Non-alcoholic Fatty Liver Disease
Conditions
Brief summary
The primary objective of this trial is to investigate the relative Bioavailability (BA) of tablet formulation of Dabigatran etexilate (DE) with and without co-administration of rabeprazole in healthy male subjects. The secondary objective is the evaluation and comparison of several pharmacokinetic parameters between the treatments.
Interventions
DRUGDabigatran Etexilate
Tablet, film coated
DRUGRabeprazol sodium
Tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
20 Years to 40 Years
Healthy volunteers
No
Inclusion 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 at informed consent * Body mass index (BMI) of 18 ≥ and ≤ 25 kg/m2 at screening * Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
* 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 (BP) outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate (PR) outside the range of 45 to 90 bpm at screening * Any laboratory value outside the reference range before administration of DE that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease judged 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 * Any history of hypochlorhydria or achlorhydria * 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. QT/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 at 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 study requirements, or has a condition that would not allow safe participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Total Dabigatran (AUC0-tz). | Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose. | This endpoint calculates area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 to the time of last quantifiable time point. |
| Maximum Concentration of Total Dabigatran in Plasma (Cmax). | Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose. | This outcome is maximum measured concentration of the total dabigatran in plasma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Free Dabigatran (AUC0-tz). | Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose. | This endpoint calculates area under the concentration-time curve of free dabigatran in plasma over the time interval from 0 to the time of last quantifiable time point. |
| Maximum Concentration of Free Dabigatran in Plasma (Cmax). | Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose. | This outcome is maximum measured concentration of the free dabigatran in plasma |
| Area Under the Concentration-time Curve of Total Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose. | This endpoint calculates area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 extrapolated to infinity |
| Area Under the Concentration-time Curve of Free Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose. | This endpoint calculates area under the concentration-time curve of free dabigatran in plasma over the time interval from 0 extrapolated to infinity. |
Countries
Japan
Participant flow
Recruitment details
This was open label, 2 period, fixed sequence (RT), single arm study in 36 healthy male Japanese subjects. All subjects were orally treated with single dose of 110 milligram (mg) dabigatran etexilate (DE) tablet formulation alone in period 1 and with 20 mg rabeprazole tablet in period 2 with 4 days of rabeprazole pre-medication.
Pre-assignment details
After it had been determined that the subject met all eligibility criteria, a unique subject number was assigned. The number was recorded on electronic Case Report Forms and correspondence regarding the subject. Once a subject number had been assigned, it could not be reassigned to any other subject. Randomisation was not planned in this study.
Participants by arm
| Arm | Count |
|---|---|
| Total Subjects Subjects were treated orally with dabigatran etexilate 110 mg tablet alone (Reference) after an overnight fast of at least 10 hours (h) without pretreatment with rabeprazole 20 mg tablet in period 1 followed by single dose of dabigatran etexilate 110 mg tablet and rabeprazole 20 mg tablets (Test) once daily with 4 days of rabeprazole pre-treatment in period 2. The treatments of dabigatran etexilate were separated by a wash-out phase of at least 4 days. | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 2 (Washout of at Least 4 Days) | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Total Subjects |
|---|---|
| Age, Continuous | 26.3 Years STANDARD_DEVIATION 4.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 36 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 35 |
| other Total, other adverse events | 0 / 36 | 0 / 35 |
| serious Total, serious adverse events | 0 / 36 | 0 / 35 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Total Dabigatran (AUC0-tz).
This endpoint calculates area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 to the time of last quantifiable time point.
Time frame: Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose.
Population: Pharmacokinetic set (PKS): All treated subjects who provided at least 1 observation for at least 1 primary endpoint without important protocol violations with respect to the statistical evaluation of Pharmacokinetic (PK) endpoints were included in PKS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate 110 mg (Reference) | Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Total Dabigatran (AUC0-tz). | 667 Nanogram*Hour/ millilitre (ng*h/mL) | Geometric Coefficient of Variation 123 |
| Dabigatran Etexilate 110 mg + Rabeprazole 20 mg Tablet (Test) | Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Total Dabigatran (AUC0-tz). | 192 Nanogram*Hour/ millilitre (ng*h/mL) | Geometric Coefficient of Variation 109 |
90% CI: [21.346, 38.996]ANOVA
Primary
Maximum Concentration of Total Dabigatran in Plasma (Cmax).
