Healthy
Conditions
Brief summary
The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics (PK) of BI 474121 in healthy male subjects following oral administration of single rising doses.
Interventions
DRUGBI 474121 tablet
BI 474121 tablet
DRUGPlacebo tablet
Placebo tablet
DRUGBI 474121 oral solution
BI 474121 oral solution
DRUGPlacebo solution
Placebo solution
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
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
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 100 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 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 * 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 (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 24 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 * Male subjects with WOCBP partner who are unwilling to use a highly effective method of birth control from time point of administration of trial medication until 30 days thereafter. Highly effective methods of birth control are: * Male subject is sexually abstinent * Male subjects is vasectomised (vasectomy at least 1 year prior to enrolment), plus condom in male subject * Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) * Use of progestogen-only hormonal contraception by female partner that inhibits ovulation (only injectables or implants), plus condom in male subject * Use of combined (estrogen and progestogen containing) hormonal contraception by female partner that prevents ovulation (oral, intravaginal or transdermal), plus condom in male subject * Female partner is surgically sterilised (including hysterectomy) * Female partner is postmenopausal, defined as no menses for 1 year without an alternative medical cause (in questionable cases a blood sample with FSH above 40 U/L and estradiol below 30 ng/L is confirmatory) Sperm donation is not allowed from the time point of drug administration until 30 days thereafter. * ALT (alanine transaminase), AST (aspartate transaminase), or serum creatinine exceed upper limit of normal range at screening, confirmed by a repeat test * Orthostatic hypotension during orthostatic testing at Day -3, that the investigator considers to be of clinical relevance (only applicable for Single-rising dose (SRD) part). * During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events. | From drug administration until 7 days after drug administration, 7 days. | For assessment of safety and tolerability of BI 474121 the percentage of participants with drug-related adverse events (AE) was calculated. All AEs occurring between first drug intake till 7 days after last drug intake were assigned to the randomised treatment. |
| Bioavailability (BA): 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 (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration. | 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) was analyzed after single dose administration of BI 474121 as: an oral solution in fasted conditions (reference treatment), an uncoated tablet in fed conditions (treatment 1) and an uncoated tablet in fasted conditions (treatment 2). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis. |
| BA: Maximum Measured Concentration of BI 474121 in Plasma (Cmax ) | Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration. | Maximum measured concentration of of BI 474121 in plasma (Cmax). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| SRD: 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 (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration. | 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) was analyzed after single dose administration of BI 474121. The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis. |
| SRD: Maximum Measured Concentration of of BI 474121 in Plasma (Cmax). | Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration. | Maximum measured concentration of of BI 474121 in plasma (Cmax). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis. |
| BA: Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration. | Area under the concentration-time curve of BI 474121 in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis. |
Countries
Germany
Participant flow
Recruitment details
This was a two part trial in healthy male subjects: A single-blind, randomized, placebo-controlled single rising dose (SRD) scheme of BI 474121 (=SRD part); An open-label, randomized, 6-sequence cross-over to assess bioavailability (BA) of BI 474121 as oral solution (fasted state), tablet (fasted state) and tablet (fed state) (=BA part).
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Participants attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Participants were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| SRD: Placebo Matching BI 474121 Oral Solution (OS) This arm comprises all placebo treated participants of the single rising dose (SRD) part treated with an oral solution (placebo treated participants of the two lowest dose group (DG)s). Participants receiving placebo were equally distributed across dose groups. A single dose of BI 474121 matching placebo powder for oral solution was administered after an overnight fast together with 240 milliliter (mL) of water to participants who were in a standing position. | 4 |
| SRD: Placebo Matching BI 474121 Tablet (T) This arm comprises all placebo treated participants of the SRD part treated with a tablet (placebo treated participants of the five upper DGs). Participants receiving placebo were equally distributed across dose groups. A single dose of BI 474121 matching placebo tablet was administered after an overnight fast together with 240 mL of water to subjects who were in a standing position. | 9 |
| SRD: 0.25 Milligram (mg) BI 474121 - OS A single dose of 0.25 mg BI 474121 was solved in 0.5 mL water and was administered after an overnight fast together with 240 mL of water to participants who were in a standing position. | 6 |
