per deciliter) | Standard Error 4.6 |
| Linagliptin 5 mg Tablet | Change From Baseline in Fasting Plasma Glucose (FPG) After 12 Weeks | -7.1 mg/dL (milligrams per deciliter) | Standard Error 3.6 |
p-value: 0.02195% CI: [-20.2, -1.7]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) After 18 Weeks
Adjusted mean change in fasting plasma glucose (FPG) from baseline at week 18
Time frame: baseline, 18 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication and had both a baseline FPG value and an on-treatment FPG value. Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Tablet | Change From Baseline in Fasting Plasma Glucose (FPG) After 18 Weeks | -2.4 mg/dL (milligrams per deciliter) | Standard Error 4.1 |
| Linagliptin 5 mg Tablet | Change From Baseline in Fasting Plasma Glucose (FPG) After 18 Weeks | -8.6 mg/dL (milligrams per deciliter) | Standard Error 2.8 |
p-value: 0.213795% CI: [-16, 3.6]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks
Adjusted mean change in fasting plasma glucose (FPG) from baseline at week 24
Time frame: baseline, 24 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication and had both a baseline FPG value and an on-treatment FPG value. Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Tablet | Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks | 0.1 mg/dL (milligrams per deciliter) | Standard Error 3.8 |
| Linagliptin 5 mg Tablet | Change From Baseline in Fasting Plasma Glucose (FPG) After 24 Weeks | -10.3 mg/dL (milligrams per deciliter) | Standard Error 2.7 |
p-value: 0.02895% CI: [-19.6, -1.1]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) After 6 Weeks
Adjusted mean change in fasting plasma glucose (FPG) from baseline at week 6
Time frame: baseline, 6 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication and had both a baseline FPG value and an on-treatment FPG value. Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Tablet | Change From Baseline in Fasting Plasma Glucose (FPG) After 6 Weeks | 12.4 mg/dL (milligrams per deciliter) | Standard Error 5.4 |
| Linagliptin 5 mg Tablet | Change From Baseline in Fasting Plasma Glucose (FPG) After 6 Weeks | -3.3 mg/dL (milligrams per deciliter) | Standard Error 4.6 |
p-value: 0.000695% CI: [-24.5, -6.8]ANCOVA
Secondary
Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 12 Weeks
Glycosylated hemoglobin is reported as a percentage of the total hemoglobin
Time frame: baseline, 12 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication and had both a baseline HbA1c value and an on-treatment HbA1c value. Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Tablet | Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 12 Weeks | -0.28 Percentage | Standard Error 0.12 |
| Linagliptin 5 mg Tablet | Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 12 Weeks | -0.82 Percentage | Standard Error 0.1 |
p-value: <0.000195% CI: [-0.79, -0.28]ANCOVA
Secondary
Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 18 Weeks
Glycosylated hemoglobin is reported as a percentage of the total hemoglobin
Time frame: baseline, 18 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication and had both a baseline HbA1c value and an on-treatment HbA1c value. Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Tablet | Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 18 Weeks | -0.37 Percentage | Standard Error 0.12 |
| Linagliptin 5 mg Tablet | Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 18 Weeks | -0.91 Percentage | Standard Error 0.1 |
p-value: <0.000195% CI: [-0.8, -0.29]ANCOVA
Secondary
Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 6 Weeks
Glycosylated hemoglobin is reported as a percentage of the total hemoglobin
Time frame: baseline, 6 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication and had both a baseline HbA1c value and an on-treatment HbA1c value. Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Tablet | Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 6 Weeks | -0.19 Percentage | Standard Error 0.11 |
