Healthy
Conditions
Brief summary
The main objectives of this trial are to investigate safety and tolerability of BI 474121 in healthy male and female young and elderly subjects following oral administration of multiple rising doses per day over 14 days.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 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 (BP, PR), 12-lead ECG, and clinical laboratory tests * Age of 18 to 45 years (inclusive) for young or 65 to 80 years (inclusive) for elderly healthy volunteers * 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 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 100 to 140 mm Hg, 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 * A positive Poly-chain reaction (PCR) test for SARS-CoV-2 and clinical symptoms suggestive for this disease at screening or on Day -3 * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Drug-related Adverse Events | For Midazolam: From first dose of midazolam (on Day -1) until first dose of BI 474121/Placebo, up to 1 day. Other groups: From first dose of BI 474121/Placebo until last dose+7 days of residual effect period, up to 21 days. | Percentage of participants with drug-related adverse events is reported. Medical judgment were used to determine the relationship between study medication and the adverse events, considering all relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as concomitant medication, concomitant diseases and relevant history. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration of BI 474121 in Plasma (Cmax) After First Dose | Within 1 hour (h) before and at 15 minutes (min), 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h45min after first dose of BI 474121. | The maximum measured concentration of BI 474121 in plasma (Cmax) after first dose is reported. |
| Area Under the Concentration-time Curve of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | Within 15 minutes (min) before and at 15 min, 30min, 1hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h after administration of BI 474121 on Day 14. | The area under the concentration-time curve of BI 474121 in plasma at steady state over a uniform dosing interval τ (dosing interval = 24 hours) (AUCτ,ss) is reported. |
| Maximum Measured Concentration of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | Within 15 minutes (min) before and at 15 min, 30min, 1hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h after administration of BI 474121 on Day 14. | The maximum measured concentration of BI 474121 in plasma at steady state over a uniform dosing interval τ (dosing interval = 24 hours) (Cmax,ss) is reported. |
| Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day -1 | Within 1 hour (h) 30 minutes (min) before and at 15min, 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h after the administration of Midazolam on Day -1. | The maximum measured concentration of Midazolam in plasma (Cmax) on Day -1 is reported. |
| Area Under the Concentration-time Curve of BI 474121 in Plasma From 0 to 24h (AUC0-24) After First Dose | Within 1 hour (h) before and at 15 minutes (min), 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h45min after first dose of BI 474121. | The area under the concentration-time curve of BI 474121 in plasma from 0 to 24h (AUC0-24) after first dose is reported. |
| Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 14 | Within 15 minutes (min) before and at 15min, 30min, 1hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h after administration of Midazolam on Day 14. | The Maximum measured concentration of Midazolam in plasma (Cmax) on Day 14 is reported. |
| Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day -1 | Within 1 hour (h) 30 minutes (min) before and at 15min, 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h after the administration of Midazolam on Day -1. | The area under the concentration-time curve of Midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) on Day -1 is reported. |
| Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 1 | Within 1 hour (h) before and at 15 minutes (min), 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h45min after administration of Midazolam on Day 1. | The Area under the concentration-time curve of Midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) on Day 1 is reported. |
| Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 14 | Within 15 minutes (min) before and at 15min, 30min, 1hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h after administration of Midazolam on Day 14. | The Area under the concentration-time curve of Midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) on Day 14 is reported. |
| Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 1 | Within 1 hour (h) before and at 15 minutes (min), 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h45min after administration of Midazolam on Day 1. | The Maximum measured concentration of Midazolam in plasma (Cmax) on Day 1 is reported. |
Countries
Germany
Participant flow
Recruitment details
This trial investigated the safety, tolerability, and pharmacokinetics (PK) of BI 474121 in healthy male and female young and elderly subjects following oral administration of multiple rising doses per day over 14 days and to investigate the effect of BI 474121 on the PK of midazolam, given as an oral microdose.
Pre-assignment details
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Part A) Young participants administered matching placebo to 2.5 milligram (mg) and 10 mg tablets once daily with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) over a treatment period of 14 days (Day 1 - Day 14).
On Day -1, 1, and 14, 75 micrograms (μg) of midazolam for injection used as oral solution were administered orally once daily with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) for placebo participants matched to 2.5mg BI, 10mg BI, 20mg BI, and 30mg BI groups. | 10 |
| BI 474121 2.5mg (Part A) Young participants administered 1 tablet of 2.5 milligrams (mg) BI 474121 orally once daily with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) over a treatment period of 14 days (Day 1 - Day 14).
