Healthy
Conditions
Brief summary
The primary objective of this trial is to establish the bioequivalence of tablet formulation of dabigatran etexilate compared to commercial capsule formulation following oral administration under fasted condition. The secondary objective is the evaluation and comparison of several pharmacokinetic parameters between the treatments.
Interventions
DRUGdabigatran etexilate
single dose
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
20 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria: * Healthy male subjects according to the investigator's assessment, based on a complete medical history including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests * Age ≥20 and ≤40 years old at informed consent * BMI ≥18 and ≤25 kg/m2 at screening * Signed and dated written informed consent prior to admission to the trial in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply: * Any finding in the medical examination (including blood pressure (BP), pulse rate (PR)or electrocardiogram (ECG)) is deviating from normal and judged as clinically relevant by the investigator * Measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 bpm at screening. Based on the clinical judge by the investigator, repeated measurements are allowed. * Any laboratory value outside the reference range before randomisation that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease considered as clinically relevant by the investigator * Any relevant bleeding history considered by the investigator * Any history or evidence of blood dyscrasia, haemorrhagic diathesis, severe thrombocytopenia, cerebrovascular haemorrhage, bleeding tendencies associated with active ulceration or overt bleeding of gastrointestinal, respiratory or genitourinary tract or any disease or condition with haemorrhagic tendencies * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair) * Planned surgeries within four weeks following the end-of trial examination * Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders * History of relevant orthostatic hypotension, fainting spells, or blackouts * Chronic or relevant acute infections * History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients) * Use of drugs within 30 days prior to administration of trial medication if that might reasonably influence the results of the trial (incl.Qc/QTc interval prolongation) * Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication, or current participation in another trial involving administration of investigational drug * Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) * Inability to refrain from smoking in-house confinement at the trial site * Alcohol abuse (consumption of more than 30 g per day: e.g., 750 mL of beer, 1.5 gous \[equivalent to 270 mL\] of Sake) * Drug abuse or positive drug screening * Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial * Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial * Inability to comply with dietary regimen of trial site * Subject is assessed as unsuitable for inclusion by the investigator, for instance, because considered not able to understand and comply with trial requirements, or has a condition that would not allow safe participation in the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tz of Free Dabigatran | 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | Area under the concentration-time curve of free dabigatran in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz). Geometric Mean (gMean) is actually Adjusted gMean & Geometric Coefficient of Variation (gCV) is actually Intra individual gCV (%gCV). PK exclusion criteria: 1) The subject experienced emesis at or before 2 times median Time from (last) dosing to the maximum measured concentration of the analyte in plasma (tmax). Median tmax was to be taken either from the median tmax for reference product or test product, depending on whether the subject had experienced emesis after taken the test or reference product. Median tmax was to be determined excluding the subjects experiencing emesis. 2) Time deviations 3) Use of restricted medications 4) A pre-dose concentration was \>5% of the Cmax value of that subject. |
| Cmax of Free Dabigatran | 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | Maximum plasma concentration of free dabigatran (Cmax). Geometric Mean is actually Adjusted geometric mean and Geometric Coefficient of Variation (gCV) is actually Intra individual gCV. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tz of Total Dabigatran | 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | Area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz ). Geometric Mean is actually Adjusted geometric mean and Geometric Coefficient of Variation (gCV) is actually Intra individual gCV. |
| Cmax of Total Dabigatran | 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | Maximum plasma concentration of total dabigatran (Cmax). Geometric Mean is actually Adjusted geometric mean and Geometric Coefficient of Variation (gCV) is actually Intra individual gCV. |
| AUC0-∞ of Total Dabigatran | 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | Area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Geometric Mean is actually Adjusted geometric mean and Geometric Coefficient of Variation (gCV) is actually Intra individual gCV. |
| AUC0-∞ of Free Dabigatran | 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration. | Area under the concentration-time curve of free dabigatran in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Geometric Mean is actually Adjusted geometric mean and Geometric Coefficient of Variation (gCV) is actually Intra individual gCV. |
Countries
Japan
Participant flow
Recruitment details
Randomised, single-dose, open-label, replicate design in a two-treatments, four-period, two-sequence crossover design (T:Dabigatran etexilate tablet formulation 110 mg and R: Dabigatran etexilate capsule formulation 110 mg)
Pre-assignment details
All subjects were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the subjects) met all implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial drug if any of the specific entry criteria was violated.
