Healthy
Conditions
Brief summary
The primary objective of this trial is to investigate safety and tolerability of BI 705564 in healthy male subjects, following oral administration of multiple rising doses. Secondary objectives are the exploration of the pharmacokinetics, including dose proportionality and investigation of linearity.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Dose Groups (DGs)1 to 5: Healthy male subjects according to the assessment of the investigator, based on a complete medical history, a physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory tests; * DG 8, only: Otherwise healthy male subjects (as defined for DGs 1 to 5) with a history (of at least 1 year) of IgE-mediated, perennial allergies, predominantly to (house) dust mite (dermatophagoides pteronyssinus or dermatophagoides farina) as documented by a positive Skin prick test (SPT)(largest diameter of wheal at screening \> 5 mm) * Age of 18 to 50 years (incl.) * Body Max Index (BMI) of 18.5 to 29.9 kg/m2 (incl.) * 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)) is deviating from normal and judged as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease judged as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy and/ or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair) * Diseases of the central nervous system (including but not limited to any kind of seizure 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 prior to administration of trial medication, if that might reasonably influence the results of the trial (incl. QT/QTc interval prolongation) * Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication, or current participation in another trial involving administration of investigational drug. * Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) * Inability to refrain from smoking on specified trial days * Alcohol abuse (consumption of more than 30 g per day) * Drug abuse or positive drug screening * Blood donation of more than 100 mL within 30 days prior to the administration of trial medication or intended 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 dietary regimen of the trial site * A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms in males) or any other relevant Electrocardiogram (ECG) finding at screening * A history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalemia, or family history of Long QT Syndrome) * Subject is assessed as unsuitable for inclusion by the investigator, for instance, because considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study In addition, the following trial-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Drug-related Adverse Events | From first drug administration until 10 days after last drug administration, up to 27 days (for dose groups 1 to 5 and Placebo Matching BI 705564) or up to 37 days (for dose group 8 and Placebo Matching BI 705564 - SPT). | Percentage of participants with drug-related adverse events is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration of BI 705564 in Plasma (Cmax) After the Administration of the First Dose | 1 hour(s) (h) prior drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after first BI 705564 dose (for dose groups 1 to 5); 1.5 h prior drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 23 h after first BI 705564 dose (for dose group 8). | Maximum measured concentration of BI 705564 in plasma (Cmax) after the administration of the first dose of BI 705564 is reported. |
| Area Under the Concentration-time Curve of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) After the Administration of the Last Dose | 1 h before last dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after last BI 705564 dose on Day 17 (for dose groups 1 to 5); 1.5 h before last dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 23 h after last BI 705564 dose on Day 28 (for dose group 8). | Area under the concentration-time curve of BI 705564 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) after the administration of the last dose of BI 705564 is reported. As per the protocol, day is counted as Day 1 = 0:00. |
| Area Under the Concentration-time Curve of BI 705564 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose (AUCτ,1) | 1 hour(s) (h) prior drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after first BI 705564 dose (for dose groups 1 to 5); 1.5 h prior drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 23 h after first BI 705564 dose (for dose group 8). | Area under the concentration-time curve of BI 705564 in plasma over a uniform dosing interval τ after administration of the first dose of BI 705564 (AUCτ,1) is reported. Here AUCτ,1 = AUC0-24. |
| Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | 1.5 h prior midazolam administration and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h after first midazolam dose on Day -1 and 1h prior midazolam administration and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h after last midazolam dose on Day 17. | Area under the concentration-time curve of Midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) after the first and last dose for Placebo Matching BI 705564 group and for dose groups 2 to 5 is reported. |
| Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | 1.5 h prior midazolam administration and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h after first midazolam dose on Day -1 and 1h prior midazolam administration and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h after last midazolam dose on Day 17. | Maximum measured concentration of Midazolam in plasma (Cmax) after the first and last dose for Placebo Matching BI 705564 group and for dose groups 2 to 5 is reported. |
| Maximum Measured Concentration of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) After the Administration of the Last Dose | 1 h before last dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after last BI 705564 dose on Day 17 (for dose groups 1 to 5); 1.5 h before last dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 23 h after last BI 705564 dose on Day 28 (for dose group 8). | Maximum measured concentration of BI 705564 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) after the administration of the last dose. As per the protocol, day is counted as Day 1 = 0:00. |
Countries
Germany
Participant flow
Recruitment details
The evaluation of multiple rising dose (MRD) of BI 705564 was designed as randomised, placebo-controlled, double-blind and parallel-group design and the evaluation of midazolam interaction was designed as nested, open-label, fixed-sequence, intra-individual comparison in healthy male participants.
