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 over 12 weeks in drug naive or previously treated type 2 diabetic patients with moderate to severe renal impairment and insufficient glycaemic control. In addition safety in this patient population with longer term (40 week) treatment in comparison to sulfonylurea drug (glimepiride).
Interventions
DRUGPlacebo
Placebo mach to 5 mg linagliptin first 12 weeks of treatment once daily
DRUGLinagliptin
5 mg once daily
DRUGGlimepiride
1-4 mg daily after 12 weeks
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 No maximum
Healthy volunteers
No
Inclusion criteria
1. Type 2 diabetes mellitus 2. GFR\<60 ml/min 3. HbA1c \>=7.0% to \<= 10% 4. Age \>= 18 years 5. BMI \<=45 kg/m2 6. Signed and dated written informed consent
Exclusion criteria
1. Myocardial infarction, stroke or TIA within 3 months prior to informed consent 2. Renal impairment requiring dialysis 3. Bariatric surgery 4. Impaired hepatic function 5. Treatment with glitazones, GLP-1 analogues, DPP-4 inhibitors 6. Treatment with anti-obesity drugs 7. Treatment with SU, glinides and metformin 8 weeks prior to informed consent
Design outcomes
Primary
| 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, renal function impairment and prior use of antidiabetic agents. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Plasma Glucose (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 prior use of insulin, week repeated within patient and week by treatment interaction. |
| Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Baseline, week 4, week 8, week 12, week 20, week 24, week 28, week 34, week 40, week 46, week 52 | This change from baseline reflects the FPG over time minus the baseline FPG. This outcome measure only provides descriptive statistics without any modelling. |
| Percentage of Patients With HbA1c <7.0% | Baseline, week 12 and week 52 | The percentage of patients with an HbA1c value below 7% at week 12 and week 52 were calculated for each treatment arm. If a patient did not have an HbA1c value at week 12 or 52 respectively, they were considered a failure, so HbA1c above 7%. |
| HbA1c Change From Baseline Over Time | Baseline, week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 34, week 40, week 46, week 52 | HbA1c is measured as a percentage. Thus, this change from baseline reflects the HbA1c percent over time minus the baseline HbA1c percent. This outcome measure only provides descriptive statistics without any modelling. |
| Percentage of Patients Who Have a HbA1c Lowering by at Least 0.5% | Baseline, week 12 and week 52 | The percentage of patients with an HbA1c reduction of ≥0.5% at week 12 and week 52 from baseline was calculated for each treatment arm. If a patient did not have an HbA1c value at week 12 or 52 respectively they were considered a failure, so HbA1c reduction less than 0.5%. |
| Plasma Concentration of Linagliptin at Trough | Week 12, 24 and 52 | Trough levels of concentration of Linagliptin in plasma. |
| Percentage of Patients With HbA1c <6.5% | Baseline, week 12 and week 52 | The percentage of patients with an HbA1c value below 6.5% at week 12 and week 52 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 12 or 52 respectively they were considered a failure, so HbA1c above 6.5%. |
Countries
Australia, Canada, Finland, Israel, Japan, New Zealand, Slovakia, Sweden, United States
Participant flow
Pre-assignment details
241 patients were randomised to treatment with linagliptin 5mg (n=118) or placebo/glimepiride (n=123). All randomised patients were treated. For the final analysis, one study site was excluded due to serious non-compliance resulting in 122 patients in the placebo/glimepiride group and 113 patients in the linagliptin group.