| Linagliptin 5 mg Tablet | Change From Baseline in HbA1c (Glycosylated Hemoglobin) After 6 Weeks | -0.60 Percentage | Standard Error 0.09 |
p-value: <0.000195% CI: [-0.61, -0.21]ANCOVA
Secondary
Occurrence of Absolute Efficacy Response (HbA1c < 6.5%) After 24 Weeks
Glycosylated hemoglobin is reported as a percentage of the total hemoglobin
Time frame: 24 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication and had HbA1c \>=6.5% at baseline (NCF). Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 6.5%) After 24 Weeks | Responder (HbA1c < 6.5%) | 5 Participants |
| Placebo Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 6.5%) After 24 Weeks | Non-responder (HbA1c >= 6.5%) | 84 Participants |
| Placebo Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 6.5%) After 24 Weeks | Missing | 0 Participants |
| Linagliptin 5 mg Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 6.5%) After 24 Weeks | Responder (HbA1c < 6.5%) | 34 Participants |
| Linagliptin 5 mg Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 6.5%) After 24 Weeks | Non-responder (HbA1c >= 6.5%) | 143 Participants |
| Linagliptin 5 mg Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 6.5%) After 24 Weeks | Missing | 1 Participants |
Comparison: Linagliptin vs Placebop-value: 0.007495% CI: [1.44, 10.572]Regression, Logistic
Secondary
Occurrence of Absolute Efficacy Response (HbA1c < 7%) After 24 Weeks
Glycosylated hemoglobin is reported as a percentage of the total hemoglobin
Time frame: 24 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication and had HbA1c \>=7.0% at baseline (NCF). Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 7%) After 24 Weeks | Responder (HbA1c < 7.0%) | 12 Participants |
| Placebo Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 7%) After 24 Weeks | Non-responder (HbA1c >= 7.0%) | 75 Participants |
| Placebo Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 7%) After 24 Weeks | Missing | 0 Participants |
| Linagliptin 5 mg Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 7%) After 24 Weeks | Responder (HbA1c < 7.0%) | 57 Participants |
| Linagliptin 5 mg Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 7%) After 24 Weeks | Non-responder (HbA1c >= 7.0%) | 118 Participants |
| Linagliptin 5 mg Tablet | Occurrence of Absolute Efficacy Response (HbA1c < 7%) After 24 Weeks | Missing | 1 Participants |
Comparison: Linagliptin vs Placebop-value: 0.003395% CI: [1.432, 6.032]Regression, Logistic
Secondary
Occurrence of Relative Efficacy Response (Reduction in HbA1c >= 0.5%) After 24 Weeks
Glycosylated hemoglobin is reported as a percentage of the total hemoglobin
Time frame: 24 weeks
Population: Full Analysis Set (FAS) includes all randomized patients who received study medication. Three subjects in each arm excluded for site non-compliance.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo Tablet | Occurrence of Relative Efficacy Response (Reduction in HbA1c >= 0.5%) After 24 Weeks | Responder (reduction in HbA1c >= 0.5%) | 44 Participants |
| Placebo Tablet | Occurrence of Relative Efficacy Response (Reduction in HbA1c >= 0.5%) After 24 Weeks | Non-responder (reduction in HbA1c < 0.5%) | 45 Participants |
| Placebo Tablet | Occurrence of Relative Efficacy Response (Reduction in HbA1c >= 0.5%) After 24 Weeks | Missing | 0 Participants |
| Linagliptin 5 mg Tablet | Occurrence of Relative Efficacy Response (Reduction in HbA1c >= 0.5%) After 24 Weeks | Responder (reduction in HbA1c >= 0.5%) | 117 Participants |
| Linagliptin 5 mg Tablet | Occurrence of Relative Efficacy Response (Reduction in HbA1c >= 0.5%) After 24 Weeks | Non-responder (reduction in HbA1c < 0.5%) | 61 Participants |
| Linagliptin 5 mg Tablet | Occurrence of Relative Efficacy Response (Reduction in HbA1c >= 0.5%) After 24 Weeks | Missing | 1 Participants |
Comparison: Linagliptin vs. Placebop-value: 0.007195% CI: [1.216, 3.485]Regression, Logistic