Pre-assignment details
All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensured that all participants met all strictly inclusion/exclusion criteria. Participants were not to be assigned to treatment groups if any of the specific entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching BI 705564 Participants were orally administered placebo matching to BI 705564 film-coated tablets (and 75 microgram (μg) Midazolam solution for injection, for dose groups 2-5) with 240 milliliter (mL) of water after a standard continental breakfast, on Day 1 and once per day on Days 4 to 17 (for placebo) and on Day -1 and Day 17 (for Midazolam). | 10 |
| Placebo Matching BI 705564 - SPT Participants with a positive skin prick test (SPT) were orally administered once daily for 28 days placebo matching to BI 705564 film-coated tablets with 240 milliliter (mL) of water after breakfast. | 2 |
| Dose Group 1: BI 705564 10 mg Participants were orally administered one single dose on Day 1 and once daily on Days 4 to 17, 1 film-coated tablet of 10 milligram (mg) of BI 705564 with 240 milliliter (mL) of water after a standard continental breakfast. | 8 |
| Dose Group 2: BI 705564 20 mg Participants were orally administered one single dose on Day 1 and once daily on Days 4 to 17, 2 film-coated tablets of 10 milligram (mg) of BI 705564 (total dosage=20 mg) with 240 milliliter (mL) of water after a standard continental breakfast. On Day -1 and on Day 17 participants were orally administered also 75 microgram (μg) of solution for injection of midazolam with 240 mL of water after a standard continental breakfast. | 8 |
| Dose Group 3: BI 705564 40 mg Participants were orally administered one single dose on Day 1 and once daily on Days 4 to 17, 4 film-coated tablets of 10 milligram (mg) of BI 705564 (total dosage=40 mg) with 240 milliliter (mL) of water after a standard continental breakfast. On Day -1 and on Day 17 participants were orally administered also 75 microgram (μg) of solution for injection of midazolam with 240 mL of water after a standard continental breakfast. | 8 |
| Dose Group 5: BI 705564 60 mg Participants were orally administered one single dose on Day 1 and once daily on Days 4 to 17, 6 film-coated tablets of 10 milligram (mg) of BI 705564 (total dosage=60 mg) with 240 milliliter (mL) of water after a standard continental breakfast. On Day -1 and on Day 17 participants were orally administered also 75 microgram (μg) of solution for injection of midazolam with 240 mL of water after a standard continental breakfast. | 8 |
| Dose Group 4: BI 705564 80 mg Participants were orally administered one single dose on Day 1 and once daily on Days 4 to 17, 8 film-coated tablets of 10 milligram (mg) of BI 705564 (total dosage=80 mg) with 240 milliliter (mL) of water after a standard continental breakfast. On Day -1 and on Day 17 participants were orally administered also 75 microgram (µg) of solution for injection of midazolam with 240 mL of water after a standard continental breakfast. | 8 |
| Dose Group 8: BI 705564 40 mg - SPT Participants with a positive skin prick test (SPT) were orally administered for 28 days once daily 4 film-coated tablets of 10 milligram (mg) of BI 705564 (total dosage=40 mg) with 240 milliliter (mL) of water after breakfast. | 8 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo Matching BI 705564 | Placebo Matching BI 705564 - SPT | Dose Group 1: BI 705564 10 mg | Dose Group 2: BI 705564 20 mg | Dose Group 3: BI 705564 40 mg | Dose Group 5: BI 705564 60 mg | Dose Group 4: BI 705564 80 mg | Dose Group 8: BI 705564 40 mg - SPT | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 40.1 Years STANDARD_DEVIATION 8.2 | 33.0 Years STANDARD_DEVIATION 2.8 | 34.8 Years STANDARD_DEVIATION 9.6 | 44.0 Years STANDARD_DEVIATION 5.7 | 32.3 Years STANDARD_DEVIATION 9.1 | 38.4 Years STANDARD_DEVIATION 8.3 | 40.5 Years STANDARD_DEVIATION 10.2 | 28.5 Years STANDARD_DEVIATION 10.7 | 36.9 Years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 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 | 10 Participants | 2 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 60 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 |
| 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 |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 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 |
| 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 |
| Race (NIH/OMB) White | 10 Participants | 1 Participants | 7 Participants | 8 Participants | 8 Participants | 7 Participants | 7 Participants | 7 Participants | 55 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 2 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 60 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 |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 2 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 5 / 10 | 2 / 2 | 3 / 8 | 2 / 8 | 4 / 8 | 5 / 8 | 2 / 8 | 7 / 8 |
| serious Total, serious adverse events | 0 / 10 | 0 / 2 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Percentage of Participants With Drug-related Adverse Events
Percentage of participants with drug-related adverse events is reported.