On Day -1, 1, and 14, 75 micrograms (μg) of midazolam for injection used as oral solution were administered orally once daily with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h). | 8 |
| BI 474121 5mg (Part A) Young participants administered 2 tablets of 2.5 mg BI 474121 orally once daily (daily dose: 5 mg) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) over a treatment period of 14 days (Day 1 - Day 14). | 8 |
| BI 474121 10mg (Part A) Young participants administered 1 tablet of 10 milligrams (mg) BI 474121 orally once daily with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) over a treatment period of 14 days (Day 1 - Day 14).
On Day -1, 1, and 14, 75 micrograms (μg) of midazolam for injection used as oral solution were administered orally once daily with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h). | 8 |
| BI 474121 20mg (Part A) Young participants administered 2 tablets of 10 milligrams (mg) BI 474121 orally once daily (daily dose: 20 mg) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) over a treatment period of 14 days (Day 1 - Day 14).
On Day -1, 1, and 14, 75 micrograms (μg) of midazolam for injection used as oral solution were administered orally once daily with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h). | 8 |
| BI 474121 30mg (Part A) Young participants administered 3 tablets of 10 milligrams (mg) BI 474121 orally once daily (daily dose: 30 mg) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) over a treatment period of 14 days (Day 1 - Day 14).
On Day -1, 1, and 14, 75 micrograms (μg) of midazolam for injection used as oral solution were administered orally once daily with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h). | 8 |
| Placebo (Part B) Elderly participants administered matching placebo to 2.5 mg and 10 mg tablets once daily with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) over a treatment period of 14 days (Day 1 - Day 14). | 4 |
| BI 474121 5mg (Part B) Elderly participants administered 2 tablets of 2.5 mg BI 474121 orally once daily (daily dose: 5 mg) with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) over a treatment period of 14 days (Day 1 - Day 14). | 8 |
| BI 474121 10mg (Part B) Elderly participants administered 1 tablet of 10 milligrams (mg) BI 474121 orally once daily with 240 milliliter (mL) of water after an overnight fast of at least 10 hours (h) over a treatment period of 14 days (Day 1 - Day 14). | 8 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Other than listed | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo (Part A) | BI 474121 2.5mg (Part A) | BI 474121 5mg (Part A) | BI 474121 10mg (Part A) | BI 474121 20mg (Part A) | BI 474121 30mg (Part A) | Placebo (Part B) | BI 474121 5mg (Part B) | BI 474121 10mg (Part B) | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 28.0 Years STANDARD_DEVIATION 5.3 | 35.4 Years STANDARD_DEVIATION 8.9 | 31.4 Years STANDARD_DEVIATION 9.5 | 31.3 Years STANDARD_DEVIATION 7.1 | 32.4 Years STANDARD_DEVIATION 7.7 | 29.3 Years STANDARD_DEVIATION 5.7 | 66.5 Years STANDARD_DEVIATION 2.4 | 70.8 Years STANDARD_DEVIATION 4.7 | 72.3 Years STANDARD_DEVIATION 5.3 | 42.4 Years STANDARD_DEVIATION 19.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 7 Participants | 8 Participants | 8 Participants | 8 Participants | 7 Participants | 4 Participants | 7 Participants | 8 Participants | 67 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 |
| 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 |
| Race (NIH/OMB) Asian | 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 | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 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 |
| 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 |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 7 Participants | 7 Participants | 8 Participants | 8 Participants | 4 Participants | 8 Participants | 8 Participants | 66 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 5 Participants | 5 Participants | 2 Participants | 1 Participants | 4 Participants | 29 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 4 Participants | 5 Participants | 3 Participants | 3 Participants | 2 Participants | 7 Participants | 4 Participants | 41 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 |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 4 | 0 / 8 | 0 / 8 | 0 / 40 |
| other Total, other adverse events | 5 / 10 | 7 / 8 | 4 / 8 | 6 / 8 | 7 / 8 | 8 / 8 | 1 / 4 | 4 / 8 | 5 / 8 | 6 / 40 |
| serious Total, serious adverse events | 0 / 10 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 4 | 0 / 8 | 0 / 8 | 0 / 40 |
Outcome results
Primary
Percentage of Participants With Drug-related Adverse Events
Percentage of participants with drug-related adverse events is reported. Medical judgment were used to determine the relationship between study medication and the adverse events, considering all relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as concomitant medication, concomitant diseases and relevant history.
Time frame: For Midazolam: From first dose of midazolam (on Day -1) until first dose of BI 474121/Placebo, up to 1 day. Other groups: From first dose of BI 474121/Placebo until last dose+7 days of residual effect period, up to 21 days.
