Healthy
Conditions
Brief summary
The primary objective of the trial is to investigate the safety and tolerability of BI 1358894 in healthy male subjects following oral administration of multiple rising doses over 14 days.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male subjects according to the investigator's assessment, 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 (incl.) * Body Mass 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 * Willingness to comply with contraception requirements. Subjects who are sexually active must use adequate contraception with their female partner throughout the study and until one month after the last administration of trial medication. Adequate methods are: * Sexual abstinence or * A vasectomy performed at least 1 year prior to screening (with medical assessment of the surgical success) or * Surgical sterilisation (including bilateral tubal occlusion, hysterectomy or bilateral oophorectomy) of the subject's female partner or * The use of condoms, if the female partner uses an adequate contraception method in addition, e.g., intrauterine device (IUD), hormonal contraception (e.g. implants, injectables, combined oral or vaginal contraceptives) that started at least 2 months prior to first drug administration, or barrier method (e.g. diaphragm with spermicide) Unprotected sexual intercourse with a female partner is not allowed throughout the study and until one month after the last administration of trial medication.
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 beats per minute (bpm) * C-Reactive Protein \> upper limit of normal (ULN), erythrocyte sedimentation rate (ESR) ≥15 millimeters/h, liver or kidney parameter above ULN, or any other laboratory value outside the reference range that the investigator considers to be of clinical relevance * Positive or missing faecal occult blood test (retest allowed) * Positive testing for faecal calprotectin (retest allowed) * 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 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 prior to administration of trial medication 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 during in-house confinement * 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 administration of trial medication or intended donation during the trial * Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial * Inability to comply with dietary regimen of 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 Electrocardiogram (ECG) finding at screening * A history of additional risk factors for Torsades 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 considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | Midazolam: Up to 1 day, BI 1358894 or Placebo + Midazolam: Up to 1 day and BI 1358894: Up to 13 days. | Number of subjects with on-treatment drug-related Adverse Events (AEs). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration of BI 1358894 in Plasma | Within 2 hours before and 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 27, 48, 72, 75, 96, 120, 123, 144, 192, 195, 240, 243, 288, 311, 312.17, 312.33, 312.5, 313, 314, 315, 316, 318, 320, 324, 336, 360, 384, 408, 432, 456, 504 hours after administration. | Maximum measured concentration of the analyte BI 1358894 in plasma (Cmax). |
| Area Under the Concentration-time Curve of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | Within 2 hours before and 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 27, 48, 72, 75, 96, 120, 123, 144, 192, 195, 240, 243, 288, 311, 312.17, 312.33, 312.5, 313, 314, 315, 316, 318, 320, 324, 336, 360, 384, 408, 432, 456, 504 hours after administration. | Area under the concentration-time curve of BI 1358894 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) |
| Maximum Measured Concentration of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | Within 2 hours before and 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 27, 48, 72, 75, 96, 120, 123, 144, 192, 195, 240, 243, 288, 311, 312.17, 312.33, 312.5, 313, 314, 315, 316, 318, 320, 324, 336, 360, 384, 408, 432, 456, 504 hours after administration. | Maximum measured concentration of BI 1358894 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) |
| Area Under the Concentration-time Curve of BI 1358894 in Plasma Over a Time Interval 0 to 24 h After Administration of the First Dose | Within 2 hours before and 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 27, 48, 72, 75, 96, 120, 123, 144, 192, 195, 240, 243, 288, 311, 312.17, 312.33, 312.5, 313, 314, 315, 316, 318, 320, 324, 336, 360, 384, 408, 432, 456, 504 hours after administration. | Area under the concentration-time curve of the analyte in plasma over a time interval 0 to 24 hours (h) after administration of the first dose (AUC0-24). |
| Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | 25.5, 23.83, 23.5, 23, 22, 21.5, 21, 20, 18, 16 and 1 hour before and 0.17, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 311, 312.33, 312.5, 313, 314, 314.5, 315, 316, 318 and 320 hours after administration of BI 1358894. | Area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). |
| Maximum Measured Concentration of Midazolam in Plasma (Day 1) | 25.5, 23.83, 23.5, 23, 22, 21.5, 21, 20, 18, 16 and 1 hour before and 0.17, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 311, 312.33, 312.5, 313, 314, 314.5, 315, 316, 318 and 320 hours after administration of BI 1358894. | Maximum measured concentration of midazolam in plasma (Cmax). |
| Maximum Measured Concentration of Midazolam in Plasma (Day 14) | 25.5, 23.83, 23.5, 23, 22, 21.5, 21, 20, 18, 16 and 1 hour before and 0.17, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 311, 312.33, 312.5, 313, 314, 314.5, 315, 316, 318 and 320 hours after administration of BI 1358894. | Maximum measured concentration of midazolam in plasma (Cmax). |
| Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | 25.5, 23.83, 23.5, 23, 22, 21.5, 21, 20, 18, 16 and 1 hour before and 0.17, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 311, 312.33, 312.5, 313, 314, 314.5, 315, 316, 318 and 320 hours after administration of BI 1358894 . | Area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). |
Countries
Germany
Participant flow
Recruitment details
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of BI 1358894 (double-blind, randomised, placebo-controlled, parallel-group design) and evaluation of midazolam interaction (nested, open, fixed-sequence, intra-individual comparison) in healthy male subjects
Pre-assignment details
All subjects were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they met all implemented inclusion/exclusion criteria, Subjects were not to be randomised to trial drug if any of the specific entry criteria was violated
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching BI 1358894 Dose Group Oral administration of placebo matching to BI 1358894 film-coated tablet with 240 milliliter (mL) of water after a standard continental breakfast once per day from day 1 to day 14
Oral administration of midazolam as solution for injection (5 mg/5 mL) diluted to 50 microgram (μg)/mL\*1.5 mL (75 μg) with 240 milliliter (mL) water as three single doses on days -1, 1 and 14, after a standard continental breakfast.
On Day 1 and 14 Placebo matching to BI 1358894 was administered immediately prior to midazolam. | 10 |
| BI 1358894 10 Milligram (mg) Dose Group Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (2\*5 mg tablet) once daily for 14 days with 240 milliliter (mL) water after a standard continental breakfast.
Oral administration of midazolam as solution for injection (5 mg/5 mL) diluted to 50 microgram (μg)/mL\*1.5 mL (75 μg) with 240 milliliter (mL) water as three single doses on days -1, 1 and 14, after a standard continental breakfast.
On Day 1 and 14 BI 1358894 was administered immediately prior to midazolam. | 8 |
| BI 1358894 25 Milligram (mg) Dose Group Oral administration of 25 milligram (mg) BI 1358894 film-coated tablet (1\*25 mg tablet) once daily for 14 days with 240 milliliter (mL) water after a standard continental breakfast.
Oral administration of midazolam as solution for injection (5 mg/5 mL) diluted to 50 microgram (μg)/mL\*1.5 mL (75 μg) with 240 milliliter (mL) water as three single doses on days -1, 1 and 14, after a standard continental breakfast.
On Day 1 and 14 BI 1358894 was administered immediately prior to midazolam. | 8 |
| BI 1358894 50 Milligram (mg) Dose Group Oral administration of 50 milligram (mg) BI 1358894 film-coated tablet (2\*25 mg tablet) once daily for 14 days with 240 milliliter (mL) water after standard continental breakfast.
Oral administration of midazolam as solution for injection (5 mg/5 mL) diluted to 50 microgram (μg)/mL\*1.5 mL (75 μg) with 240 milliliter (mL) water as three single doses on days -1, 1 and 14, after a standard continental breakfast.
On Day 1 and 14 BI 1358894 was administered immediately prior to midazolam. | 8 |
| BI 1358894 100 Milligram (mg) Dose Group Oral administration of 100 milligram (mg) BI 1358894 film-coated tablet (1\*100 mg tablet) once daily for 14 days with 240 milliliter (mL) water after standard continental breakfast.
Oral administration of midazolam as solution for injection (5 mg/5 mL) diluted to 50 microgram (μg)/mL\*1.5 mL (75 μg) with 240 milliliter (mL) water as three single doses on days -1, 1 and 14, after a standard continental breakfast.
