Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the effect on the exposure of BI 474121 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 474121
BI 474121 oral solution
DRUGItraconazole
Itraconazole oral solution
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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 (BP, PR), 12-lead ECG, and clinical laboratory tests * Age of 18 to 50 years (inclusive) * 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 GCP and local legislation
Exclusion criteria
* Any finding in the medical examination (including blood pressure, pulse rate or ECG) deviating from normal and assessed as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 100 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 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 7, 8, 10, 12, 24, 34, 46, 70, 94, 118, 142 hours after BI 474121 administration in each period. In addition at 166, 190, 214, 238, 262 hours after BI 474121 administration in period 2. | Area under the concentration-time curve of BI 474121 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Model used was an analysis of variance (ANOVA) model on the logarithmic scale. Data were log-transformed (natural logarithm) prior to fitting the ANOVA model. The effect 'subjects' was considered as random effect, whereas 'treatment' was considered as fixed effect. |
| Maximum Measured Concentration of BI 474121 in Plasma (Cmax) | Within 3 hours before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 7, 8, 10, 12, 24, 34, 46, 70, 94, 118, 142 hours after BI 474121 administration in each period. In addition at 166, 190, 214, 238, 262 hours after BI 474121 administration in period 2. | Maximum measured concentration of BI 474121 in plasma (Cmax). Model used was an analysis of variance (ANOVA) model on the logarithmic scale. Data were log-transformed (natural logarithm) prior to fitting the ANOVA model. The effect 'subjects' was considered as random effect, whereas 'treatment' was considered as fixed effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 7, 8, 10, 12, 24, 34, 46, 70, 94, 118, 142 hours after BI 474121 administration in each period. In addition at 166, 190, 214, 238, 262 hours after BI 474121 administration in period 2. | Area under the concentration-time curve of BI 474121 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Model used was an analysis of variance (ANOVA) model on the logarithmic scale. Data were log-transformed (natural logarithm) prior to fitting the ANOVA model. The effect 'subjects' was considered as random effect, whereas 'treatment' was considered as fixed effect. |
Countries
Germany
Participant flow
Recruitment details
The study was an open-label, two-treatment, two-period, fixed-sequence design trial in healthy male subjects that explored the effect of multiple doses of itraconazole on the single-dose pharmacokinetics of BI 474121.
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 |
|---|---|
| Sequence: BI 474121 Alone (Reference) - Itraconazole + BI 474121 (Test) Period 1:
Reference (R) treatment: Healthy subjects received a single dose of 0.5 milligram (Powder for oral solution, 0.5 milligram (mg)/milliliter (mL) formulation) BI 474121 on day 1 of period 1.
Period 2:
Test (T) treatment: Healthy subjects received a daily dose of 200 milligram (oral solution, 10 mg/mL) Itraconazole for 14 days (days -3 to 11 of period 2) and a single dose of 0.5 milligram (Powder for oral solution, 0.5 milligram mg/mL formulation) BI 474121 on day 1 of period 2.
BI 474121 administrations in treatment R and treatment T were separated by a wash-out period of at least 10 days.
Administration of trial medication with 240 mL of water was performed after subjects had fasted overnight; fasting was to start no later than 10 hours before the scheduled dosing of BI 474121 or 9 hours before itraconazole administration. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 2: Itraconazole Alone | COVID-19 related reason | 1 |
| Period 2: Itraconazole Alone | Not treated: positive alcohol test | 1 |
Baseline characteristics
| Characteristic | Sequence: BI 474121 Alone (Reference) - Itraconazole + BI 474121 (Test) |
|---|---|
| Age, Continuous | 35.5 years STANDARD_DEVIATION 8.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 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 | 1 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 | 13 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 / 13 | 0 / 12 |
| other Total, other adverse events | 2 / 14 | 0 / 13 | 1 / 12 |
| serious Total, serious adverse events | 0 / 14 | 0 / 13 | 0 / 12 |
Outcome results
Primary
Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of BI 474121 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Model used was an analysis of variance (ANOVA) model on the logarithmic scale. Data were log-transformed (natural logarithm) prior to fitting the ANOVA model. The effect 'subjects' was considered as random effect, whereas 'treatment' was considered as fixed effect.
Time frame: Within 3 hours before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 7, 8, 10, 12, 24, 34, 46, 70, 94, 118, 142 hours after BI 474121 administration in each period. In addition at 166, 190, 214, 238, 262 hours after BI 474121 administration in period 2.
Population: Pharmacokinetic parameter analysis set (PKS): all subjects who were treated with at least one dose of study 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.~Only subjects with non-missing values were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Reference (R) Treatment: BI 474121 Alone | Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | NA hours*nanomole/Liter |
| Test (T) Treatment: Itraconazole + BI 474121 | Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | NA hours*nanomole/Liter |
Comparison: Relative bioavailability. Model used was an analysis of variance (ANOVA) model on the logarithmic scale. Data were log-transformed (natural logarithm) prior to fitting the ANOVA model. The effect 'subjects' was considered as random effect, whereas 'treatment' was considered as fixed effect.90% CI: [187.9, 208.15]
Primary
Maximum Measured Concentration of BI 474121 in Plasma (Cmax)
Maximum measured concentration of BI 474121 in plasma (Cmax). Model used was an analysis of variance (ANOVA) model on the logarithmic scale. Data were log-transformed (natural logarithm) prior to fitting the ANOVA model. The effect 'subjects' was considered as random effect, whereas 'treatment' was considered as fixed effect.
Time frame: Within 3 hours before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 7, 8, 10, 12, 24, 34, 46, 70, 94, 118, 142 hours after BI 474121 administration in each period. In addition at 166, 190, 214, 238, 262 hours after BI 474121 administration in period 2.
Population: Pharmacokinetic parameter analysis set (PKS): all subjects who were treated with at least one dose of study 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.~Only subjects with non-missing values were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Reference (R) Treatment: BI 474121 Alone | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) | NA Nanomole/Liter |
| Test (T) Treatment: Itraconazole + BI 474121 | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) | NA Nanomole/Liter |
Comparison: Relative bioavailability. Model used was an analysis of variance (ANOVA) model on the logarithmic scale. Data were log-transformed (natural logarithm) prior to fitting the ANOVA model. The effect 'subjects' was considered as random effect, whereas 'treatment' was considered as fixed effect.90% CI: [121.92, 168.6]
Secondary
Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of BI 474121 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Model used was an analysis of variance (ANOVA) model on the logarithmic scale. Data were log-transformed (natural logarithm) prior to fitting the ANOVA model. The effect 'subjects' was considered as random effect, whereas 'treatment' was considered as fixed effect.
Time frame: Within 3 hours before and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 7, 8, 10, 12, 24, 34, 46, 70, 94, 118, 142 hours after BI 474121 administration in each period. In addition at 166, 190, 214, 238, 262 hours after BI 474121 administration in period 2.
Population: Pharmacokinetic parameter analysis set (PKS): all subjects who were treated with at least one dose of study 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.~Only subjects with non-missing values were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Reference (R) Treatment: BI 474121 Alone | Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | NA Hours*nanomole/Liter |
| Test (T) Treatment: Itraconazole + BI 474121 | Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | NA Hours*nanomole/Liter |
Comparison: Relative bioavailability. Model used was an analysis of variance (ANOVA) model on the logarithmic scale. Data were log-transformed (natural logarithm) prior to fitting the ANOVA model. The effect 'subjects' was considered as random effect, whereas 'treatment' was considered as fixed effect.90% CI: [192.23, 211.52]