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 during long term treatment (52 weeks and longer) in combination with basal insulin in patients with type 2 diabetes mellitus with insufficient glycaemic control.
Interventions
DRUGPlacebo
Placebo, identical to Linagliptin tablet
DRUGLinagliptin
intended final marketed dose
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. Diabetes type 2, detectable C-peptide, HbA1c 7-10% 2. Pretreatment with basal insulin +/- Metformin or/and +/- Pioglitazone 3 Age \> 18 years, BMI \<= 45 kg/m2
Exclusion criteria
1. Uncontrolled hyperglycemia during Run-in 2. Myocardial infarction, stroke or TIA within 3 months prior to informed consent 3. Liver impairment; gastric surgery; medical history of cancer in last 5 years 4. Other antidiabetic drugs, antiobesity drugs, systemic steroids, other investigational drug before randomisation 5. Unsufficient birth control, pregnancy and nursing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c After 24 Weeks | Baseline and 24 weeks | HbA1c is measured as a percentage. Adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant Oral antidiabetic drugs (OAD) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c by Visit at Week 18 | Baseline and 18 weeks | Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs |
| Change From Baseline in HbA1c by Visit at Week 32 | Baseline and 32 weeks | Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs |
| Number of Patients With HbA1c < 7.0 Percent | 24 and 52 weeks | — |
| Number of Patients Lowering HbA1c by at Least 0.5 Percent | 24 and 52 weeks | — |
| Change From Baseline in HbA1c by Visit at Week 6 | Baseline and 6 weeks | Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs |
| Change From Baseline in HbA1c by Visit at Week 12 | Baseline and 12 weeks | Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs |
| Change From Baseline in HbA1c by Visit at Week 40 | Baseline and 40 weeks | Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs |
| Change From Baseline in Fasting Plasma Glucose (FPG) at 24 Weeks of Treatment | Baseline and 24 weeks | Means adjusted for treatment, baseline HbA1c, baseline FPG, categorical renal function impairment and concomitant OADs |
| Change From Baseline in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | Baseline and 52 weeks | — |
| Change From Baseline in FPG | Baseline, 6, 12, 18, 24, 32 and 40 weeks | — |
| Change From Baseline in Mean Insulin Dose at 52 Weeks of Treatment | Baseline and 52 weeks | Means adjusted for treatment, continous baseline HbA1c, continous baseline weight, continous baseline Insulin, categorical renal function impairment and concomitant OADs |
| Change From Baseline in Weighted Mean Daily Glucose After 24 and 52 Weeks of Treatment | Baseline, 24 and 52 weeks | Mean Daily Glucose was calculated using the 8-point blood glucose profile |
| Change From Baseline in Incremental Post-prandial Glucose (iPPG) After 24 Weeks of Treatment | Baseline and 24 weeks: post-breakfast, post-lunch, post-dinner | — |
| Change From Baseline in HbA1c by Visit at Week 52 | Baseline and 52 weeks | Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs |
Other
| Measure | Time frame |
|---|---|
| Number of Patients With HbA1c < 6.5 Percent | 24 and 52 weeks |
Countries
Argentina, Belgium, Brazil, Canada, Czechia, Finland, Germany, Greece, Italy, Mexico, Netherlands, Norway, Peru, Russia, Slovakia, South Korea, Spain, Taiwan, United States
Participant flow
Pre-assignment details
Randomised, double-blind, placebo-controlled, parallel group study. Whilst 1263 were randomised, only 1261 were treated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients randomized to receive treatment with matching placebo, orally taken, once daily. During the first 24 weeks of the randomised treatment period, the background dose of basal insulin and/or oral antidiabetic agents was to remain stable. From 24 weeks after randomisation until the end of the trial, adjustments to the dose of basal insulin (but not oral antidiabetic agents) were permitted. | 630 |