| SRD: 1 mg BI 474121 - OS A single dose of 1 mg BI 474121 was solved in 2mL water and was administered after an overnight fast together with 240 mL of water to participants who were in a standing position. | 6 |
| SRD: 2.5 mg BI 474121 - T A single dose of 2.5 mg BI 474121 was administered as 1 uncoated 2.5 mg tablet after an overnight fast together with 240 mL of water to participants who were in a standing position. | 6 |
| SRD: 5 mg BI 474121 - T A single dose of 5.0 mg BI 474121 was administered as 2 uncoated 2.5 mg tablets after an overnight fast together with 240 mL of water to participants who were in a standing position. | 6 |
| SRD: 10 mg BI 474121 - T A single dose of 10.0 mg BI 474121 was administered as 1 uncoated 10.0 mg tablet after an overnight fast together with 240 mL of water to participants who were in a standing position. | 6 |
| SRD: 20 mg BI 474121 - T A single dose of 20.0 mg BI 474121 was administered as 2 uncoated 10.0 mg tablets after an overnight fast together with 240 mL of water to participants who were in a standing position. | 5 |
| SRD: 40 mg BI 474121 - T A single dose of 40.0 mg BI 474121 was administered as 4 uncoated 10.0 mg tablets after an overnight fast together with 240 mL of water to participants who were in a standing position. | 6 |
| BA: BI 474121 10 mg as: OS Fasted (Reference (R)) / T Fasted (T2) / T Fed (T1) Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (Reference (R)), in period 2 as 1 uncoated tablet with 240 mL of water after an overnight fast (Test 2 (T2)) and in period 3 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (Test 1 (T1)). Between periods was a wash-out period of at least 7 days. | 2 |
| BA: BI 474121 10 mg as: R / T1 / T2 Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R), in period 2 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1) and in period 3 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2). Between periods was a wash-out period of at least 7 days. | 2 |
| BA: BI 474121 10mg as: T2 / R / T1 Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2), in period 2 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R) and in period 3 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1). Between periods was a wash-out period of at least 7 days. | 2 |
| BA: BI 474121 10mg as: T2 / T1 / R Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2), in period 2 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1) and in period 3 as oral solution solved in 20 mL water with 240 mL of water after an overnight fast (R). Between periods was a wash-out period of at least 7 days. | 2 |
| BA: BI 474121 10mg: T1 / R / T2 Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1), in period 2 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R) and in period 3 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2). Between periods was a wash-out period of at least 7 days. | 2 |
| BA: BI 474121 10mg: T1 / T2 / R Participants received a single dose of 10.0 mg BI 474121 in each period, in period 1 as 1 uncoated tablet in fed conditions after a high-fat / high-caloric breakfast with 240 mL of water (T1), in period 2 as 1 uncoated tablet with 240 mL of water after an overnight fast (T2) and in period 3 as oral solution solved in 20 mL of water with 240 mL of water after an overnight fast (R). Between periods was a wash-out period of at least 7 days. | 2 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Wash-out Period 2 (BA Part Only) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | SRD: Placebo Matching BI 474121 Oral Solution (OS) | SRD: Placebo Matching BI 474121 Tablet (T) | SRD: 0.25 Milligram (mg) BI 474121 - OS | SRD: 1 mg BI 474121 - OS | SRD: 2.5 mg BI 474121 - T | SRD: 5 mg BI 474121 - T | SRD: 10 mg BI 474121 - T | SRD: 20 mg BI 474121 - T | SRD: 40 mg BI 474121 - T | BA: BI 474121 10 mg as: OS Fasted (Reference (R)) / T Fasted (T2) / T Fed (T1) | BA: BI 474121 10 mg as: R / T1 / T2 | BA: BI 474121 10mg as: T2 / R / T1 | BA: BI 474121 10mg as: T2 / T1 / R | BA: BI 474121 10mg: T1 / R / T2 | BA: BI 474121 10mg: T1 / T2 / R | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 32.5 Years STANDARD_DEVIATION 6.8 | 28.9 Years STANDARD_DEVIATION 4.8 | 35.2 Years STANDARD_DEVIATION 8.2 | 35.0 Years STANDARD_DEVIATION 6.4 | 31.0 Years STANDARD_DEVIATION 6.3 | 32.0 Years STANDARD_DEVIATION 7.5 | 30.5 Years STANDARD_DEVIATION 6.9 | 35.8 Years STANDARD_DEVIATION 6.5 | 32.5 Years STANDARD_DEVIATION 5.4 | 29.0 Years STANDARD_DEVIATION 5.7 | 30.5 Years STANDARD_DEVIATION 0.7 | 34.5 Years STANDARD_DEVIATION 10.6 | 36.0 Years STANDARD_DEVIATION 12.7 | 31.0 Years STANDARD_DEVIATION 1.4 | 34.0 Years STANDARD_DEVIATION 9.9 | 32.4 Years STANDARD_DEVIATION 6.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 9 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 5 Participants | 6 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 9 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 5 Participants | 5 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 65 Participants |
| Sex/Gender, Customized Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex/Gender, Customized Male | 4 Participants | 9 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 5 Participants | 6 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 2 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 9 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 12 | 0 / 12 | 0 / 11 |
| other Total, other adverse events | 0 / 4 | 4 / 9 | 0 / 6 | 1 / 6 | 2 / 6 | 1 / 6 | 0 / 6 | 1 / 5 | 3 / 6 | 3 / 12 | 3 / 12 | 1 / 11 |
| serious Total, serious adverse events | 0 / 4 | 0 / 9 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 12 | 0 / 12 | 0 / 11 |
Outcome results
Primary
BA: Maximum Measured Concentration of BI 474121 in Plasma (Cmax )
Maximum measured concentration of of BI 474121 in plasma (Cmax). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis.