Time frame: From first drug administration until 10 days after last drug administration, up to 27 days (for dose groups 1 to 5 and Placebo Matching BI 705564) or up to 37 days (for dose group 8 and Placebo Matching BI 705564 - SPT).
Population: Treated Set (TS): This subject set includes all subjects who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo Matching BI 705564 | Percentage of Participants With Drug-related Adverse Events | 20.0 Percentage of participants (%) |
| Placebo Matching BI 705564 - SPT | Percentage of Participants With Drug-related Adverse Events | 50.0 Percentage of participants (%) |
| Dose Group 1: BI 705564 10 mg | Percentage of Participants With Drug-related Adverse Events | 12.5 Percentage of participants (%) |
| Dose Group 2: BI 705564 20 mg | Percentage of Participants With Drug-related Adverse Events | 0.0 Percentage of participants (%) |
| Dose Group 3: BI 705564 40 mg | Percentage of Participants With Drug-related Adverse Events | 50.0 Percentage of participants (%) |
| Dose Group 5: BI 705564 60 mg | Percentage of Participants With Drug-related Adverse Events | 50.0 Percentage of participants (%) |
| Dose Group 4: BI 705564 80 mg | Percentage of Participants With Drug-related Adverse Events | 12.5 Percentage of participants (%) |
| Dose Group 8: BI 705564 40 mg - SPT | Percentage of Participants With Drug-related Adverse Events | 75.0 Percentage of participants (%) |
Secondary
Area Under the Concentration-time Curve of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) After the Administration of the Last Dose
Area under the concentration-time curve of BI 705564 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) after the administration of the last dose of BI 705564 is reported. As per the protocol, day is counted as Day 1 = 0:00.
Time frame: 1 h before last dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after last BI 705564 dose on Day 17 (for dose groups 1 to 5); 1.5 h before last dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 23 h after last BI 705564 dose on Day 28 (for dose group 8).
Population: Pharmacokinetic (PK) parameter analysis set (PKS) included all subjects in the TS who provided at least one PK parameter that was not excluded. Only participants with evaluable results for this PK parameter are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching BI 705564 | Area Under the Concentration-time Curve of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) After the Administration of the Last Dose | 45.9 nanomole *hour/liter (nmol*h/L) | Geometric Coefficient of Variation 34.2 |
| Placebo Matching BI 705564 - SPT | Area Under the Concentration-time Curve of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) After the Administration of the Last Dose | 84.8 nanomole *hour/liter (nmol*h/L) | Geometric Coefficient of Variation 25.9 |
| Dose Group 1: BI 705564 10 mg | Area Under the Concentration-time Curve of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) After the Administration of the Last Dose | 164.0 nanomole *hour/liter (nmol*h/L) | Geometric Coefficient of Variation 34.3 |
| Dose Group 2: BI 705564 20 mg | Area Under the Concentration-time Curve of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) After the Administration of the Last Dose | 170.0 nanomole *hour/liter (nmol*h/L) | Geometric Coefficient of Variation 62.1 |
| Dose Group 3: BI 705564 40 mg | Area Under the Concentration-time Curve of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) After the Administration of the Last Dose | 204.0 nanomole *hour/liter (nmol*h/L) | Geometric Coefficient of Variation 179 |
| Dose Group 5: BI 705564 60 mg | Area Under the Concentration-time Curve of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) After the Administration of the Last Dose | 138.0 nanomole *hour/liter (nmol*h/L) | Geometric Coefficient of Variation 32.1 |
Comparison: The basic model for the investigation of dose proportionality is a power model that describes the functional relationship between the dose and PK endpoints. Statistical hypotheses were not tested in a confirmatory sense.90% CI: [0.4922, 0.9412]
Secondary
Area Under the Concentration-time Curve of BI 705564 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose (AUCτ,1)
Area under the concentration-time curve of BI 705564 in plasma over a uniform dosing interval τ after administration of the first dose of BI 705564 (AUCτ,1) is reported. Here AUCτ,1 = AUC0-24.