| Linagliptin 5 mg Patients randomized to receive treatment with Linagliptin 5mg, orally taken, once daily. During the first 24 weeks of the randomised treatment period, the background dose of basal insulin and/or oral antidiabetic agents was to remain stable. From 24 weeks after randomisation until the end of the trial, adjustments to the dose of basal insulin (but not oral antidiabetic agents) were permitted. | 631 |
| Total | 1,261 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 33 | 25 |
| Overall Study | Lack of Efficacy | 17 | 3 |
| Overall Study | Lost to Follow-up | 8 | 14 |
| Overall Study | Other | 21 | 18 |
| Overall Study | Protocol Violation | 5 | 7 |
| Overall Study | Withdrawal by Subject | 26 | 21 |
Baseline characteristics
| Characteristic | Placebo | Linagliptin 5 mg | Total |
|---|---|---|---|
| Age, Continuous | 60.4 Years STANDARD_DEVIATION 10 | 59.7 Years STANDARD_DEVIATION 9.9 | 60.0 Years STANDARD_DEVIATION 10 |
| Baseline HbA1c | 8.29 Percentage STANDARD_DEVIATION 0.85 | 8.31 Percentage STANDARD_DEVIATION 0.85 | 8.30 Percentage STANDARD_DEVIATION 0.85 |
| Sex: Female, Male Female | 301 Participants | 302 Participants | 603 Participants |
| Sex: Female, Male Male | 329 Participants | 329 Participants | 658 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 354 / 630 | 354 / 631 |
| serious Total, serious adverse events | 83 / 630 | 87 / 631 |
Outcome results
Primary
Change From Baseline in HbA1c After 24 Weeks
HbA1c is measured as a percentage. Adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant Oral antidiabetic drugs (OAD)
Time frame: Baseline and 24 weeks
Population: The Full Analysis Set (FAS) with a last observation carried forward (LOCF) approach. The FAS comprises all randomised patients who were treated with at least one dose of study medication, had a baseline HbA1c measurement, and had at least one on-treatment HbA1c measurement within the first 24 weeks of double-blind treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c After 24 Weeks | 0.07 Percentage | Standard Error 0.08 |
| Linagliptin 5 mg | Change From Baseline in HbA1c After 24 Weeks | -0.58 Percentage | Standard Error 0.08 |
p-value: <0.000195% CI: [-0.74, -0.55]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment
Time frame: Baseline and 52 weeks
Population: FAS (LOCF), further restricted to patients with a baseline FPG measurement and at least one on-treatment FPG measurement
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | 0.63 mg/dL | Standard Deviation 56.44 |
| Linagliptin 5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) After 52 Weeks of Treatment | -2.55 mg/dL | Standard Deviation 55.01 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at 24 Weeks of Treatment
Means adjusted for treatment, baseline HbA1c, baseline FPG, categorical renal function impairment and concomitant OADs
Time frame: Baseline and 24 weeks
Population: FAS (LOCF), further restricted to patients with a baseline FPG measurement and at least one on-treatment FPG measurement
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at 24 Weeks of Treatment | 4.52 mg/dL | Standard Error 3.94 |
| Linagliptin 5 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at 24 Weeks of Treatment | -7.09 mg/dL | Standard Error 3.97 |
p-value: <0.000195% CI: [-16.49, -6.71]ANCOVA
Secondary
Change From Baseline in FPG
Time frame: Baseline, 6, 12, 18, 24, 32 and 40 weeks
Population: FAS, observed cases (OC)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in FPG | after 6 weeks of treatment | 2.97 mg/dL | Standard Deviation 50.89 |
| Placebo | Change From Baseline in FPG | after 12 weeks of treatment (N=556, N=590) | -0.33 mg/dL | Standard Deviation 51.09 |
| Placebo | Change From Baseline in FPG | after 18 weeks of treatment (N=533, N=567) | 2.10 mg/dL | Standard Deviation 53.21 |
| Placebo | Change From Baseline in FPG | after 24 weeks of treatment (N=499, N=533) | 0.04 mg/dL | Standard Deviation 54.94 |
| Placebo | Change From Baseline in FPG | after 32 weeks of treatment (N=436, N=491) | -2.67 mg/dL | Standard Deviation 52.43 |
| Placebo | Change From Baseline in FPG | after 40 weeks of treatment (N=357, N=429) | -3.99 mg/dL | Standard Deviation 50.29 |
| Linagliptin 5 mg | Change From Baseline in FPG | after 32 weeks of treatment (N=436, N=491) | -6.30 mg/dL | Standard Deviation 48.16 |
| Linagliptin 5 mg | Change From Baseline in FPG | after 6 weeks of treatment | -5.29 mg/dL | Standard Deviation 44.74 |