Time frame: Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration.
Population: Pharmacokinetic parameter analysis set (PKS):~The PKS included all participants in the TS who provided at least 1 primary or secondary pharmacokinetic (PK) endpoint that were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment. Descriptive and model-based analyses of PK parameters were based on the PKS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SRD: Placebo Matching BI 474121 Oral Solution (OS) | BA: Maximum Measured Concentration of BI 474121 in Plasma (Cmax ) | 165 Nanomole per litre | Geometric Coefficient of Variation 39.6 |
| SRD: Placebo Matching BI 474121 Tablet (T) | BA: Maximum Measured Concentration of BI 474121 in Plasma (Cmax ) | 79.4 Nanomole per litre | Geometric Coefficient of Variation 39 |
| SRD: 0.25 Milligram (mg) BI 474121 - OS | BA: Maximum Measured Concentration of BI 474121 in Plasma (Cmax ) | 95.3 Nanomole per litre | Geometric Coefficient of Variation 22.8 |
Comparison: No formal hypothesis was tested.90% CI: [41.86, 55.09]ANOVA
Comparison: No formal hypothesis was tested.90% CI: [105.04, 143.56]ANOVA
Primary
Bioavailability (BA): 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) was analyzed after single dose administration of BI 474121 as: an oral solution in fasted conditions (reference treatment), an uncoated tablet in fed conditions (treatment 1) and an uncoated tablet in fasted conditions (treatment 2). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis.
Time frame: Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration.
Population: Pharmacokinetic parameter analysis set (PKS):~The PKS included all participants in the TS who provided at least 1 primary or secondary pharmacokinetic (PK) endpoint that were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment. Descriptive and model-based analyses of PK parameters were based on the PKS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SRD: Placebo Matching BI 474121 Oral Solution (OS) | Bioavailability (BA): 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). | 1180 Hour times nanomole per litre | Geometric Coefficient of Variation 42.6 |
| SRD: Placebo Matching BI 474121 Tablet (T) | Bioavailability (BA): 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). | 1150 Hour times nanomole per litre | Geometric Coefficient of Variation 51 |
| SRD: 0.25 Milligram (mg) BI 474121 - OS | Bioavailability (BA): 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). | 1300 Hour times nanomole per litre | Geometric Coefficient of Variation 37.8 |
Comparison: No formal hypothesis was tested.90% CI: [91.45, 104.4]ANOVA
Comparison: No formal hypothesis was tested.90% CI: [98.82, 128.94]ANOVA
Primary
Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events.
For assessment of safety and tolerability of BI 474121 the percentage of participants with drug-related adverse events (AE) was calculated. All AEs occurring between first drug intake till 7 days after last drug intake were assigned to the randomised treatment.
Time frame: From drug administration until 7 days after drug administration, 7 days.
Population: Treated set (TS) The TS included all participants who were randomized and treated with at least 1 dose of trial drug. The treatment assignment was determined based on the first treatment the participant received. The TS was used for safety analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SRD: Placebo Matching BI 474121 Oral Solution (OS) | Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events. | 0.0 Percentage of participants |
| SRD: Placebo Matching BI 474121 Tablet (T) | Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events. | 11.1 Percentage of participants |
| SRD: 0.25 Milligram (mg) BI 474121 - OS | Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events. | 0.0 Percentage of participants |
| SRD: 1 mg BI 474121 - OS | Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events. | 0.0 Percentage of participants |
| SRD: 2.5 mg BI 474121 - T | Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events. | 16.7 Percentage of participants |
| SRD: 5 mg BI 474121 - T | Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events. | 16.7 Percentage of participants |
| SRD: 10 mg BI 474121 - T | Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events. | 0.0 Percentage of participants |
| SRD: 20 mg BI 474121 - T | Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events. | 20.0 Percentage of participants |
| SRD: 40 mg BI 474121 - T | Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events. | 33.3 Percentage of participants |
Secondary
BA: 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-∞). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis.
Time frame: Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration.