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Glimepiride Patients randomized to receive treatment with matching placebo for 12 weeks and then switch to glimepiride for further 40 weeks. | 122 |
| Linagliptin 5 mg Patients randomized to receive treatment with Linagliptin 5mg | 113 |
| Total | 235 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Up to Final Analysis (Week 52) | Adverse Event | 17 | 10 |
| Up to Final Analysis (Week 52) | Lack of Efficacy | 1 | 2 |
| Up to Final Analysis (Week 52) | Lost to Follow-up | 2 | 0 |
| Up to Final Analysis (Week 52) | Other reason not described above | 5 | 4 |
| Up to Final Analysis (Week 52) | Protocol Violation | 4 | 0 |
| Up to Final Analysis (Week 52) | Study site excluded from analysis | 1 | 5 |
| Up to Final Analysis (Week 52) | Withdrawal by Subject | 3 | 2 |
| Up to Interim Analysis (Week 12) | Adverse Event | 5 | 4 |
| Up to Interim Analysis (Week 12) | Lack of Efficacy | 1 | 0 |
| Up to Interim Analysis (Week 12) | Other reason not described above | 1 | 2 |
| Up to Interim Analysis (Week 12) | Protocol Violation | 1 | 1 |
| Up to Interim Analysis (Week 12) | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Linagliptin 5 mg | Total | Placebo/Glimepiride |
|---|---|---|---|
| Age, Continuous | 66.9 years STANDARD_DEVIATION 9.4 | 66.2 years STANDARD_DEVIATION 9.7 | 65.9 Years STANDARD_DEVIATION 9.4 |
| Body mass index (BMI) continuous | 32.20 kg/m^2 STANDARD_DEVIATION 6.13 | 32.09 kg/m^2 STANDARD_DEVIATION 6.13 | 31.97 kg/m^2 STANDARD_DEVIATION 6.28 |
| eGFR based on Modification of Diet in Renal Disease (MDRD) formula <30 (severe or endstage renal impairment) | 35 Participants | 81 participants | 45 Participants |
| eGFR based on Modification of Diet in Renal Disease (MDRD) formula 30 to <60 (moderate renal impairment) | 76 participants | 149 participants | 73 participants |
| eGFR based on Modification of Diet in Renal Disease (MDRD) formula 60 to <90 (mild renal impairment) | 6 Participants | 10 Participants | 5 participants |
| eGFR based on Modification of Diet in Renal Disease (MDRD) formula >=90 (normal renal function) | 0 participants | 0 participants | 0 participants |
| Fasting Plasma Glucose (FPG) | 155.3 mg/dL STANDARD_DEVIATION 45.6 | 151.8 mg/dL STANDARD_DEVIATION 49.7 | 149.7 mg/dL STANDARD_DEVIATION 53.1 |
| Gender Female | 44 participants | 87 participants | 43 participants |
| Gender Male | 74 participants | 154 participants | 80 participants |
| Glycosylated Hemoglobin A1 (HbA1c) | 8.08 Percent STANDARD_DEVIATION 0.89 | 8.05 Percent STANDARD_DEVIATION 0.91 | 8.03 Percent STANDARD_DEVIATION 0.94 |
| Sex: Female, Male Female | 43 Participants | 86 Participants | 43 Participants |
| Sex: Female, Male Male | 70 Participants | 149 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 110 / 122 | 95 / 113 |
| serious Total, serious adverse events | 36 / 122 | 28 / 113 |
Outcome results
Primary
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, renal function impairment and prior use of antidiabetic agents.
Time frame: Baseline and week 12
Population: FAS consisting of all randomised patients who were treated with at least one dose of study drug, had a baseline, and at least 1 on-treatment HbA1c measurement. Last observation carried forward (LOCF) was used as the imputation rule.~Results for primary endpoint below are the ones reproduced without patients from the excluded study site.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | HbA1c Change From Baseline to Week 12 | -0.11 Percent | Standard Error 0.11 |
| Linagliptin 5 mg | HbA1c Change From Baseline to Week 12 | -0.53 Percent | Standard Error 0.11 |
p-value: <0.000195% CI: [-0.6, -0.24]ANCOVA
Secondary
Fasting Plasma Glucose (FPG) Change From Baseline Over Time
This change from baseline reflects the FPG over time minus the baseline FPG. This outcome measure only provides descriptive statistics without any modelling.
