Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the relative bioavailability of BI 1358894 in plasma when given as oral single dose together with multiple oral doses of itraconazole (Test, T) as compared to when given alone as oral single dose (Reference, R).
Interventions
DRUGBI 1358894
Oral administration of single dose of 10 milligram (mg) BI 1358894 (2 tablets of 5 mg) with 240 milliliter (mL) of water after an high-fat, high-calorie breakfast on Day 1 of Treatment Period 1.
DRUGItraconazole
Oral administration of 200 mg itraconazole (20 mL of 10 mg/mL solution) with 240 mL of water after an overnight fast for at least 10 h once daily for 14 days on Days -3 to 11 combined with a single dose of 10 mg BI 1358894 (2 tablets of 5 mg) on Day 1 of Treatment Period 2, 1.5 hours after administration of itraconazole.
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male 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 45 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) * Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation * Willingness to comply with contraception requirements. Subjects who are sexually active must use adequate contraception with their female partner throughout the study and until 1 month after the last administration of trial medication. Adequate methods are: * Sexual abstinence or * A vasectomy performed at least 1 year prior to screening (with medical assessment of the surgical success) or * Surgical sterilisation (including bilateral tubal occlusion, hysterectomy or bilateral oophorectomy) of the subject's female partner or * The use of condoms, if the female partner uses an adequate contraception method in addition, e.g., intrauterine device (IUD), hormonal contraception (e.g. implants, injectables, combined oral or vaginal contraceptives) that started at least 2 months prior to first drug administration, or barrier method (e.g. diaphragm with spermicide) Unprotected sexual intercourse with a female partner is not allowed throughout the study and until 1 month after the last administration of trial medication.
Exclusion criteria
* Any finding in the medical examination (including Blood pressure (BP), Pulse rate (PR) or Electrocardiogram (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 50 to 90 beats per minute (bpm) * C-reactive protein (CRP)\> Upper limit of normal (ULN), Erythrocyte sedimentation rate (ESR)≥15 millimeters/h, liver or kidney parameter above ULN, or any other 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 * Chronic or relevant acute infections * History of relevant allergy or hypersensitivity (including allergy to the trial medications or their excipients) * Use of drugs within 30 days of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause 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 on specified trial days * Alcohol abuse (consumption of more than 30 g per day) * Drug abuse or positive drug screening * Blood donation of more than 100 mL within 30 days of planned administration of trial medication or intended blood donation during the trial * Intention to perform excessive physical activities within one week prior to the administration of trial medication or during the trial * Inability to comply with the dietary regimen of the trial site * A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening * A history of additional risk factors for Torsade de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome) * Subject is assessed as unsuitable for inclusion by the investigator, for instance, because the subject is not considered able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study * Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behaviour) * Any suicidal ideation of type 2 to 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) in the past 12 months (i.e. active suicidal thought, active suicidal thought with method, active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent) * Any history of drug-induced liver failure. * History of ventricular dysfunction or congestive heart failure. * 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 Extrapolated to Infinity | For each period: within 2.5 hours prior and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 7, 8, 10, 12, 16, 24, 34, 48, 72, 96, 120, 144, 168, 192, 216, 240, 312 and 480* hours after administration of BI 1358894. *only in the second period. | Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Data presented come from an analysis of variance (ANOVA) model on the logarithmic scale, this model included effects accounting for 'subject' and 'treatment'. The 'subject' effect was considered as random, whereas the 'treatment' effect was considered as fixed. |
| Maximum Measured Concentration of BI 1358894 in Plasma | For each period: within 2.5 hours prior and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 7, 8, 10, 12, 16, 24, 34, 48, 72, 96, 120, 144, 168, 192, 216, 240, 312 and 480* hours after administration of BI 1358894. *only in the second period. | Maximum measured concentration of BI 1358894 in plasma (Cmax). Data presented come from an analysis of variance (ANOVA) model on the logarithmic scale, this model included effects accounting for 'subject' and 'treatment'. The 'subject' effect was considered as random, whereas the 'treatment' effect was considered as fixed. |
Secondary
| 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 | For each period: within 2.5 hours prior and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 7, 8, 10, 12, 16, 24, 34, 48, 72, 96, 120, 144, 168, 192, 216, 240, 312 and 480* hours after administration of BI 1358894. *only in the second period. | Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 to the last quantifiable data point. Data presented come from an analysis of variance (ANOVA) model on the logarithmic scale, this model included effects accounting for 'subject' and 'treatment'. The 'subject' effect was considered as random, whereas the 'treatment' effect was considered as fixed. |
Countries
Germany
Participant flow
Recruitment details
The trial was performed as an open-label, 2-treatment, 2-period, fixed sequence trial in healthy male subjects. Each subject was allocated to the same treatment sequence (Reference (R)-Test (T)).
