Healthy
Conditions
Brief summary
To investigate the relative bioavailability of dabigatran etexilate as pellets on food and of dabigatran etexilate as granules resolved in reconstitution solution, each with dabigatran etexilate as capsule following oral administration. To evaluate acceptability and palatability of Pellets sprinkled on food and Oral Liquid Formulation
Interventions
DRUGDabigatran etexilate
Pellets (multiple dose of dabigatran)
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males according to the investigator's assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (Blood Pressure, Pulse Rate), 12-lead electrocardiogram, and clinical laboratory tests 2. Age 18 to 55 years (incl.) 3. Body Mass Index 18.5 to 29.9 kg/m2 (incl.) 4. Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation
Exclusion criteria
1. Any finding in the medical examination (including Blood Pressure, Pulse Rate or electrocardiogram) deviating from normal and judged clinically relevant by the investigator. 2. Repeated measurement of systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg 3. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance 4. Any evidence of a concomitant disease judged clinically relevant by the investigator 5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders 6. Surgery of the gastrointestinal tract that could interfere with kinetics of the study drug 7. Diseases of the central nervous system (such as epilepsy), other neurological disorders or psychiatric disorders 8. Subjects who in the investigator's judgement are perceived as having an increased risk of bleeding, for example because of: * Hemorrhagic disorders or bleeding diathesis * Occult blood in faeces or haematuria * Trauma or surgery within the last month or as long as an excessive risk of bleeding persists after these events, or planned surgery during trial participation * History of arteriovenous malformation or aneurysm * History of gastroduodenal ulcer disease or gastrointestinal haemorrhage * History of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intraarticular bleeding * Anemia at screening * Thrombocytopenia (platelet count less than 100/nL)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran. | 47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration | Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval t for total dabigatran. |
| Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran. | 47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration | Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval t for total dabigatran. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran. | 47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration | Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval t for free dabigatran. |
| Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran. | 47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration | Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval t for free dabigatran. |
| Acceptability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | once on day 3 (48 hours after first dose) | Acceptability question: Would you accept to take this medication for chronic use? with 3 possible answers: Yes - No - I am not sure. |
| Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | once on day 3 (48 hours after first dose) | Palatability question: How do you rank the taste? with 5 possible answers: Very good - Good - Fair - Acceptable - Not acceptable. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall A randomised, open-label, 3-way crossover, multiple dose trial consisting of 3 identical treatment periods of 3 days. Study drug (150 mg dabigatran etexilate) was administrated twice daily on Day 1 and Day 2 and once on Day 3. The dosage forms used were: hard capsule, granules resolved in reconstitution solution and pellets on food. Treatment periods were separated by a washout phase of at least 5 days between last drug administration of one treatment and the first drug administration of the next treatment. | 54 |
| Total | 54 |
Baseline characteristics
| Characteristic | Overall |
|---|---|
| Age, Continuous | 36.2 years STANDARD_DEVIATION 10.6 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 54 | 3 / 54 | 1 / 54 |
| serious Total, serious adverse events | 0 / 54 | 0 / 54 | 0 / 54 |
Outcome results
Primary
Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran.
Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval t for total dabigatran.
Time frame: 47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration
Population: Pharmacokinetic analysis set (PKS) included all treated subjects that provided at least 1 observation for at least 1 primary or secondary PK endpoint without relevant protocol deviations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| T1 (Treatment A) | Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran. | 1220 ng∙h/mL | Geometric Coefficient of Variation 34.1 |
| T2 (Treatment B) | Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran. | 1160 ng∙h/mL | Geometric Coefficient of Variation 27 |
| R (Reference) | Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran. | 893 ng∙h/mL | Geometric Coefficient of Variation 46.8 |
Comparison: Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.90% CI: [125.773, 149.25]
Comparison: Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.90% CI: [119.628, 142.2]
Primary
Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran.
Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval t for total dabigatran.