Participants by arm
| Arm | Count |
|---|---|
| T-R-R-T Subjects were treated with single oral dose, started in period 1 with 110 milligram (mg) Dabigatran etexilate tablet with 200 milliliter (mL) of water after an overnight fast of at least 10 hour (h), followed in period 2 and period 3 by 110 mg Dabigatran etexilate capsule with 200 mL of water after an overnight fast of at least 10 h, and in period 4 by 110 mg Dabigatran etexilate tablet with 200 mL of water after an overnight fast of at least 10 h. Treatment periods were separated by a wash-out phase of at least 4 days. | 80 |
| R-T-T-R Subjects were treated with single oral dose, started in period 1 with 110 mg Dabigatran etexilate capsule with 200 mL of water after an overnight fast of at least 10 h, followed in period 2 and period 3 by 110 mg Dabigatran etexilate tablet with 200 mL of water after an overnight fast of at least 10 h, and in period 4 by 110 mg Dabigatran etexilate capsule with 200 mL of water after an overnight fast of at least 10 h. Treatment periods were separated by a wash-out phase of at least 4 days. | 80 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 2 + Washout | Other Adverse Event | 0 | 1 |
| Treatment Period 4 + Washout | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | R-T-T-R | Total | T-R-R-T |
|---|---|---|---|
| Age, Continuous | 27.3 Years STANDARD_DEVIATION 4.2 | 27.2 Years STANDARD_DEVIATION 4.2 | 27.2 Years STANDARD_DEVIATION 4.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 80 Participants | 160 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 80 Participants | 160 Participants | 80 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 80 Participants | 160 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 159 | 0 / 160 |
| other Total, other adverse events | 0 / 159 | 0 / 160 |
| serious Total, serious adverse events | 0 / 159 | 0 / 160 |
Outcome results
Primary
AUC0-tz of Free Dabigatran
Area under the concentration-time curve of free dabigatran in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz). Geometric Mean (gMean) is actually Adjusted gMean & Geometric Coefficient of Variation (gCV) is actually Intra individual gCV (%gCV). PK exclusion criteria: 1) The subject experienced emesis at or before 2 times median Time from (last) dosing to the maximum measured concentration of the analyte in plasma (tmax). Median tmax was to be taken either from the median tmax for reference product or test product, depending on whether the subject had experienced emesis after taken the test or reference product. Median tmax was to be determined excluding the subjects experiencing emesis. 2) Time deviations 3) Use of restricted medications 4) A pre-dose concentration was \>5% of the Cmax value of that subject.
Time frame: 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.
Population: Pharmacokinetic set (PKS): All subjects from Treated Set (TS) who provided at least 1 observation for at least 1 primary endpoint that was not excluded as per PK exclusion criteria (defined in the description).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate Tablet (T) | AUC0-tz of Free Dabigatran | 725.03686 Nanogram*hour/milliliter (ng･h/mL) | Geometric Coefficient of Variation 57.00406 |
| Dabigatran Etexilate Capsule (R) | AUC0-tz of Free Dabigatran | 668.42714 Nanogram*hour/milliliter (ng･h/mL) | Geometric Coefficient of Variation 52.33393 |
Comparison: The statistical model was an analysis of variance (ANOVA) on the logarithmic scale including effects for 'sequence', 'subjects nested within sequences', 'period' and 'treatment'.90% CI: [101.44605, 115.97833]ANOVA
Primary
Cmax of Free Dabigatran
Maximum plasma concentration of free dabigatran (Cmax). Geometric Mean is actually Adjusted geometric mean and Geometric Coefficient of Variation (gCV) is actually Intra individual gCV.