Population: Treated set (TS): The TS included all subjects who were randomised and treated with at least 1 dose of trial drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (Part A) | Percentage of Participants With Drug-related Adverse Events | 40.0 Percentage of participants |
| BI 474121 2.5mg (Part A) | Percentage of Participants With Drug-related Adverse Events | 75.0 Percentage of participants |
| BI 474121 5mg (Part A) | Percentage of Participants With Drug-related Adverse Events | 50.0 Percentage of participants |
| BI 474121 10mg (Part A) | Percentage of Participants With Drug-related Adverse Events | 75.0 Percentage of participants |
| BI 474121 20mg (Part A) | Percentage of Participants With Drug-related Adverse Events | 87.5 Percentage of participants |
| BI 474121 30mg (Part A) | Percentage of Participants With Drug-related Adverse Events | 100.0 Percentage of participants |
| Placebo (Part B) | Percentage of Participants With Drug-related Adverse Events | 25.0 Percentage of participants |
| BI 474121 5mg (Part B) | Percentage of Participants With Drug-related Adverse Events | 25.0 Percentage of participants |
| BI 474121 10mg (Part B) | Percentage of Participants With Drug-related Adverse Events | 50.0 Percentage of participants |
| Midazolam | Percentage of Participants With Drug-related Adverse Events | 12.5 Percentage of participants |
Secondary
Area Under the Concentration-time Curve of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss)
The area under the concentration-time curve of BI 474121 in plasma at steady state over a uniform dosing interval τ (dosing interval = 24 hours) (AUCτ,ss) is reported.
Time frame: Within 15 minutes (min) before and at 15 min, 30min, 1hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h after administration of BI 474121 on Day 14.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 471 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 28.3 |
| BI 474121 2.5mg (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 797 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 31.6 |
| BI 474121 5mg (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 1280 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 25.1 |
| BI 474121 10mg (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 2870 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 26.4 |
| BI 474121 20mg (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 4350 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 27.4 |
| BI 474121 30mg (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 764 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 39.4 |
| Placebo (Part B) | Area Under the Concentration-time Curve of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) | 1640 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 19.7 |
Secondary
Area Under the Concentration-time Curve of BI 474121 in Plasma From 0 to 24h (AUC0-24) After First Dose
The area under the concentration-time curve of BI 474121 in plasma from 0 to 24h (AUC0-24) after first dose is reported.
Time frame: Within 1 hour (h) before and at 15 minutes (min), 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h45min after first dose of BI 474121.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma From 0 to 24h (AUC0-24) After First Dose | 230 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 20.9 |
| BI 474121 2.5mg (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma From 0 to 24h (AUC0-24) After First Dose | 486 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 23.1 |
| BI 474121 5mg (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma From 0 to 24h (AUC0-24) After First Dose | 862 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 19.1 |
| BI 474121 10mg (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma From 0 to 24h (AUC0-24) After First Dose | 1650 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 23.4 |
| BI 474121 20mg (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma From 0 to 24h (AUC0-24) After First Dose | 2430 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 20 |
| BI 474121 30mg (Part A) | Area Under the Concentration-time Curve of BI 474121 in Plasma From 0 to 24h (AUC0-24) After First Dose | 410 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 34.2 |
| Placebo (Part B) | Area Under the Concentration-time Curve of BI 474121 in Plasma From 0 to 24h (AUC0-24) After First Dose | 891 hour * nanomole / Liter (h*nmol/L) | Geometric Coefficient of Variation 13.7 |
Secondary
Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 1
The Area under the concentration-time curve of Midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) on Day 1 is reported.
Time frame: Within 1 hour (h) before and at 15 minutes (min), 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h45min after administration of Midazolam on Day 1.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 1 | 2760 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 58.3 |
| BI 474121 2.5mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 1 | 2020 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 25.8 |
| BI 474121 5mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 1 | 2720 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 31.4 |
| BI 474121 10mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 1 | 2290 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 85.8 |
| BI 474121 20mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 1 | 2360 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 40.7 |
Secondary
Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day -1
The area under the concentration-time curve of Midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) on Day -1 is reported.
Time frame: Within 1 hour (h) 30 minutes (min) before and at 15min, 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h after the administration of Midazolam on Day -1.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day -1 | 2830 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 59.8 |
| BI 474121 2.5mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day -1 | 1920 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 27.2 |
| BI 474121 5mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day -1 | 3080 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 30.8 |
| BI 474121 10mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day -1 | 2610 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 56.9 |
| BI 474121 20mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day -1 | 2350 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 38.5 |
Secondary
Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 14
The Area under the concentration-time curve of Midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) on Day 14 is reported.
