Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the relative bioavailability of BI 894416 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
DRUGItraconazole
Oral solution
DRUGBI 894416
Tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, one-way crossover design
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 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 50 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
Exclusion criteria
* Any finding in the medical examination (including Blood Pressure (BP), Pulse Rate (PR) or Electrocardiogram (ECG) and including the neurological examination) 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 beats per minute (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 * 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 of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause QT/QTc interval prolongation) * Intake of an investigational drug in another clinical trial within 60 days of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administered * Smoker (unless the subject quit smoking for at least 1 year prior to first planned administration of trial medication) * 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) 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 * History of relevant neurological disorder affecting the peripheral or central nervous system (this includes, but is not limited to: stroke, epilepsy, inflammatory or atrophic diseases affecting the nervous system, cluster headache or any cancer of the nervous system). Febrile seizures in childhood or adolescence, recovered carpal tunnel syndrome, recovered uncomplicated meningitis, recovered herpes zoster, tension headache, occasional benign tics (e.g. due to stress) or minor par- or dysesthesia (e.g. as a side effect of prior blood withdrawal) do not constitute a history of relevant neurological disorder. * History of immunological disease except allergy not relevant to the trial (such as mild hay fever or dust mite allergy) and except asthma in childhood or adolescence * History of cancer (other than successfully treated basal cell carcinoma) * Within 10 days prior to administration of trial medication, use of any drug that could reasonably inhibit platelet aggregation or coagulation (e.g., acetylsalicylic acid) * Liver enzyme (ALT, AST, gGT) values above upper limit of normal at the screening examination * History of drug-induced liver injury * History of heart failure, or any evidence of ventricular dysfunction in the history * History of hereditary fructose intolerance * Male subjects with woman of child bearing potential (WOCBP) partner who are unwilling to use male contraception (condom or sexual abstinence) from time point of first administration of trial medication until 30 days after the last administration of trial medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 894416 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Up to 34 h (period 1) and up to 72 h (period 2) (please refer timeframe in detail in description) | AUC0-tz, area under the concentration-time curve of BI 894416 in plasma over the time interval from 0 to the last quantifiable data point is presented. Standard Error (SE) is actually a geometric (g) SE. Pharmacokinetic (PK) samples were collected 3 hours (h) prior dosing and 15 minutes (min), 30 min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h and 34h after BI 894416 on day 1 of both periods and additionally on 48h and 72h after BI 894416 administration in period 2. |
| Maximum Measured Concentration of BI 894416 in Plasma (Cmax) | Up to 34 h (period 1) and up to 72 h (period 2) (please refer timeframe in detail in description) | Cmax, maximum measured concentration of BI 894416 in plasma is presented. Standard error (SE) is actually geometric (g) SE. Pharmacokinetic (PK) samples were collected 3 hours (h) prior dosing and 15minutes (min), 30 min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h and 34h after BI 894416 on day 1 of both periods and additionally on 48h and 72h after BI 894416 administration in period 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 894416 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Up to 34 h (period 1) and up to 72 h (period 2) (please refer timeframe in detail in description) | AUC0-∞, area under the concentration-time curve of BI 894416 in plasma over the time interval from 0 extrapolated to infinity is presented. Standard error (SE) is actually geometric (g) SE. Pharmacokinetic (PK) samples were collected 3 hours (h) prior dosing and 15minutes (min), 30 min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h and 34h after BI 894416 on day 1 of both periods and additionally on 48h and 72h after BI 894416 administration in period 2. |
Countries
Germany
Participant flow
Recruitment details
Open-label, two-treatment periods one-way crossover trial in healthy male participants to compare BI 894416+Itraconazole (Treatment(T)) versus BI 894416 alone (Reference(R)). All participants underwent treatment R in Period 1 (Visit 2) and treatment T in Period 2 (Visit 3). There was at least 6 days washout between the administrations of BI 894416.
Pre-assignment details
All participants were screened for eligibility to participate in the trial. Participants attended specialist site which would then ensure that all participants met all inclusion/exclusion criteria. Participants were not to be entered to trial treatment if any one of the specific entry criteria were not met.
Participants by arm
| Arm | Count |
|---|---|
| BI 894416 Alone (R) / BI 894416+Itraconazole (T) Participants were administered 3 milligram (mg) BI 894416 tablet (1 mg X 3 tablets) orally on Day 1 alone in treatment period 1 (R), and along with 20 milliliter (mL) of 10 mg/ mL Itraconazole oral solution in treatment period 2 (T).