Time frame: 47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration
Population: Pharmacokinetic analysis set (PKS) included all treated subjects that provided at least 1 observation for at least 1 primary or secondary PK endpoint without relevant protocol deviations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| T1 (Treatment A) | Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran. | 191 ng/mL | Geometric Coefficient of Variation 37.4 |
| T2 (Treatment B) | Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran. | 184 ng/mL | Geometric Coefficient of Variation 27.3 |
| R (Reference) | Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Total Dabigatran. | 131 ng/mL | Geometric Coefficient of Variation 50.8 |
Comparison: Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.90% CI: [132.217, 161.576]
Comparison: Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.90% CI: [127.644, 155.876]
Secondary
Acceptability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question.
Acceptability question: Would you accept to take this medication for chronic use? with 3 possible answers: Yes - No - I am not sure.
Time frame: once on day 3 (48 hours after first dose)
Population: Treated set including all subjects that provided at least 1 observation for at least 1 of the questions for at least 1 of the test products.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T1 (Treatment A) | Acceptability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Yes | 37 participants |
| T1 (Treatment A) | Acceptability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | No | 9 participants |
| T1 (Treatment A) | Acceptability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | I am not sure | 7 participants |
| T2 (Treatment B) | Acceptability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Yes | 29 participants |
| T2 (Treatment B) | Acceptability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | No | 17 participants |
| T2 (Treatment B) | Acceptability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | I am not sure | 7 participants |
Secondary
Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran.
Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval t for free dabigatran.
Time frame: 47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration
Population: Pharmacokinetic analysis set (PKS) included all treated subjects that provided at least 1 observation for at least 1 primary or secondary PK endpoint without relevant protocol deviations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| T1 (Treatment A) | Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran. | 1000 ng*h/mL | Geometric Coefficient of Variation 35.8 |
| T2 (Treatment B) | Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran. | 958 ng*h/mL | Geometric Coefficient of Variation 27.6 |
| R (Reference) | Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran. | 727 ng*h/mL | Geometric Coefficient of Variation 50.8 |
Comparison: Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.90% CI: [126.418, 149.797]
Comparison: Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.90% CI: [120.714, 144.342]
Secondary
Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran.
Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval t for free dabigatran.
Time frame: 47:55, 48:30, 49:00, 49:30, 50:00, 50:30, 51:00, 51:30, 52:00, 54:00, 56:00, 58:00, 60:00 relative to first drug administration
Population: Pharmacokinetic analysis set (PKS) included all treated subjects that provided at least 1 observation for at least 1 primary or secondary PK endpoint without relevant protocol deviations with respect to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| T1 (Treatment A) | Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran. | 157 ng/mL | Geometric Coefficient of Variation 37.9 |
| T2 (Treatment B) | Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran. | 154 ng/mL | Geometric Coefficient of Variation 27.6 |
| R (Reference) | Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t for Free Dabigatran. | 106 ng/mL | Geometric Coefficient of Variation 55.1 |
Comparison: Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.90% CI: [133.384, 163.779]
Comparison: Analysis of variance (ANOVA) on the logarithmic scale was used including effects for 'sequence', 'period' and 'treatment' as fixed effects and 'subjects within sequences' as random effect. CIs were calculated based on the residual error from ANOVA.90% CI: [130.853, 160.242]
Secondary
Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question.
Palatability question: How do you rank the taste? with 5 possible answers: Very good - Good - Fair - Acceptable - Not acceptable.
Time frame: once on day 3 (48 hours after first dose)
Population: Treated set including all subjects that provided at least 1 observation for at least 1 of the questions for at least 1 of the test products.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| T1 (Treatment A) | Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Good | 20 participants |
| T1 (Treatment A) | Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Acceptable | 11 participants |
| T1 (Treatment A) | Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Fair | 18 participants |
| T1 (Treatment A) | Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Not acceptable | 2 participants |
| T1 (Treatment A) | Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Very good | 2 participants |
| T2 (Treatment B) | Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Not acceptable | 7 participants |
| T2 (Treatment B) | Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Very good | 0 participants |
| T2 (Treatment B) | Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Good | 15 participants |
| T2 (Treatment B) | Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Fair | 17 participants |
| T2 (Treatment B) | Palatability Rating for Pellets (on Food) and Oral Solution Will be Assessed by Asking the Subjects 1 Multiple Choice Verbal Question. | Acceptable | 14 participants |