This outcome is maximum measured concentration of the total dabigatran in plasma
Time frame: Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate 110 mg (Reference) | Maximum Concentration of Total Dabigatran in Plasma (Cmax). | 83.1 Nano gram per milliliter (ng/mL) | Geometric Coefficient of Variation 118 |
| Dabigatran Etexilate 110 mg + Rabeprazole 20 mg Tablet (Test) | Maximum Concentration of Total Dabigatran in Plasma (Cmax). | 21.8 Nano gram per milliliter (ng/mL) | Geometric Coefficient of Variation 105 |
90% CI: [20.066, 34.665]ANOVA
Secondary
Area Under the Concentration-time Curve of Free Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞).
This endpoint calculates area under the concentration-time curve of free dabigatran in plasma over the time interval from 0 extrapolated to infinity.
Time frame: Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate 110 mg (Reference) | Area Under the Concentration-time Curve of Free Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | 618 Nanogram*Hour/ millilitre (ng*h/mL) | Geometric Coefficient of Variation 107 |
| Dabigatran Etexilate 110 mg + Rabeprazole 20 mg Tablet (Test) | Area Under the Concentration-time Curve of Free Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | 188 Nanogram*Hour/ millilitre (ng*h/mL) | Geometric Coefficient of Variation 93.4 |
90% CI: [23.404, 40.037]ANOVA
Secondary
Area Under the Concentration-time Curve of Total Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞).
This endpoint calculates area under the concentration-time curve of total dabigatran in plasma over the time interval from 0 extrapolated to infinity
Time frame: Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate 110 mg (Reference) | Area Under the Concentration-time Curve of Total Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | 702 Nanogram*Hour/ millilitre (ng*h/mL) | Geometric Coefficient of Variation 110 |
| Dabigatran Etexilate 110 mg + Rabeprazole 20 mg Tablet (Test) | Area Under the Concentration-time Curve of Total Dabigatran in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | 214 Nanogram*Hour/ millilitre (ng*h/mL) | Geometric Coefficient of Variation 96.6 |
90% CI: [23.26, 40.234]ANOVA
Secondary
Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Free Dabigatran (AUC0-tz).
This endpoint calculates area under the concentration-time curve of free dabigatran in plasma over the time interval from 0 to the time of last quantifiable time point.
Time frame: Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate 110 mg (Reference) | Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Free Dabigatran (AUC0-tz). | 588 Nanogram*Hour/ millilitre (ng*h/mL) | Geometric Coefficient of Variation 119 |
| Dabigatran Etexilate 110 mg + Rabeprazole 20 mg Tablet (Test) | Area Under the Plasma Concentration-time Curve From 0 to Time of Last Quantifiable Time Point (tz) of Free Dabigatran (AUC0-tz). | 164 Nanogram*Hour/ millilitre (ng*h/mL) | Geometric Coefficient of Variation 110 |
90% CI: [20.914, 37.537]ANOVA
Secondary
Maximum Concentration of Free Dabigatran in Plasma (Cmax).
This outcome is maximum measured concentration of the free dabigatran in plasma
Time frame: Samples were collected 1 hour Pre-dose and at 0:30, 1:00, 1:30, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00 36:00 and 48:00 hours post dose.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dabigatran Etexilate 110 mg (Reference) | Maximum Concentration of Free Dabigatran in Plasma (Cmax). | 72.9 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 114 |
| Dabigatran Etexilate 110 mg + Rabeprazole 20 mg Tablet (Test) | Maximum Concentration of Free Dabigatran in Plasma (Cmax). | 20.0 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 103 |
90% CI: [21.023, 36.118]ANOVA