Time frame: 1 hour(s) (h) prior drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after first BI 705564 dose (for dose groups 1 to 5); 1.5 h prior drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 23 h after first BI 705564 dose (for dose group 8).
Population: Pharmacokinetic (PK) parameter analysis set (PKS) included all subjects in the TS who provided at least one PK parameter that was not excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching BI 705564 | Area Under the Concentration-time Curve of BI 705564 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose (AUCτ,1) | 42.1 nanomole*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 40.6 |
| Placebo Matching BI 705564 - SPT | Area Under the Concentration-time Curve of BI 705564 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose (AUCτ,1) | 70.8 nanomole*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 31.7 |
| Dose Group 1: BI 705564 10 mg | Area Under the Concentration-time Curve of BI 705564 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose (AUCτ,1) | 131.0 nanomole*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 22.4 |
| Dose Group 2: BI 705564 20 mg | Area Under the Concentration-time Curve of BI 705564 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose (AUCτ,1) | 168.0 nanomole*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 40.1 |
| Dose Group 3: BI 705564 40 mg | Area Under the Concentration-time Curve of BI 705564 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose (AUCτ,1) | 238.0 nanomole*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 46.6 |
| Dose Group 5: BI 705564 60 mg | Area Under the Concentration-time Curve of BI 705564 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose (AUCτ,1) | 120.0 nanomole*hour/liter (nmol*h/L) | Geometric Coefficient of Variation 33.9 |
Comparison: The basic model for the investigation of dose proportionality is a power model that describes the functional relationship between the dose and PK endpoints. Statistical hypotheses were not tested in a confirmatory sense.90% CI: [0.6966, 0.941]
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) After the First and Last Dose
Area under the concentration-time curve of Midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) after the first and last dose for Placebo Matching BI 705564 group and for dose groups 2 to 5 is reported.
Time frame: 1.5 h prior midazolam administration and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h after first midazolam dose on Day -1 and 1h prior midazolam administration and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h after last midazolam dose on Day 17.
Population: Pharmacokinetic (PK) parameter analysis set (PKS)-midazolam set (PKS-Mida): This set included all subjects in dose groups 2 to 5 who received midazolam (including placebo-treated subjects). Only participants with evaluable results for this PK parameter are reported.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo Matching BI 705564 | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | After last dose: Midazolam + BI705564 or Midazolam + Placebo (Treatment (T)) | 4478.58 picomole*hour/Liter (pmol*h/L) |
| Placebo Matching BI 705564 | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | After first dose: Midazolam alone (Reference (R)) | 4356.03 picomole*hour/Liter (pmol*h/L) |
| Placebo Matching BI 705564 - SPT | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | After last dose: Midazolam + BI705564 or Midazolam + Placebo (Treatment (T)) | 3463.24 picomole*hour/Liter (pmol*h/L) |
| Placebo Matching BI 705564 - SPT | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | After first dose: Midazolam alone (Reference (R)) | 3721.70 picomole*hour/Liter (pmol*h/L) |
| Dose Group 1: BI 705564 10 mg | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | After last dose: Midazolam + BI705564 or Midazolam + Placebo (Treatment (T)) | 4812.45 picomole*hour/Liter (pmol*h/L) |
| Dose Group 1: BI 705564 10 mg | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | After first dose: Midazolam alone (Reference (R)) | 4382.24 picomole*hour/Liter (pmol*h/L) |
| Dose Group 2: BI 705564 20 mg | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | After first dose: Midazolam alone (Reference (R)) | 3191.16 picomole*hour/Liter (pmol*h/L) |
| Dose Group 2: BI 705564 20 mg | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | After last dose: Midazolam + BI705564 or Midazolam + Placebo (Treatment (T)) | 3458.32 picomole*hour/Liter (pmol*h/L) |