Population: Pharmacokinetic parameter analysis set (PKS):~The PKS included all participants in the TS who provided at least 1 primary or secondary pharmacokinetic (PK) endpoint that were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment. Descriptive and model-based analyses of PK parameters were based on the PKS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SRD: Placebo Matching BI 474121 Oral Solution (OS) | BA: Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | 1210 Hour times nanomole per litre | Geometric Coefficient of Variation 45 |
| SRD: Placebo Matching BI 474121 Tablet (T) | BA: Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | 1190 Hour times nanomole per litre | Geometric Coefficient of Variation 53.6 |
| SRD: 0.25 Milligram (mg) BI 474121 - OS | BA: Area Under the Concentration-time Curve of BI 474121 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞). | 1340 Hour times nanomole per litre | Geometric Coefficient of Variation 41 |
Comparison: No formal hypothesis was tested.90% CI: [91.98, 105.09]ANOVA
Comparison: No formal hypothesis was tested.90% CI: [98.75, 129.18]ANOVA
Secondary
SRD: 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) was analyzed after single dose administration of BI 474121. The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis.
Time frame: Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration.
Population: Pharmacokinetic parameter analysis set (PKS) The PKS included all participants in the TS who provided at least 1 primary or secondary pharmacokinetic (PK) endpoint that were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment. Descriptive and model-based analyses of PK parameters were based on the PKS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SRD: Placebo Matching BI 474121 Oral Solution (OS) | SRD: 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). | 31.3 Hour times nanomole per litre | Geometric Coefficient of Variation 17 |
| SRD: Placebo Matching BI 474121 Tablet (T) | SRD: 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). | 115 Hour times nanomole per litre | Geometric Coefficient of Variation 17.1 |
| SRD: 0.25 Milligram (mg) BI 474121 - OS | SRD: 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). | 314 Hour times nanomole per litre | Geometric Coefficient of Variation 22.9 |
| SRD: 1 mg BI 474121 - OS | SRD: 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). | 599 Hour times nanomole per litre | Geometric Coefficient of Variation 33.4 |
| SRD: 2.5 mg BI 474121 - T | SRD: 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). | 1130 Hour times nanomole per litre | Geometric Coefficient of Variation 31 |
| SRD: 5 mg BI 474121 - T | SRD: 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). | 2410 Hour times nanomole per litre | Geometric Coefficient of Variation 31.4 |
| SRD: 10 mg BI 474121 - T | SRD: 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). | 5130 Hour times nanomole per litre | Geometric Coefficient of Variation 30.2 |
Secondary
SRD: Maximum Measured Concentration of of BI 474121 in Plasma (Cmax).
Maximum measured concentration of of BI 474121 in plasma (Cmax). The geometric mean and geometric coefficient of variation were calculated by noncompartmental analysis.
Time frame: Within 3 hours (h) before drug administration and 15 minutes (min), 30min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h, 72h, and 96h after drug administration.
Population: Pharmacokinetic parameter analysis set (PKS) The PKS included all participants in the TS who provided at least 1 primary or secondary pharmacokinetic (PK) endpoint that were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a participant was included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment. Descriptive and model-based analyses of PK parameters were based on the PKS.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| SRD: Placebo Matching BI 474121 Oral Solution (OS) | SRD: Maximum Measured Concentration of of BI 474121 in Plasma (Cmax). | 5.40 Nanomole per litre | Geometric Coefficient of Variation 26.3 |
| SRD: Placebo Matching BI 474121 Tablet (T) | SRD: Maximum Measured Concentration of of BI 474121 in Plasma (Cmax). | 19.4 Nanomole per litre | Geometric Coefficient of Variation 16.9 |
| SRD: 0.25 Milligram (mg) BI 474121 - OS | SRD: Maximum Measured Concentration of of BI 474121 in Plasma (Cmax). | 24.8 Nanomole per litre | Geometric Coefficient of Variation 12.6 |
| SRD: 1 mg BI 474121 - OS | SRD: Maximum Measured Concentration of of BI 474121 in Plasma (Cmax). | 44.3 Nanomole per litre | Geometric Coefficient of Variation 7.19 |
| SRD: 2.5 mg BI 474121 - T | SRD: Maximum Measured Concentration of of BI 474121 in Plasma (Cmax). | 77.8 Nanomole per litre | Geometric Coefficient of Variation 29.4 |
| SRD: 5 mg BI 474121 - T | SRD: Maximum Measured Concentration of of BI 474121 in Plasma (Cmax). | 189 Nanomole per litre | Geometric Coefficient of Variation 40 |
| SRD: 10 mg BI 474121 - T | SRD: Maximum Measured Concentration of of BI 474121 in Plasma (Cmax). | 298 Nanomole per litre | Geometric Coefficient of Variation 29.2 |