Time frame: 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate Tablet (T) | Cmax of Free Dabigatran | 86.26026 Nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 56.43338 |
| Dabigatran Etexilate Capsule (R) | Cmax of Free Dabigatran | 79.16785 Nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 55.20456 |
Comparison: The statistical model was an analysis of variance (ANOVA) on the logarithmic scale including effects for 'sequence', 'subjects nested within sequences', 'period' and 'treatment'.90% CI: [101.78627, 116.63654]ANOVA
Secondary
AUC0-∞ of Free Dabigatran
Area under the concentration-time curve of free dabigatran in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Geometric Mean is actually Adjusted geometric mean and Geometric Coefficient of Variation (gCV) is actually Intra individual gCV.
Time frame: 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate Tablet (T) | AUC0-∞ of Free Dabigatran | 753.13668 ng•h/mL | Geometric Coefficient of Variation 51.62318 |
| Dabigatran Etexilate Capsule (R) | AUC0-∞ of Free Dabigatran | 694.57320 ng•h/mL | Geometric Coefficient of Variation 49.42941 |
Comparison: The statistical model was an analysis of variance (ANOVA) on the logarithmic scale including effects for 'sequence', 'subjects nested within sequences', 'period' and 'treatment'.90% CI: [101.87254, 115.41292]ANOVA
Secondary
AUC0-∞ of Total Dabigatran
Area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Geometric Mean is actually Adjusted geometric mean and Geometric Coefficient of Variation (gCV) is actually Intra individual gCV.
Time frame: 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate Tablet (T) | AUC0-∞ of Total Dabigatran | 877.70198 ng•h/mL | Geometric Coefficient of Variation 52.0426 |
| Dabigatran Etexilate Capsule (R) | AUC0-∞ of Total Dabigatran | 813.94379 ng•h/mL | Geometric Coefficient of Variation 49.99079 |
Comparison: The statistical model was an analysis of variance (ANOVA) on the logarithmic scale including effects for 'sequence', 'subjects nested within sequences', 'period' and 'treatment'.90% CI: [101.25584, 114.8379]ANOVA
Secondary
AUC0-tz of Total Dabigatran
Area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC0-tz ). Geometric Mean is actually Adjusted geometric mean and Geometric Coefficient of Variation (gCV) is actually Intra individual gCV.
Time frame: 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate Tablet (T) | AUC0-tz of Total Dabigatran | 847.26720 ng•h/mL | Geometric Coefficient of Variation 57.32236 |
| Dabigatran Etexilate Capsule (R) | AUC0-tz of Total Dabigatran | 787.31279 ng•h/mL | Geometric Coefficient of Variation 52.53129 |
Comparison: The statistical model was an analysis of variance (ANOVA) on the logarithmic scale including effects for 'sequence', 'subjects nested within sequences', 'period' and 'treatment'.90% CI: [100.61938, 115.09714]ANOVA
Secondary
Cmax of Total Dabigatran
Maximum plasma concentration of total dabigatran (Cmax). Geometric Mean is actually Adjusted geometric mean and Geometric Coefficient of Variation (gCV) is actually Intra individual gCV.
Time frame: 1:00h before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 3:00h, 4:00h, 6:00h, 8:00h, 12:00h, 24:00h, 36:00h and 48:00h after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate Tablet (T) | Cmax of Total Dabigatran | 99.81133 ng/mL | Geometric Coefficient of Variation 58.31846 |
| Dabigatran Etexilate Capsule (R) | Cmax of Total Dabigatran | 93.54769 ng/mL | Geometric Coefficient of Variation 56.54651 |
Comparison: The statistical model was an analysis of variance (ANOVA) on the logarithmic scale including effects for 'sequence', 'subjects nested within sequences', 'period' and 'treatment'.90% CI: [99.50139, 114.4101]ANOVA