| Linagliptin 5 mg | Change From Baseline in FPG | after 24 weeks of treatment (N=499, N=533) | -7.07 mg/dL | Standard Deviation 44.7 |
| Linagliptin 5 mg | Change From Baseline in FPG | after 12 weeks of treatment (N=556, N=590) | -7.59 mg/dL | Standard Deviation 48.5 |
| Linagliptin 5 mg | Change From Baseline in FPG | after 40 weeks of treatment (N=357, N=429) | -6.50 mg/dL | Standard Deviation 50 |
| Linagliptin 5 mg | Change From Baseline in FPG | after 18 weeks of treatment (N=533, N=567) | -3.30 mg/dL | Standard Deviation 55.51 |
Secondary
Change From Baseline in HbA1c by Visit at Week 12
Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs
Time frame: Baseline and 12 weeks
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c by Visit at Week 12 | 0.02 Percentage | Standard Error 0.07 |
| Linagliptin 5 mg | Change From Baseline in HbA1c by Visit at Week 12 | -0.59 Percentage | Standard Error 0.07 |
p-value: <0.000195% CI: [-0.69, -0.52]ANCOVA
Secondary
Change From Baseline in HbA1c by Visit at Week 18
Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs
Time frame: Baseline and 18 weeks
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c by Visit at Week 18 | 0.03 Percentage | Standard Error 0.08 |
| Linagliptin 5 mg | Change From Baseline in HbA1c by Visit at Week 18 | -0.64 Percentage | Standard Error 0.08 |
p-value: <0.000195% CI: [-0.76, -0.57]ANCOVA
Secondary
Change From Baseline in HbA1c by Visit at Week 32
Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs
Time frame: Baseline and 32 weeks
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c by Visit at Week 32 | 0.01 Percentage | Standard Error 0.08 |
| Linagliptin 5 mg | Change From Baseline in HbA1c by Visit at Week 32 | -0.56 Percentage | Standard Error 0.08 |
p-value: <0.000195% CI: [-0.67, -0.47]ANCOVA
Secondary
Change From Baseline in HbA1c by Visit at Week 40
Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs
Time frame: Baseline and 40 weeks
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c by Visit at Week 40 | 0.05 Percentage | Standard Error 0.08 |
| Linagliptin 5 mg | Change From Baseline in HbA1c by Visit at Week 40 | -0.50 Percentage | Standard Error 0.08 |
p-value: <0.000195% CI: [-0.65, -0.45]ANCOVA
Secondary
Change From Baseline in HbA1c by Visit at Week 52
Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs
Time frame: Baseline and 52 weeks
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c by Visit at Week 52 | 0.05 Percentage | Standard Error 0.08 |
| Linagliptin 5 mg | Change From Baseline in HbA1c by Visit at Week 52 | -0.48 Percentage | Standard Error 0.08 |
p-value: <0.000195% CI: [-0.64, -0.43]ANCOVA
Secondary
Change From Baseline in HbA1c by Visit at Week 6
Means adjusted for treatment, baseline HbA1c, categorical renal function impairment and concomitant OADs
Time frame: Baseline and 6 weeks
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c by Visit at Week 6 | 0.00 Percentage | Standard Error 0.05 |
| Linagliptin 5 mg | Change From Baseline in HbA1c by Visit at Week 6 | -0.45 Percentage | Standard Error 0.05 |
p-value: <0.000195% CI: [-0.51, -0.39]ANCOVA
Secondary
Change From Baseline in Incremental Post-prandial Glucose (iPPG) After 24 Weeks of Treatment
Time frame: Baseline and 24 weeks: post-breakfast, post-lunch, post-dinner
Population: FAS (OC)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Incremental Post-prandial Glucose (iPPG) After 24 Weeks of Treatment | post-breakfast incremental glucose | 9.31 mmol*hr/L | Standard Deviation 44.02 |
| Placebo | Change From Baseline in Incremental Post-prandial Glucose (iPPG) After 24 Weeks of Treatment | post-lunch incremental glucose (N=34, N=41) | -17.80 mmol*hr/L | Standard Deviation 61.94 |
| Placebo | Change From Baseline in Incremental Post-prandial Glucose (iPPG) After 24 Weeks of Treatment | post-dinner incremental glucose (N=46, N=57) | -1.71 mmol*hr/L | Standard Deviation 68.15 |
| Linagliptin 5 mg | Change From Baseline in Incremental Post-prandial Glucose (iPPG) After 24 Weeks of Treatment | post-breakfast incremental glucose | -3.78 mmol*hr/L | Standard Deviation 63.63 |