In period 2 (T), participants received 200 mg ((20 milliliter (mL)) of Itraconazole oral solution once daily for 5 days, from Day -3 to Day 2. On Day 1 participants received additionally after the Itraconazole dosing, 3 mg BI 894416 tablet (1 mg X 3 tablets) orally in treatment period 2 (T). Both treatment periods were separated by a washout period of at least 6 days between BI 894416 administrations. In both treatments, BI 894416 was administered to subjects in the fasting state. | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | BI 894416 Alone (R) / BI 894416+Itraconazole (T) |
|---|---|
| Age, Continuous | 40.9 Years STANDARD_DEVIATION 8.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 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 | 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 | 14 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 3 / 14 | 8 / 14 | 5 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Area Under the Concentration-time Curve of BI 894416 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
AUC0-tz, area under the concentration-time curve of BI 894416 in plasma over the time interval from 0 to the last quantifiable data point is presented. Standard Error (SE) is actually a geometric (g) SE. Pharmacokinetic (PK) samples were collected 3 hours (h) prior dosing and 15 minutes (min), 30 min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h and 34h after BI 894416 on day 1 of both periods and additionally on 48h and 72h after BI 894416 administration in period 2.
Time frame: Up to 34 h (period 1) and up to 72 h (period 2) (please refer timeframe in detail in description)
Population: Pharmacokinetic (PK) parameter set (PKS): PKS included all subjects in the TS who provided at least 1 PK parameter that was not excluded because of important protocol deviation (IPDs) relevant to the statistical evaluation the PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 894416 Alone (R) | Area Under the Concentration-time Curve of BI 894416 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 371.77 Nanomole*hour / Litre (nmol*h/ L) | Standard Error 1.13 |
| BI 894416 + Itraconazole (T) | Area Under the Concentration-time Curve of BI 894416 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 526.50 Nanomole*hour / Litre (nmol*h/ L) | Standard Error 1.13 |
Comparison: Point estimates for the ratios of the geometric means (gMeans) (T/R) for AUC0-tz and their 2-sided 90% confidence intervals (CIs) were provided. The difference between the expected means for log(T) - log(R) were estimated by the difference in the corresponding adjusted means (Least Squares Means).90% CI: [129.64, 154.71]ANOVA
Primary
Maximum Measured Concentration of BI 894416 in Plasma (Cmax)
Cmax, maximum measured concentration of BI 894416 in plasma is presented. Standard error (SE) is actually geometric (g) SE. Pharmacokinetic (PK) samples were collected 3 hours (h) prior dosing and 15minutes (min), 30 min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h and 34h after BI 894416 on day 1 of both periods and additionally on 48h and 72h after BI 894416 administration in period 2.
Time frame: Up to 34 h (period 1) and up to 72 h (period 2) (please refer timeframe in detail in description)
Population: Pharmacokinetic (PK) parameter set (PKS): PKS included all subjects in the TS who provided at least 1 PK parameter that was not excluded because of important protocol deviation (IPDs) relevant to the statistical evaluation the PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 894416 Alone (R) | Maximum Measured Concentration of BI 894416 in Plasma (Cmax) | 59.93 Nanomole/ Litre (nmol/ L) | Standard Error 1.07 |
| BI 894416 + Itraconazole (T) | Maximum Measured Concentration of BI 894416 in Plasma (Cmax) | 67.91 Nanomole/ Litre (nmol/ L) | Standard Error 1.07 |
Comparison: Point estimates for the ratios of the gMeans (T/R) for Cmax and their 2-sided 90% CIs were provided. The difference between the expected means for log(T) - log(R) were estimated by the difference in the corresponding adjusted means (Least Squares Means).90% CI: [102.47, 125.32]ANOVA
Secondary
Area Under the Concentration-time Curve of BI 894416 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
AUC0-∞, area under the concentration-time curve of BI 894416 in plasma over the time interval from 0 extrapolated to infinity is presented. Standard error (SE) is actually geometric (g) SE. Pharmacokinetic (PK) samples were collected 3 hours (h) prior dosing and 15minutes (min), 30 min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 24h and 34h after BI 894416 on day 1 of both periods and additionally on 48h and 72h after BI 894416 administration in period 2.
Time frame: Up to 34 h (period 1) and up to 72 h (period 2) (please refer timeframe in detail in description)
Population: Pharmacokinetic (PK) parameter set (PKS): PKS included all subjects in the TS who provided at least 1 PK parameter that was not excluded because of important protocol deviation (IPDs) relevant to the statistical evaluation the PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BI 894416 Alone (R) | Area Under the Concentration-time Curve of BI 894416 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 384.01 Nanomole*hour / Litre (nmol*h/ L) | Standard Error 1.13 |
| BI 894416 + Itraconazole (T) | Area Under the Concentration-time Curve of BI 894416 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 547.36 Nanomole*hour / Litre (nmol*h/ L) | Standard Error 1.13 |
Comparison: Point estimates for the ratios of the gMeans (T/R) for AUC0-∞ and their 2-sided 90% CIs were provided. The difference between the expected means for log(T) - log(R) were estimated by the difference in the corresponding adjusted means (Least Squares Means).90% CI: [130.3, 155.93]ANOVA