Healthy
Conditions
Brief summary
To investigate the relative bioavailability of the intended Commercial Formulation (iCF) (Test, T) compared with Trial Formulation 2 (TFII) (Reference, R) and to assess potential food effects following oral administration of BI 1358894.
Interventions
DRUGBI 1358894, intended Commercial Formulation (iCF) (T)
A single dose of 100 mg (milligram) BI 1358894 given orally as a film-coated tablet in the morning
DRUGBI 1358894, Trial Formulation 2 (TFII) (R)
A single dose of 100 mg (milligram) BI 1358894 given orally as a film-coated tablet in the morning.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female subjects according to the assessment of the investigator, as 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 of 18 to 55 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 kg/m\^2 (inclusive) * Signed and dated written informed consent in accordance with International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial * Either male subject, or female subject who meet any of the following criteria for a highly effective contraception from at least 30 days before administration of trial medication until 30 days after trial completion: * Use of combined (estrogen and progestogen containing) hormonal contraception that prevents ovulation (oral, intravaginal or transdermal), plus one additional barrier * Use of progestogen-only hormonal contraception that inhibits ovulation (only injectables or implants), plus one additional barrier * Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS), plus one additional barrier * Sexually abstinent * A vasectomised sexual partner who received medical assessment of the surgical success (documented absence of sperm) and provided that partner is the sole sexual partner of the trial participant plus one additional barrier * Bilateral tubal ligation plus one additional barrier * Surgically sterilised (including hysterectomy, bilateral salpingectomy, bilateral oophorectomy) * Postmenopausal, defined as no menses for 1 year without an alternative medical cause (in questionable cases a blood sample with levels of Follicle-stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory)
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator * Repeated 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 * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease assessed as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) * 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 Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48, 72, 96, 120, 144, 240 and 312 hours following drug administration in each treatment period. | Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). |
| Maximum Measured Concentration of BI 1358894 in Plasma (Cmax) | Within 3 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48, 72, 96, 120, 144, 240 and 312 hours following drug administration in each treatment period. | Maximum measured concentration of BI 1358894 in plasma (Cmax). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48, 72, 96, 120, 144, 240 and 312 hours following drug administration in each treatment period. | Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). |
Countries
Germany
Participant flow
Recruitment details
This was a randomised, open-label, single-dose, four-period and four-sequence crossover trial in healthy male and female subjects.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Test Fasted - Reference Fasted - Test Fed - Reference Fed Four-period crossover with Reference and Test treatments given under either fed or faster condition in the following order: Test fasted - Reference fasted - Test fed - Reference fed, treatments were separated by a wash-out phase of at least 17 days.
Reference: a single dose of 100 mg (milligram) BI 1358894 given orally as of two 50 mg film-coated tablets in the morning.
Test: a single dose of 100 mg (milligram) BI 1358894 given orally as a film-coated tablet in the morning.
Fed: treatment given following a high-fat, high-calorie meal.
Fasted: treatment following an overnight fast of at least 10 hours. | 6 |
| Reference Fasted - Test Fasted - Reference Fed - Test Fed Four-period crossover with Reference and Test treatments given under either fed or faster condition in the following order: Reference fasted - Test fasted - Reference fed - Test fed, treatments were separated by a wash-out phase of at least 17 days.
Reference: a single dose of 100 mg (milligram) BI 1358894 given orally as of two 50 mg film-coated tablets in the morning.
Test: a single dose of 100 mg (milligram) BI 1358894 given orally as a film-coated tablet in the morning.
Fed: treatment given following a high-fat, high-calorie meal.
Fasted: treatment following an overnight fast of at least 10 hours. | 6 |
| Test Fed - Reference Fed - Reference Fasted - Test Fasted Four-period crossover with Reference and Test treatments given under either fed or faster condition in the following order: Test fed - Reference fed - Reference fasted - Test fasted, treatments were separated by a wash-out phase of at least 17 days.
Reference: a single dose of 100 mg (milligram) BI 1358894 given orally as of two 50 mg film-coated tablets in the morning.
Test: a single dose of 100 mg (milligram) BI 1358894 given orally as a film-coated tablet in the morning.
Fed: treatment given following a high-fat, high-calorie meal.
Fasted: treatment following an overnight fast of at least 10 hours. | 6 |
| Reference Fed - Test Fed - Test Fasted - Reference Fasted Four-period crossover with Reference and Test treatments given under either fed or faster condition in the following order: Reference fed - Test fed - Test fasted - Reference fasted, treatments were separated by a wash-out phase of at least 17 days.
Reference: a single dose of 100 mg (milligram) BI 1358894 given orally as of two 50 mg film-coated tablets in the morning.