On Day 1 and 14 BI 1358894 was administered immediately prior to midazolam. | 8 |
| BI 1358894 200 Milligram (mg) Dose Group Oral administration of 200 milligram (mg) BI 1358894 film-coated tablet (2\*100 mg tablet) once daily for 14 days with 240 milliliter (mL) water after standard continental breakfast.
Oral administration of midazolam as solution for injection (5 mg/5 mL) diluted to 50 microgram (μg)/mL\*1.5 mL (75 μg) with 240 milliliter (mL) water as three single doses on days -1, 1 and 14, after a standard continental breakfast.
On Day 1 and 14 BI 1358894 was administered immediately prior to midazolam. | 8 |
| Total | 50 |
Baseline characteristics
| Characteristic | Placebo Matching BI 1358894 Dose Group | BI 1358894 10 Milligram (mg) Dose Group | BI 1358894 25 Milligram (mg) Dose Group | BI 1358894 50 Milligram (mg) Dose Group | BI 1358894 100 Milligram (mg) Dose Group | BI 1358894 200 Milligram (mg) Dose Group | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 32.1 Years STANDARD_DEVIATION 9.7 | 32.0 Years STANDARD_DEVIATION 8.1 | 32.4 Years STANDARD_DEVIATION 6.8 | 32.3 Years STANDARD_DEVIATION 7.7 | 29.3 Years STANDARD_DEVIATION 1.8 | 26.3 Years STANDARD_DEVIATION 5.1 | 30.8 Years STANDARD_DEVIATION 7.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 8 Participants | 8 Participants | 8 Participants | 6 Participants | 8 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 |
| Race (NIH/OMB) Asian | 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 | 1 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 |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 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 |
| Race (NIH/OMB) White | 10 Participants | 8 Participants | 7 Participants | 8 Participants | 8 Participants | 8 Participants | 49 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 50 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 | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 10 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 10 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 2 / 50 | 1 / 10 | 4 / 8 | 4 / 8 | 3 / 8 | 4 / 8 | 5 / 8 | 7 / 10 | 3 / 8 | 6 / 8 | 1 / 8 | 4 / 8 | 5 / 8 |
| serious Total, serious adverse events | 0 / 50 | 0 / 10 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 10 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Number of Subjects With On-treatment Drug-related Adverse Events (AEs).
Number of subjects with on-treatment drug-related Adverse Events (AEs).
Time frame: Midazolam: Up to 1 day, BI 1358894 or Placebo + Midazolam: Up to 1 day and BI 1358894: Up to 13 days.
Population: Treated set (TS): all subjects who received at least one dose of study drug. This was the full analysis set population in the sense of ICH-E9.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Midazolam | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 0 Participants |
| Placebo + Midazolam | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 1 Participants |
| BI 1358894 10 mg + Midazolam | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 4 Participants |
| BI 1358894 25 mg + Midazolam | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 4 Participants |
| BI 1358894 50 mg + Midazolam | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 3 Participants |
| BI 1358894 100 mg + Midazolam | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 4 Participants |
| BI 1358894 200 mg + Midazolam | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 5 Participants |
| Placebo Matching BI 1358894 Dose Group | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 6 Participants |
| BI 1358894 10 Milligram (mg) Dose Group | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 2 Participants |
| BI 1358894 25 Milligram (mg) Dose Group | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 5 Participants |
| BI 1358894 50 Milligram (mg) Dose Group | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 1 Participants |
| BI 1358894 100 Milligram (mg) Dose Group | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 4 Participants |
| BI 1358894 200 Milligram (mg) Dose Group | Number of Subjects With On-treatment Drug-related Adverse Events (AEs). | 5 Participants |
Secondary
Area Under the Concentration-time Curve of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ
Area under the concentration-time curve of BI 1358894 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss)
Time frame: Within 2 hours before and 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 27, 48, 72, 75, 96, 120, 123, 144, 192, 195, 240, 243, 288, 311, 312.17, 312.33, 312.5, 313, 314, 315, 316, 318, 320, 324, 336, 360, 384, 408, 432, 456, 504 hours after administration.