Time frame: Within 15 minutes (min) before and at 15min, 30min, 1hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h after administration of Midazolam on Day 14.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 14 | 3570 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 44.7 |
| BI 474121 2.5mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 14 | 2130 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 30.6 |
| BI 474121 5mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 14 | 2710 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 38 |
| BI 474121 10mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 14 | 2390 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 74.2 |
| BI 474121 20mg (Part A) | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) - Day 14 | 2570 hour * picomole / Liter (h * pmol/L) | Geometric Coefficient of Variation 37.6 |
Secondary
Maximum Measured Concentration of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss)
The maximum measured concentration of BI 474121 in plasma at steady state over a uniform dosing interval τ (dosing interval = 24 hours) (Cmax,ss) is reported.
Time frame: Within 15 minutes (min) before and at 15 min, 30min, 1hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h after administration of BI 474121 on Day 14.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part A) | Maximum Measured Concentration of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 40.1 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 26.3 |
| BI 474121 2.5mg (Part A) | Maximum Measured Concentration of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 67.8 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 22.2 |
| BI 474121 5mg (Part A) | Maximum Measured Concentration of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 113 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 19.6 |
| BI 474121 10mg (Part A) | Maximum Measured Concentration of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 249 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 23.9 |
| BI 474121 20mg (Part A) | Maximum Measured Concentration of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 385 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 26.8 |
| BI 474121 30mg (Part A) | Maximum Measured Concentration of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 60.6 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 40 |
| Placebo (Part B) | Maximum Measured Concentration of BI 474121 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) | 142 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 12.2 |
Secondary
Maximum Measured Concentration of BI 474121 in Plasma (Cmax) After First Dose
The maximum measured concentration of BI 474121 in plasma (Cmax) after first dose is reported.
Time frame: Within 1 hour (h) before and at 15 minutes (min), 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h45min after first dose of BI 474121.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part A) | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) After First Dose | 22.6 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 29.7 |
| BI 474121 2.5mg (Part A) | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) After First Dose | 43.9 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 19.8 |
| BI 474121 5mg (Part A) | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) After First Dose | 82.4 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 25.9 |
| BI 474121 10mg (Part A) | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) After First Dose | 167 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 33.2 |
| BI 474121 20mg (Part A) | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) After First Dose | 229 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 20.2 |
| BI 474121 30mg (Part A) | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) After First Dose | 44.3 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 37.7 |
| Placebo (Part B) | Maximum Measured Concentration of BI 474121 in Plasma (Cmax) After First Dose | 89.4 nanomole / Liter (nmol/L) | Geometric Coefficient of Variation 15 |
Secondary
Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 1
The Maximum measured concentration of Midazolam in plasma (Cmax) on Day 1 is reported.
Time frame: Within 1 hour (h) before and at 15 minutes (min), 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h45min after administration of Midazolam on Day 1.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 1 | 1090 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 44.7 |
| BI 474121 2.5mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 1 | 913 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 35.2 |
| BI 474121 5mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 1 | 1210 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 36.3 |
| BI 474121 10mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 1 | 934 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 44.8 |
| BI 474121 20mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 1 | 987 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 31.3 |
Secondary
Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day -1
The maximum measured concentration of Midazolam in plasma (Cmax) on Day -1 is reported.
Time frame: Within 1 hour (h) 30 minutes (min) before and at 15min, 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 23h after the administration of Midazolam on Day -1.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day -1 | 980 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 34.8 |
| BI 474121 2.5mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day -1 | 747 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 20.2 |
| BI 474121 5mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day -1 | 1460 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 37.4 |
| BI 474121 10mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day -1 | 981 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 32.7 |
| BI 474121 20mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day -1 | 901 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 28.8 |
Secondary
Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 14
The Maximum measured concentration of Midazolam in plasma (Cmax) on Day 14 is reported.
Time frame: Within 15 minutes (min) before and at 15min, 30min, 1hour (h), 1h30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h after administration of Midazolam on Day 14.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects in the treated set who provided at least 1 PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 14 | 1250 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 42 |
| BI 474121 2.5mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 14 | 1010 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 28.2 |
| BI 474121 5mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 14 | 1160 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 45.4 |
| BI 474121 10mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 14 | 1090 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 51.9 |
| BI 474121 20mg (Part A) | Maximum Measured Concentration of Midazolam in Plasma (Cmax) - Day 14 | 931 picomole / Liter (pmol/L) | Geometric Coefficient of Variation 31.3 |