Test: a single dose of 100 mg (milligram) BI 1358894 given orally as a film-coated tablet in the morning.
Fed: treatment given following a high-fat, high-calorie meal.
Fasted: treatment following an overnight fast of at least 10 hours. | 6 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Wash-out Period 1 to 2 | Adverse Event | 0 | 0 | 0 | 2 |
| Wash-out Period 3 to 4 | Temporal availability | 3 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Test Fasted - Reference Fasted - Test Fed - Reference Fed | Reference Fasted - Test Fasted - Reference Fed - Test Fed | Test Fed - Reference Fed - Reference Fasted - Test Fasted | Reference Fed - Test Fed - Test Fasted - Reference Fasted | Total |
|---|---|---|---|---|---|
| Age, Continuous | 43.0 years STANDARD_DEVIATION 6.5 | 36.2 years STANDARD_DEVIATION 7.5 | 44.5 years STANDARD_DEVIATION 13 | 34.2 years STANDARD_DEVIATION 6 | 39.5 years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 24 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 5 Participants | 3 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 21 | 0 / 21 | 0 / 21 |
| other Total, other adverse events | 15 / 21 | 13 / 21 | 13 / 21 | 13 / 21 |
| serious Total, serious adverse events | 0 / 21 | 0 / 21 | 0 / 21 | 0 / 21 |
Outcome results
Primary
Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz).
Time frame: Within 3 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48, 72, 96, 120, 144, 240 and 312 hours following drug administration in each treatment period.
Population: All subjects who were treated with at least one dose of the trial drug and who provided at least one pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability were included in the pharmacokinetic analysis set (PKS). Only subjects with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 1358894 - Test - Fasted | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 7360 hours*nanomole/Liter | Geometric Coefficient of Variation 38.7 |
| BI 1358894 - Test - Fed | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 14700 hours*nanomole/Liter | Geometric Coefficient of Variation 26.3 |
| BI 1358894 - Reference - Fasted | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 8430 hours*nanomole/Liter | Geometric Coefficient of Variation 28.6 |
| BI 1358894 - Reference - Fed | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 14900 hours*nanomole/Liter | Geometric Coefficient of Variation 26.6 |
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [79.5, 99.7]
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [94.4, 101.9]
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [180.1, 227.5]
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [158.3, 190.8]
Primary
Maximum Measured Concentration of BI 1358894 in Plasma (Cmax)
Maximum measured concentration of BI 1358894 in plasma (Cmax).
Time frame: Within 3 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48, 72, 96, 120, 144, 240 and 312 hours following drug administration in each treatment period.
Population: All subjects who were treated with at least one dose of the trial drug and who provided at least one pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability were included in the pharmacokinetic analysis set (PKS).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 1358894 - Test - Fasted | Maximum Measured Concentration of BI 1358894 in Plasma (Cmax) | 292 nanomole/Liter | Geometric Coefficient of Variation 54.9 |
| BI 1358894 - Test - Fed | Maximum Measured Concentration of BI 1358894 in Plasma (Cmax) | 445 nanomole/Liter | Geometric Coefficient of Variation 26.1 |
| BI 1358894 - Reference - Fasted | Maximum Measured Concentration of BI 1358894 in Plasma (Cmax) | 378 nanomole/Liter | Geometric Coefficient of Variation 52.3 |
| BI 1358894 - Reference - Fed | Maximum Measured Concentration of BI 1358894 in Plasma (Cmax) | 440 nanomole/Liter | Geometric Coefficient of Variation 23.2 |
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [69.6, 99]
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [88.7, 112]
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [126, 187.3]
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [99.6, 147.8]
Secondary
Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞).
Time frame: Within 3 hours before and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 34, 48, 72, 96, 120, 144, 240 and 312 hours following drug administration in each treatment period.
Population: All subjects who were treated with at least one dose of the trial drug and who provided at least one pharmacokinetic (PK) endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability were included in the pharmacokinetic analysis set (PKS). Only subjects with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 1358894 - Test - Fasted | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 8020 hours*nanomole/Liter | Geometric Coefficient of Variation 37.3 |
| BI 1358894 - Test - Fed | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 16100 hours*nanomole/Liter | Geometric Coefficient of Variation 30.3 |
| BI 1358894 - Reference - Fasted | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 9120 hours*nanomole/Liter | Geometric Coefficient of Variation 28 |
| BI 1358894 - Reference - Fed | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 15900 hours*nanomole/Liter | Geometric Coefficient of Variation 28.1 |
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [80.4, 100.4]
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [96.8, 104.1]
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [179.6, 228.5]
Comparison: Analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [158.2, 187.7]