| Dose Group 3: BI 705564 40 mg | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | After last dose: Midazolam + BI705564 or Midazolam + Placebo (Treatment (T)) | 3759.20 picomole*hour/Liter (pmol*h/L) |
| Dose Group 3: BI 705564 40 mg | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) After the First and Last Dose | After first dose: Midazolam alone (Reference (R)) | 3445.42 picomole*hour/Liter (pmol*h/L) |
Comparison: Placebo matching BI 705564. Relative bioavailability of midazolam is analyzed using analysis of variance (ANOVA) model on logarithmic scale including random effects for subjects and fixed effects for time point.90% CI: [87.18, 121.25]
Comparison: BI 705564 dose group 2. Relative bioavailability of midazolam is analyzed using analysis of variance (ANOVA) model on logarithmic scale including random effects for subjects and fixed effects for time point.90% CI: [79.94, 108.32]
Comparison: BI 705564 dose group 3. Relative bioavailability of midazolam is analyzed using analysis of variance (ANOVA) model on logarithmic scale including random effects for subjects and fixed effects for time point.90% CI: [103.59, 116.42]
Comparison: BI 705564 dose group 5. Relative bioavailability of midazolam is analyzed using analysis of variance (ANOVA) model on logarithmic scale including random effects for subjects and fixed effects for time point.90% CI: [92, 127.66]
Comparison: BI 705564 dose group 4. Relative bioavailability of midazolam is analyzed using analysis of variance (ANOVA) model on logarithmic scale including random effects for subjects and fixed effects for time point.90% CI: [92.43, 128.79]
Secondary
Maximum Measured Concentration of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) After the Administration of the Last Dose
Maximum measured concentration of BI 705564 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) after the administration of the last dose. As per the protocol, day is counted as Day 1 = 0:00.
Time frame: 1 h before last dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after last BI 705564 dose on Day 17 (for dose groups 1 to 5); 1.5 h before last dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 23 h after last BI 705564 dose on Day 28 (for dose group 8).
Population: Pharmacokinetic (PK) parameter analysis set (PKS) included all subjects in the TS who provided at least one PK parameter that was not excluded. Only participants with evaluable results for this PK parameter are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching BI 705564 | Maximum Measured Concentration of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) After the Administration of the Last Dose | 13.3 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 29.4 |
| Placebo Matching BI 705564 - SPT | Maximum Measured Concentration of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) After the Administration of the Last Dose | 19.8 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 23.7 |
| Dose Group 1: BI 705564 10 mg | Maximum Measured Concentration of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) After the Administration of the Last Dose | 41.8 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 21.4 |
| Dose Group 2: BI 705564 20 mg | Maximum Measured Concentration of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) After the Administration of the Last Dose | 43.4 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 57.2 |
| Dose Group 3: BI 705564 40 mg | Maximum Measured Concentration of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) After the Administration of the Last Dose | 52.6 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 201 |
| Dose Group 5: BI 705564 60 mg | Maximum Measured Concentration of BI 705564 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss) After the Administration of the Last Dose | 39.2 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 28.3 |
Comparison: The basic model for the investigation of dose proportionality is a power model that describes the functional relationship between the dose and PK endpoints. Statistical hypotheses were not tested in a confirmatory sense.90% CI: [0.4556, 0.9094]
Secondary
Maximum Measured Concentration of BI 705564 in Plasma (Cmax) After the Administration of the First Dose
Maximum measured concentration of BI 705564 in plasma (Cmax) after the administration of the first dose of BI 705564 is reported.
Time frame: 1 hour(s) (h) prior drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after first BI 705564 dose (for dose groups 1 to 5); 1.5 h prior drug administration and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 23 h after first BI 705564 dose (for dose group 8).
