Healthy
Conditions
Brief summary
The objective of this Phase I trial is to demonstrate the bioequivalence of two capsules of dabigatran etexilate made from two different drug product batches. The reference batch is dabigatran etexilate hard capsules 150 mg using the currently approved capsule shell (Qualicaps). The test batch is dabigatran etexilate 150 mg hard capsules using a new capsule shell (Capsugel). The test batch is the drug product intended for future commercial use.
Interventions
DRUGDabigatran etexilate
150 mg Capsugel (T)
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males and females according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), clinical laboratory tests 2. Age =21 and = 55 years 3. Body Mass Index (BMI) =18.5 and BMI = 29.9 kg/m\^2 4. Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and the local legislation
Exclusion criteria
1. Clinically relevant gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders 2. Clinically relevant surgery of gastrointestinal tract or evidence of significant gastrointestinal motility problems that could affect absorption of the drug 3. Diseases of the central nervous system (included but not limited to any kind of seizures, stroke or psychiatric disorders) within the past 6 month 4. Any history or evidence of blood dyscrasia, hemorrhagic diathesis, severe thrombocytopenia, cerebrovascular hemorrhage, bleeding tendencies associated with active ulceration or overt bleeding of gastrointestinal, respiratory or genitourinary tract or any disease or condition with hemorrhagic tendencies 5. History of relevant orthostatic hypotension, fainting spells or blackouts 6. Chronic or relevant acute infections 7. History of allergy/hypersensitivity (including drug allergy in particular to study drug or its excipients) which is deemed relevant to the trial as judged by the investigator 8. Use of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial 9. Alcohol abuse (more than 20 g/day) 10. Drug abuse 11. Any laboratory value outside the reference range that is of clinical relevance (especially hemoglobin, thrombocytes, prothrombin time (PT) and Activated Partial Thromboplastin Time (Measure of the clotting time) (aPTT) or positive drug or virus screening 12. Planned surgeries within four weeks following the end-of study examination 13. Recent or contemplated diagnostic or therapeutic procedures with potential for uncontrollable bleeding within 14 days before or after end-of study examination
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve 0 to tz (AUC0-tz) of Total Dabigatran | 60 hours | Area under the concentration-time curve of total dabigatran in plasma from time 0 to the time of the last quantifiable data point, adjusted for treatment, period and sequence (all fixed effects), and random subject effect. |
| Maximum Measured Concentration (Cmax) of Total Dabigatran in Plasma | 60 hours | Adjusted for treatment, period and sequence (all fixed effects), and random subject effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve 0 to Infinity (AUC0-∞) of Total Dabigatran. | 60 hours | Area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 extrapolated to infinity. Adjusted for treatment, period and sequence (all fixed effects), and random subject effect. |
| AUC0-tz of Free Dabigatran. | 60 hours | Area under the concentration-time curve of free dabigatran in plasma from time 0 to the time of the last quantifiable data point. Adjusted for treatment, period and sequence (all fixed effects), and random subject effect. |
| Cmax of Free Dabigatran in Plasma. | 60 hours | Adjusted for treatment, period and sequence (all fixed effects), and random subject effect. |
| AUC0-∞ of Free Dabigatran. | 60 hours | Area under the concentration-time curve of free dabigatran in plasma over the time interval from 0 extrapolated to infinity. Adjusted for treatment, period and sequence (all fixed effects), and random subject effect. |
Countries
Germany
Participant flow
Pre-assignment details
In this crossover study, subjects were randomly assigned to one of the 2 sequences, with 2 treatment arms. In general terms, Ref-Test-Ref-Test and Test-Ref-Test-Ref. The aim was bioequivalence comparing (Ref) Dabigatran 150mg in the currently approved capsule shell (Qualicaps) to the test of Dabigatran 150mg in a new shell (Capsugel).
Participants by arm
| Arm | Count |
|---|---|
| Sequence: Qualicaps - Capsugel - Qualicaps - Capsugel Dabigatran 150mg in currently approved Qualicaps, followed by Dabigatran 150mg in new Capsugel, followed by Dabigatran 150mg in currently approved Qualicaps, followed by Dabigatran 150mg in new Capsugel (RTRT) | 90 |
| Sequence: Capsugel - Qualicaps - Capsugel - Qualicaps Dabigatran 150mg in new Capsugel, followed by Dabigatran 150mg in currently approved Qualicaps, followed by Dabigatran 150mg in new Capsugel, followed by Dabigatran 150mg in currently approved Qualicaps (TRTR) | 90 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
Baseline characteristics
| Characteristic | Sequence: Qualicaps - Capsugel - Qualicaps - Capsugel | Sequence: Capsugel - Qualicaps - Capsugel - Qualicaps | Total |
|---|---|---|---|
| Age, Continuous | 39.8 Years STANDARD_DEVIATION 10.1 | 39.4 Years STANDARD_DEVIATION 9.1 | 39.6 Years STANDARD_DEVIATION 9.6 |
| Sex: Female, Male Female | 46 Participants | 47 Participants | 93 Participants |
| Sex: Female, Male Male | 44 Participants | 43 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 180 | 34 / 180 |
| serious Total, serious adverse events | 0 / 180 | 0 / 180 |
Outcome results
Primary
Area Under the Curve 0 to tz (AUC0-tz) of Total Dabigatran
Area under the concentration-time curve of total dabigatran in plasma from time 0 to the time of the last quantifiable data point, adjusted for treatment, period and sequence (all fixed effects), and random subject effect.