| Linagliptin 5 mg | Change From Baseline in Incremental Post-prandial Glucose (iPPG) After 24 Weeks of Treatment | post-lunch incremental glucose (N=34, N=41) | -11.00 mmol*hr/L | Standard Deviation 68.04 |
| Linagliptin 5 mg | Change From Baseline in Incremental Post-prandial Glucose (iPPG) After 24 Weeks of Treatment | post-dinner incremental glucose (N=46, N=57) | -3.26 mmol*hr/L | Standard Deviation 66.51 |
Secondary
Change From Baseline in Mean Insulin Dose at 52 Weeks of Treatment
Means adjusted for treatment, continous baseline HbA1c, continous baseline weight, continous baseline Insulin, categorical renal function impairment and concomitant OADs
Time frame: Baseline and 52 weeks
Population: FAS (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Insulin Dose at 52 Weeks of Treatment | 4.18 International units (IU) | Standard Error 0.84 |
| Linagliptin 5 mg | Change From Baseline in Mean Insulin Dose at 52 Weeks of Treatment | 2.60 International units (IU) | Standard Error 0.84 |
p-value: 0.002995% CI: [-2.61, -0.54]ANCOVA
Secondary
Change From Baseline in Weighted Mean Daily Glucose After 24 and 52 Weeks of Treatment
Mean Daily Glucose was calculated using the 8-point blood glucose profile
Time frame: Baseline, 24 and 52 weeks
Population: FAS (OC)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Weighted Mean Daily Glucose After 24 and 52 Weeks of Treatment | after 24 weeks of treatment | 0.03 mmol*hr/L | Standard Deviation 2.28 |
| Placebo | Change From Baseline in Weighted Mean Daily Glucose After 24 and 52 Weeks of Treatment | after 52 weeks of treatment (N=25, N=15) | 0.10 mmol*hr/L | Standard Deviation 3.06 |
| Linagliptin 5 mg | Change From Baseline in Weighted Mean Daily Glucose After 24 and 52 Weeks of Treatment | after 24 weeks of treatment | -0.01 mmol*hr/L | Standard Deviation 1.98 |
| Linagliptin 5 mg | Change From Baseline in Weighted Mean Daily Glucose After 24 and 52 Weeks of Treatment | after 52 weeks of treatment (N=25, N=15) | -0.50 mmol*hr/L | Standard Deviation 2.35 |
Secondary
Number of Patients Lowering HbA1c by at Least 0.5 Percent
Time frame: 24 and 52 weeks
Population: FAS (NCF)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients Lowering HbA1c by at Least 0.5 Percent | after 24 weeks of treatment | 137 Participants |
| Placebo | Number of Patients Lowering HbA1c by at Least 0.5 Percent | after 52 weeks of treatment | 104 Participants |
| Linagliptin 5 mg | Number of Patients Lowering HbA1c by at Least 0.5 Percent | after 24 weeks of treatment | 333 Participants |
| Linagliptin 5 mg | Number of Patients Lowering HbA1c by at Least 0.5 Percent | after 52 weeks of treatment | 231 Participants |
Secondary
Number of Patients With HbA1c < 7.0 Percent
Time frame: 24 and 52 weeks
Population: FAS using the non-completers considered failure (NCF) approach, in which missing data due to premature discontinuation of a patient were considered as failure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With HbA1c < 7.0 Percent | after 52 weeks of treatment | 44 Participants |
| Placebo | Number of Patients With HbA1c < 7.0 Percent | after 24 weeks of treatment | 56 Participants |
| Linagliptin 5 mg | Number of Patients With HbA1c < 7.0 Percent | after 24 weeks of treatment | 134 Participants |
| Linagliptin 5 mg | Number of Patients With HbA1c < 7.0 Percent | after 52 weeks of treatment | 109 Participants |
Comparison: FAS with baseline HbA1c \>= 7.0 percent (NCF); there are 593 available values for Placebo and 595 for Linagliptin 5mgp-value: <0.000195% CI: [1.949, 4.419]Regression, Logistic
Other Pre-specified
Number of Patients With HbA1c < 6.5 Percent
Time frame: 24 and 52 weeks
Population: FAS (NCF)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With HbA1c < 6.5 Percent | after 24 weeks of treatment | 10 Participants |
| Placebo | Number of Patients With HbA1c < 6.5 Percent | after 52 weeks of treatment | 12 Participants |
| Linagliptin 5 mg | Number of Patients With HbA1c < 6.5 Percent | after 24 weeks of treatment | 50 Participants |
| Linagliptin 5 mg | Number of Patients With HbA1c < 6.5 Percent | after 52 weeks of treatment | 46 Participants |
Comparison: FAS with baseline HbA1c \>= 6.5 percent (NCF); there are 615 available values for Placebo and 616 for Linagliptin 5mgp-value: <0.000195% CI: [2.221, 8.43]Regression, Logistic