Population: Pharmacokinetic (PK) parameter analysis set (PKS) included all subjects in the TS who provided at least one PK parameter that was not excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Matching BI 705564 | Maximum Measured Concentration of BI 705564 in Plasma (Cmax) After the Administration of the First Dose | 11.4 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 42.2 |
| Placebo Matching BI 705564 - SPT | Maximum Measured Concentration of BI 705564 in Plasma (Cmax) After the Administration of the First Dose | 18.8 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 38.2 |
| Dose Group 1: BI 705564 10 mg | Maximum Measured Concentration of BI 705564 in Plasma (Cmax) After the Administration of the First Dose | 36.5 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 17.8 |
| Dose Group 2: BI 705564 20 mg | Maximum Measured Concentration of BI 705564 in Plasma (Cmax) After the Administration of the First Dose | 41.0 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 28.1 |
| Dose Group 3: BI 705564 40 mg | Maximum Measured Concentration of BI 705564 in Plasma (Cmax) After the Administration of the First Dose | 58.1 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 54.4 |
| Dose Group 5: BI 705564 60 mg | Maximum Measured Concentration of BI 705564 in Plasma (Cmax) After the Administration of the First Dose | 31.7 nanomole/Liter (nmol/L) | Geometric Coefficient of Variation 35.2 |
Comparison: The basic model for the investigation of dose proportionality is a power model that describes the functional relationship between the dose and PK endpoints. Statistical hypotheses were not tested in a confirmatory sense.90% CI: [0.6449, 0.8967]
Secondary
Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose
Maximum measured concentration of Midazolam in plasma (Cmax) after the first and last dose for Placebo Matching BI 705564 group and for dose groups 2 to 5 is reported.
Time frame: 1.5 h prior midazolam administration and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h after first midazolam dose on Day -1 and 1h prior midazolam administration and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 h after last midazolam dose on Day 17.
Population: Pharmacokinetic (PK) parameter analysis set (PKS)-midazolam set (PKS-Mida): This set included all subjects in dose groups 2 to 5 who received midazolam (including placebo-treated subjects). Only participants with evaluable results for this PK parameter are reported.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo Matching BI 705564 | Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | After last dose: Midazolam +BI 705564 or Midazolam +Placebo (Treatment (T)) | 1197.89 picomole/Liter (pmol/L) |
| Placebo Matching BI 705564 | Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | After first dose: Midazolam alone (Reference (R)) | 1196.63 picomole/Liter (pmol/L) |
| Placebo Matching BI 705564 - SPT | Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | After last dose: Midazolam +BI 705564 or Midazolam +Placebo (Treatment (T)) | 1040.42 picomole/Liter (pmol/L) |
| Placebo Matching BI 705564 - SPT | Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | After first dose: Midazolam alone (Reference (R)) | 1232.26 picomole/Liter (pmol/L) |
| Dose Group 1: BI 705564 10 mg | Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | After last dose: Midazolam +BI 705564 or Midazolam +Placebo (Treatment (T)) | 1255.36 picomole/Liter (pmol/L) |
| Dose Group 1: BI 705564 10 mg | Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | After first dose: Midazolam alone (Reference (R)) | 1147.40 picomole/Liter (pmol/L) |
| Dose Group 2: BI 705564 20 mg | Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | After first dose: Midazolam alone (Reference (R)) | 1031.18 picomole/Liter (pmol/L) |
| Dose Group 2: BI 705564 20 mg | Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | After last dose: Midazolam +BI 705564 or Midazolam +Placebo (Treatment (T)) | 984.14 picomole/Liter (pmol/L) |
| Dose Group 3: BI 705564 40 mg | Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | After last dose: Midazolam +BI 705564 or Midazolam +Placebo (Treatment (T)) | 1058.32 picomole/Liter (pmol/L) |
| Dose Group 3: BI 705564 40 mg | Maximum Measured Concentration of Midazolam in Plasma (Cmax) After the First and Last Dose | After first dose: Midazolam alone (Reference (R)) | 1175.41 picomole/Liter (pmol/L) |
Comparison: Placebo matching BI 705564. Relative bioavailability of midazolam is analyzed using analysis of variance (ANOVA) model on logarithmic scale including random effects for subjects and fixed effects for time point.90% CI: [83.99, 119.31]
Comparison: BI 705564 dose group 2. Relative bioavailability of midazolam is analyzed using analysis of variance (ANOVA) model on logarithmic scale including random effects for subjects and fixed effects for time point.90% CI: [72.29, 98.62]
Comparison: BI 705564 dose group 3. Relative bioavailability of midazolam is analyzed using analysis of variance (ANOVA) model on logarithmic scale including random effects for subjects and fixed effects for time point.90% CI: [94.34, 126.88]
Comparison: BI 705564 dose group 5. Relative bioavailability of midazolam is analyzed using analysis of variance (ANOVA) model on logarithmic scale including random effects for subjects and fixed effects for time point.90% CI: [79.75, 114.21]
Comparison: BI 705564 dose group 4. Relative bioavailability of midazolam is analyzed using analysis of variance (ANOVA) model on logarithmic scale including random effects for subjects and fixed effects for time point.90% CI: [70.75, 114.59]