Time frame: Baseline, week 4, week 8, week 12, week 20, week 24, week 28, week 34, week 40, week 46, week 52
Population: FAS. Last observation carried forward (LOCF) was used as the imputation rule. Results do not contain data of patients from the excluded study site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 4 (N=119, 112) | 9.80 mg/dL | Standard Deviation 54.94 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 8 (N=119, 112) | 8.96 mg/dL | Standard Deviation 53.3 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 12 (N=119, 112) | 6.23 mg/dL | Standard Deviation 58.2 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 20 (N=119, 112) | -9.66 mg/dL | Standard Deviation 60.6 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 24 (N=119, 112) | -8.83 mg/dL | Standard Deviation 54.84 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 28 (N=119, 112) | -9.67 mg/dL | Standard Deviation 58.31 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 34 (N=119, 112) | -9.95 mg/dL | Standard Deviation 58.47 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 40 (N=119, 112) | -0.75 mg/dL | Standard Deviation 61.94 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 46 (N=119, 112) | -2.64 mg/dL | Standard Deviation 60.83 |
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 52 (N=119, 112) | -3.10 mg/dL | Standard Deviation 58.27 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 40 (N=119, 112) | -2.69 mg/dL | Standard Deviation 68.43 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 4 (N=119, 112) | -10.55 mg/dL | Standard Deviation 45.8 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 28 (N=119, 112) | -9.31 mg/dL | Standard Deviation 61.01 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 8 (N=119, 112) | -11.25 mg/dL | Standard Deviation 52.32 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 52 (N=119, 112) | 3.09 mg/dL | Standard Deviation 69.03 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 12 (N=119, 112) | -6.26 mg/dL | Standard Deviation 52.59 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 34 (N=119, 112) | -2.78 mg/dL | Standard Deviation 64.55 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 20 (N=119, 112) | -5.92 mg/dL | Standard Deviation 57.68 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 46 (N=119, 112) | -2.03 mg/dL | Standard Deviation 71.3 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline Over Time | Week 24 (N=119, 112) | -12.78 mg/dL | Standard Deviation 62.29 |
Secondary
Fasting Plasma Glucose (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 prior use of insulin, week repeated within patient and week by treatment interaction.
Time frame: Baseline and week 12
Population: One patient in the Placebo/Glimepiride arm and one patient in the Linagliptin arm without FPG on-treatment value. Results do not contain data of patients from the excluded study site.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Fasting Plasma Glucose (FPG) Change From Baseline to Week 12 | 9.53 mg/dL | Standard Error 8.01 |
| Linagliptin 5 mg | Fasting Plasma Glucose (FPG) Change From Baseline to Week 12 | 0.24 mg/dL | Standard Error 7.71 |
p-value: 0.160295% CI: [-22.28, 3.7]ANCOVA
Secondary
HbA1c Change From Baseline Over Time
HbA1c is measured as a percentage. Thus, this change from baseline reflects the HbA1c percent over time minus the baseline HbA1c percent. This outcome measure only provides descriptive statistics without any modelling.
Time frame: Baseline, week 4, week 8, week 12, week 16, week 20, week 24, week 28, week 34, week 40, week 46, week 52
Population: FAS. Last observation carried forward (LOCF) was used as the imputation rule. Results do not contain data of patients from the excluded study site.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | HbA1c Change From Baseline Over Time | Week 16 (N=120, 113) | -0.31 Percent | Standard Deviation 0.84 |
| Placebo | HbA1c Change From Baseline Over Time | Week 28 (N=120, 113) | -0.47 Percent | Standard Deviation 0.93 |
| Placebo | HbA1c Change From Baseline Over Time | Week 12 (N=120, 113) | -0.08 Percent | Standard Deviation 0.79 |
| Placebo | HbA1c Change From Baseline Over Time | Week 34 (N=120, 113) | -0.37 Percent | Standard Deviation 0.93 |
| Placebo | HbA1c Change From Baseline Over Time | Week 20 (N=120, 113) | -0.48 Percent | Standard Deviation 0.88 |
| Placebo | HbA1c Change From Baseline Over Time | Week 40 (N=120, 113) | -0.23 Percent | Standard Deviation 0.95 |
| Placebo | HbA1c Change From Baseline Over Time | Week 8 (N=120, 113) | -0.09 Percent | Standard Deviation 0.68 |
| Placebo | HbA1c Change From Baseline Over Time | Week 46 (N=120, 113) | -0.24 Percent | Standard Deviation 0.96 |
| Placebo | HbA1c Change From Baseline Over Time | Week 24 (N=120, 113) | -0.51 Percent | Standard Deviation 0.93 |
| Placebo | HbA1c Change From Baseline Over Time | Week 52 (N=120, 113) | -0.25 Percent | Standard Deviation 0.92 |
| Placebo | HbA1c Change From Baseline Over Time | Week 4 (N=120, 113) | -0.08 Percent | Standard Deviation 0.42 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 52 (N=120, 113) | -0.40 Percent | Standard Deviation 0.77 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 4 (N=120, 113) | -0.29 Percent | Standard Deviation 0.35 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 8 (N=120, 113) | -0.47 Percent | Standard Deviation 0.49 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 12 (N=120, 113) | -0.50 Percent | Standard Deviation 0.59 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 16 (N=120, 113) | -0.47 Percent | Standard Deviation 0.61 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 20 (N=120, 113) | -0.48 Percent | Standard Deviation 0.63 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 24 (N=120, 113) | -0.52 Percent | Standard Deviation 0.66 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 28 (N=120, 113) | -0.50 Percent | Standard Deviation 0.68 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 34 (N=120, 113) | -0.45 Percent | Standard Deviation 0.69 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 40 (N=120, 113) | -0.42 Percent | Standard Deviation 0.73 |
| Linagliptin 5 mg | HbA1c Change From Baseline Over Time | Week 46 (N=120, 113) | -0.40 Percent | Standard Deviation 0.75 |
Secondary
Percentage of Patients Who Have a HbA1c Lowering by at Least 0.5%
The percentage of patients with an HbA1c reduction of ≥0.5% at week 12 and week 52 from baseline was calculated for each treatment arm. If a patient did not have an HbA1c value at week 12 or 52 respectively they were considered a failure, so HbA1c reduction less than 0.5%.