Time frame: 60 hours
Population: This subject set, the pharmacokinetic set (PKS), includes all subjects of the treated set who provide at least one evaluable observation for at least one of the three PK endpoints of total dabigatran, which is obtained in a period without important protocol violations relevant to the evaluation of bioequivalence.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Capsugel | Area Under the Curve 0 to tz (AUC0-tz) of Total Dabigatran | 1147.64 ng*hr/mL | Geometric Coefficient of Variation 32.32 |
| Qualicaps | Area Under the Curve 0 to tz (AUC0-tz) of Total Dabigatran | 908.48 ng*hr/mL | Geometric Coefficient of Variation 49.83 |
Comparison: Capsugel minus QualicapsMixed Models Analysis
Comparison: Capsugel vs Qualicaps90% CI: [119.45, 133.6]Mixed Models Analysis
Primary
Maximum Measured Concentration (Cmax) of Total Dabigatran in Plasma
Adjusted for treatment, period and sequence (all fixed effects), and random subject effect.
Time frame: 60 hours
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Capsugel | Maximum Measured Concentration (Cmax) of Total Dabigatran in Plasma | 134.44 ng/mL | Geometric Coefficient of Variation 31.1 |
| Qualicaps | Maximum Measured Concentration (Cmax) of Total Dabigatran in Plasma | 107.13 ng/mL | Geometric Coefficient of Variation 49.67 |
Comparison: Capsugel minus QualicapsMixed Models Analysis
Comparison: Capsugel vs Qualicaps90% CI: [118.69, 132.67]Mixed Models Analysis
Secondary
Area Under the Curve 0 to Infinity (AUC0-∞) of Total Dabigatran.
Area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 extrapolated to infinity. Adjusted for treatment, period and sequence (all fixed effects), and random subject effect.
Time frame: 60 hours
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Capsugel | Area Under the Curve 0 to Infinity (AUC0-∞) of Total Dabigatran. | 1175.05 ng*hr/mL | Geometric Coefficient of Variation 30.81 |
| Qualicaps | Area Under the Curve 0 to Infinity (AUC0-∞) of Total Dabigatran. | 941.99 ng*hr/mL | Geometric Coefficient of Variation 46.53 |
Comparison: Capsugel vs Qualicaps90% CI: [118.32, 131.51]Mixed Models Analysis
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. Adjusted for treatment, period and sequence (all fixed effects), and random subject effect.
Time frame: 60 hours
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Capsugel | AUC0-∞ of Free Dabigatran. | 888.86 ng*hr/mL | Geometric Coefficient of Variation 31.2 |
| Qualicaps | AUC0-∞ of Free Dabigatran. | 714.01 ng*hr/mL | Geometric Coefficient of Variation 47.16 |
Comparison: Capsugel vs Qualicaps90% CI: [118.11, 131.21]Mixed Models Analysis
Secondary
AUC0-tz of Free Dabigatran.
Area under the concentration-time curve of free dabigatran in plasma from time 0 to the time of the last quantifiable data point. Adjusted for treatment, period and sequence (all fixed effects), and random subject effect.
Time frame: 60 hours
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Capsugel | AUC0-tz of Free Dabigatran. | 856.31 ng*hr/mL | Geometric Coefficient of Variation 33.15 |
| Qualicaps | AUC0-tz of Free Dabigatran. | 678.43 ng*hr/mL | Geometric Coefficient of Variation 50.85 |
Comparison: Capsugel vs Qualicaps90% CI: [119.36, 133.47]Mixed Models Analysis
Secondary
Cmax of Free Dabigatran in Plasma.
Adjusted for treatment, period and sequence (all fixed effects), and random subject effect.
Time frame: 60 hours
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Capsugel | Cmax of Free Dabigatran in Plasma. | 106.66 ng/mL | Geometric Coefficient of Variation 31.34 |
| Qualicaps | Cmax of Free Dabigatran in Plasma. | 85.12 ng/mL | Geometric Coefficient of Variation 50.33 |
Comparison: Capsugel vs Qualicaps90% CI: [118.42, 132.59]Mixed Models Analysis