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 |
|---|---|
| Total of the 2-treatment, 2-period, Fixed-sequence Trial Treatment period 1 (Reference (R)): Oral administration of single dose of 10 milligram (mg) BI 1358894 (2 tablets of 5 mg) with 240 milliliter (mL) of water after an high-fat, high-calorie breakfast on Day 1 of Treatment Period 1.
Treatment period 2 (Test (T)): Oral administration of 200 mg itraconazole (20 mL of 10 mg/mL solution) with 240 mL of water after an overnight fast for at least 10 h once daily for 14 days on Days -3 to 11 combined with a single dose of 10 mg BI 1358894 (2 tablets of 5 mg) on Day 1 of Treatment Period 2, 1.5 hours after administration of itraconazole.
Administrations of BI 1358894 were separated by a washout interval of at least 17 days. | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Total of the 2-treatment, 2-period, Fixed-sequence Trial |
|---|---|
| Age, Continuous | 35.3 Years STANDARD_DEVIATION 6.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 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 | 15 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 8 / 16 | 2 / 16 | 8 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity
Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Data presented come from an analysis of variance (ANOVA) model on the logarithmic scale, this model included effects accounting for 'subject' and 'treatment'. The 'subject' effect was considered as random, whereas the 'treatment' effect was considered as fixed.
Time frame: For each period: within 2.5 hours prior and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 7, 8, 10, 12, 16, 24, 34, 48, 72, 96, 120, 144, 168, 192, 216, 240, 312 and 480* hours after administration of BI 1358894. *only in the second period.
Population: Pharmacokinetic parameter analysis set (PKS) included all subjects in the treated set who provided at least 1 PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of pharmacokinetic (PK) or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1358894 | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity | 1623.89 Nanomoles*Hour per Liter |
| BI 1358894 + Itraconazole | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 Extrapolated to Infinity | 3128.75 Nanomoles*Hour per Liter |
Comparison: The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for 'subject' and 'treatment'. The 'subject' effect was considered as random, whereas the 'treatment' effect was considered as fixed.90% CI: [175.19, 211.89]
Primary
Maximum Measured Concentration of BI 1358894 in Plasma
Maximum measured concentration of BI 1358894 in plasma (Cmax). Data presented come from an analysis of variance (ANOVA) model on the logarithmic scale, this model included effects accounting for 'subject' and 'treatment'. The 'subject' effect was considered as random, whereas the 'treatment' effect was considered as fixed.
Time frame: For each period: within 2.5 hours prior and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 7, 8, 10, 12, 16, 24, 34, 48, 72, 96, 120, 144, 168, 192, 216, 240, 312 and 480* hours after administration of BI 1358894. *only in the second period.
Population: Pharmacokinetic parameter analysis set (PKS) included all subjects in the treated set who provided at least 1 PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of pharmacokinetic (PK) or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1358894 | Maximum Measured Concentration of BI 1358894 in Plasma | 48.26 Nanomoles per Liter |
| BI 1358894 + Itraconazole | Maximum Measured Concentration of BI 1358894 in Plasma | 58.25 Nanomoles per Liter |
Comparison: The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for 'subject' and 'treatment'. The 'subject' effect was considered as random, whereas the 'treatment' effect was considered as fixed.90% CI: [105.69, 137.87]
Secondary
Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point
Area under the concentration-time curve of BI 1358894 in plasma over the time interval from 0 to the last quantifiable data point. Data presented come from an analysis of variance (ANOVA) model on the logarithmic scale, this model included effects accounting for 'subject' and 'treatment'. The 'subject' effect was considered as random, whereas the 'treatment' effect was considered as fixed.
Time frame: For each period: within 2.5 hours prior and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 7, 8, 10, 12, 16, 24, 34, 48, 72, 96, 120, 144, 168, 192, 216, 240, 312 and 480* hours after administration of BI 1358894. *only in the second period.
Population: Pharmacokinetic parameter analysis set (PKS) included all subjects in the treated set who provided at least 1 PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of pharmacokinetic (PK) or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1358894 | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point | 1464.49 Nanomoles*Hour per Liter |
| BI 1358894 + Itraconazole | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point | 2686.23 Nanomoles*Hour per Liter |
Comparison: The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for 'subject' and 'treatment'. The 'subject' effect was considered as random, whereas the 'treatment' effect was considered as fixed.90% CI: [105.69, 137.87]