Time frame: Baseline, week 12 and week 52
Population: FAS with non-completers considered as failure imputation (NCF). Results after Week 12 include patients from the excluded study site.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Patients Who Have a HbA1c Lowering by at Least 0.5% | Week 52 (N=120, 113) | 23.3 percentage of patients |
| Placebo | Percentage of Patients Who Have a HbA1c Lowering by at Least 0.5% | Week 12 (N= 121, 117) | 24.0 percentage of patients |
| Linagliptin 5 mg | Percentage of Patients Who Have a HbA1c Lowering by at Least 0.5% | Week 52 (N=120, 113) | 34.5 percentage of patients |
| Linagliptin 5 mg | Percentage of Patients Who Have a HbA1c Lowering by at Least 0.5% | Week 12 (N= 121, 117) | 49.6 percentage of patients |
Secondary
Percentage of Patients With HbA1c <6.5%
The percentage of patients with an HbA1c value below 6.5% at week 12 and week 52 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 12 or 52 respectively they were considered a failure, so HbA1c above 6.5%.
Time frame: Baseline, week 12 and week 52
Population: FAS with baseline HbA1c \>=6.5% and non-completers considered as failure imputation (NCF). Results after Week 12 include patients from the excluded study site.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Patients With HbA1c <6.5% | Week 52 (N=119, 111) | 6.7 percentage of patients |
| Placebo | Percentage of Patients With HbA1c <6.5% | Week 12 (N=120, 115) | 5.0 percentage of patients |
| Linagliptin 5 mg | Percentage of Patients With HbA1c <6.5% | Week 52 (N=119, 111) | 9.9 percentage of patients |
| Linagliptin 5 mg | Percentage of Patients With HbA1c <6.5% | Week 12 (N=120, 115) | 6.1 percentage of patients |
Secondary
Percentage of Patients With HbA1c <7.0%
The percentage of patients with an HbA1c value below 7% at week 12 and week 52 were calculated for each treatment arm. If a patient did not have an HbA1c value at week 12 or 52 respectively, they were considered a failure, so HbA1c above 7%.
Time frame: Baseline, week 12 and week 52
Population: FAS with baseline HbA1c \>=7% and non-completers considered as failure imputation (NCF). Results after Week 12 include patients from the excluded study site.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Patients With HbA1c <7.0% | Week 52 (N=110, 104) | 11.8 percentage of patients |
| Placebo | Percentage of Patients With HbA1c <7.0% | Week 12 (N=110, 108) | 9.1 percentage of patients |
| Linagliptin 5 mg | Percentage of Patients With HbA1c <7.0% | Week 52 (N=110, 104) | 22.1 percentage of patients |
| Linagliptin 5 mg | Percentage of Patients With HbA1c <7.0% | Week 12 (N=110, 108) | 19.4 percentage of patients |
Secondary
Plasma Concentration of Linagliptin at Trough
Trough levels of concentration of Linagliptin in plasma.
Time frame: Week 12, 24 and 52
Population: FAS original results (OR). Original results analysis means that data is analyzed exactly as observed, values after rescue medication are not set to missing and no imputation rule is applied for replacing the missing values.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Concentration of Linagliptin at Trough | Week 12 (N=103) | 7.77 Nmol/L | Geometric Coefficient of Variation 36.43 |
| Placebo | Plasma Concentration of Linagliptin at Trough | Week 24 (N=103) | 7.62 Nmol/L | Geometric Coefficient of Variation 41.04 |
| Placebo | Plasma Concentration of Linagliptin at Trough | Week 52 (N=105) | 5.94 Nmol/L | Geometric Coefficient of Variation 107.4 |