Diabetes Mellitus, Type 2
Conditions
Brief summary
The data from this study will be used to compare the kinetic profile of metformin 500mg in linagliptin/metformin fixed dose combination tablet versus Canadian metformin reference product administered concomitantly with linagliptin 2.5 mg tablet.
Interventions
DRUGMetformin Single Tablet
Metformin medium doseTablet
DRUGLinagliptin/Metformin Combo
Fixed dose combination
DRUGLinagliptin Single Tablet
Linagliptin Single medium dose Tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1\. Healthy male and female subjects.
Exclusion criteria
1\. Any relevant deviation from healthy conditions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | Prior to drug administration and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 24, 30, and 36 hours post dose in each treatment period | Maximum measured concentration of metformin in plasma, per period. |
| Area Under the Curve 0 to Last Measurable Value (AUC0-t) | Prior to drug administration and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 24, 30, and 36 hours post dose in each treatment period | AUC0-t is the area under the concentration versus time curve of metformin in plasma, from time zero (0) to the time of the last measurable analyte concentration (t), as calculated by the linear trapezoidal method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve 0 to Inf (AUC0-inf) | Prior to drug administration and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 24, 30, and 36 hours post dose in each treatment period | AUC0-inf is the area under the concentration versus time curve of metformin in plasma from time zero extrapolated to infinity. |
Countries
Canada
Participant flow
Recruitment details
18 subjects were enrolled in the original study (June 2011 to July 2011) and 40 in the add-on study (November 2011 to December 2011) which was an option provided by protocol to increase the subject number. As no significant STUDY and STUDY-by-TREATMENT effect was revealed in analysis of pooled data, final analysis was performed on pooled data.
Pre-assignment details
This is a 2 period, 2 sequence, 2 treatment crossover. Subjects were randomized to one of the two sequences AB or BA. The duration of washout was at least 35 days between dosing.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Total number of subjects randomised and treated in the study. | 58 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 5 | 3 |
| Period 1 | Non-compliance | 3 | 0 |
| Period 1 | Out of Range Mid-study-Test | 0 | 1 |
| Period 1 | Personal | 0 | 2 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 35 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 32 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 52 | 21 / 50 |
| serious Total, serious adverse events | 0 / 52 | 0 / 50 |
Outcome results
Primary
Area Under the Curve 0 to Last Measurable Value (AUC0-t)
AUC0-t is the area under the concentration versus time curve of metformin in plasma, from time zero (0) to the time of the last measurable analyte concentration (t), as calculated by the linear trapezoidal method.
Time frame: Prior to drug administration and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 24, 30, and 36 hours post dose in each treatment period
Population: All subjects having all samples in all periods and subjects who missed samples that may not affect the estimation of pharmacokinetic parameters in any period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lina/Met 2.5mg/500mg | Area Under the Curve 0 to Last Measurable Value (AUC0-t) | 7079.65 ng*h/ml | Standard Deviation 1688.14 |
| Lina 2.5mg Plus Met 500mg | Area Under the Curve 0 to Last Measurable Value (AUC0-t) | 6808.27 ng*h/ml | Standard Deviation 1708.2 |
Comparison: The two formulations are shown to be bioequivalent if the 90 percent confidence interval of geometric mean ratio is entirely contained within the 80 to125 percent range both on measured data (statistical analysis 1) and potency corrected data (percent potency of label claim) (statistical analysis 2). ANOVA was applied to log-transformed AUC0-t and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction.90% CI: [101, 108]
Comparison: ANOVA was applied to log-transformed AUC0-t and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction. Results were potency corrected (GMR multiplied by the quotient of DP of Met in single tablet and DP of Met in combination tablet).90% CI: [105, 112]
Primary
Maximum Plasma Concentration (Cmax)
Maximum measured concentration of metformin in plasma, per period.
Time frame: Prior to drug administration and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 24, 30, and 36 hours post dose in each treatment period
Population: All subjects having all samples in all periods and subjects who missed samples that may not affect the estimation of pharmacokinetic parameters in any period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lina/Met 2.5mg/500mg | Maximum Plasma Concentration (Cmax) | 901.82 ng/ml | Standard Deviation 262.45 |
| Lina 2.5mg Plus Met 500mg | Maximum Plasma Concentration (Cmax) | 770.52 ng/ml | Standard Deviation 189.44 |
Comparison: The two formulations are shown to be bioequivalent if the geometric mean ratio is contained within the 80 to 125 percent range both on measured data (statistical analysis 1) and on potency corrected data (percent potency of label claim) (statistical analysis 2). ANOVA was applied to log-transformed Cmax and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction.90% CI: [111, 125]
Comparison: ANOVA was applied to log-transformed Cmax and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction. Results were potency corrected (GMR multiplied by the quotient of drug potency (DP) of Met in single tablet and DP of Met in combination tablet).90% CI: [114, 130]
Secondary
Area Under the Curve 0 to Inf (AUC0-inf)
AUC0-inf is the area under the concentration versus time curve of metformin in plasma from time zero extrapolated to infinity.
Time frame: Prior to drug administration and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 24, 30, and 36 hours post dose in each treatment period
Population: All subjects having all samples in all periods and subjects who missed samples that may not affect the estimation of pharmacokinetic parameters in any period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lina/Met 2.5mg/500mg | Area Under the Curve 0 to Inf (AUC0-inf) | 7198.79 ng*h/ml | Standard Deviation 1689.89 |
| Lina 2.5mg Plus Met 500mg | Area Under the Curve 0 to Inf (AUC0-inf) | 6923.79 ng*h/ml | Standard Deviation 1714.08 |
Comparison: ANOVA was applied to log-transformed AUC0-inf and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction.90% CI: [101, 108]
Comparison: ANOVA was applied to log-transformed AUC0-inf and included study, subject-within-study, period-within-study, treatment and study-by-treatment interaction. Results were potency corrected (GMR multiplied by the quotient of DP of Met in single tablet and DP of Met in combination tablet).90% CI: [105, 112]