Population: Pharmacokinetic parameter set (PKS): all subjects in the TS who provided at least 1 PK parameter that was not excluded due to a protocol deviation relevant to the statistical evaluation of PK endpoints or due to PK non-evaluability, only subjects with available data were included in the endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Area Under the Concentration-time Curve of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | 2070 nanomol * hours per liter | Geometric Coefficient of Variation 27.1 |
| Placebo + Midazolam | Area Under the Concentration-time Curve of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | 3520 nanomol * hours per liter | Geometric Coefficient of Variation 27.8 |
| BI 1358894 10 mg + Midazolam | Area Under the Concentration-time Curve of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | 5890 nanomol * hours per liter | Geometric Coefficient of Variation 35.1 |
| BI 1358894 25 mg + Midazolam | Area Under the Concentration-time Curve of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | 12600 nanomol * hours per liter | Geometric Coefficient of Variation 16.3 |
| BI 1358894 50 mg + Midazolam | Area Under the Concentration-time Curve of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | 18900 nanomol * hours per liter | Geometric Coefficient of Variation 13.5 |
Secondary
Area Under the Concentration-time Curve of BI 1358894 in Plasma Over a Time Interval 0 to 24 h After Administration of the First Dose
Area under the concentration-time curve of the analyte in plasma over a time interval 0 to 24 hours (h) after administration of the first dose (AUC0-24).
Time frame: Within 2 hours before and 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 27, 48, 72, 75, 96, 120, 123, 144, 192, 195, 240, 243, 288, 311, 312.17, 312.33, 312.5, 313, 314, 315, 316, 318, 320, 324, 336, 360, 384, 408, 432, 456, 504 hours after administration.
Population: Pharmacokinetic parameter set (PKS): all subjects in the TS who provided at least 1 PK parameter that was not excluded due to a protocol deviation relevant to the statistical evaluation of PK endpoints or due to PK non-evaluability, only subjects with available data were included in the endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over a Time Interval 0 to 24 h After Administration of the First Dose | 801 nanomols * hours per liter | Geometric Coefficient of Variation 22.7 |
| Placebo + Midazolam | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over a Time Interval 0 to 24 h After Administration of the First Dose | 1570 nanomols * hours per liter | Geometric Coefficient of Variation 28 |
| BI 1358894 10 mg + Midazolam | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over a Time Interval 0 to 24 h After Administration of the First Dose | 2690 nanomols * hours per liter | Geometric Coefficient of Variation 17.5 |
| BI 1358894 25 mg + Midazolam | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over a Time Interval 0 to 24 h After Administration of the First Dose | 5520 nanomols * hours per liter | Geometric Coefficient of Variation 18.3 |
| BI 1358894 50 mg + Midazolam | Area Under the Concentration-time Curve of BI 1358894 in Plasma Over a Time Interval 0 to 24 h After Administration of the First Dose | 8200 nanomols * hours per liter | Geometric Coefficient of Variation 13.3 |
Secondary
Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1)
Area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz).
Time frame: 25.5, 23.83, 23.5, 23, 22, 21.5, 21, 20, 18, 16 and 1 hour before and 0.17, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 311, 312.33, 312.5, 313, 314, 314.5, 315, 316, 318 and 320 hours after administration of BI 1358894 .
Population: PKS-Midazolam (PKS-MDZ): all subjects from the TS receiving BI 1358894 or placebo and midazolam who provided at least one secondary PK parameter for midazolam that was not excluded according to the description above. It was used for investigation of relative bioavailability
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam + BI 1358894 or Placebo | 2960 picomol * hours per liter | Geometric Coefficient of Variation 31.8 |
| Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam | 3030 picomol * hours per liter | Geometric Coefficient of Variation 28.6 |
| Placebo + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam | 3790 picomol * hours per liter | Geometric Coefficient of Variation 46 |
| Placebo + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam + BI 1358894 or Placebo | 3630 picomol * hours per liter | Geometric Coefficient of Variation 47.2 |
| BI 1358894 10 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam | 3090 picomol * hours per liter | Geometric Coefficient of Variation 28.6 |
| BI 1358894 10 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam + BI 1358894 or Placebo | 3120 picomol * hours per liter | Geometric Coefficient of Variation 29.6 |
| BI 1358894 25 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam + BI 1358894 or Placebo | 2810 picomol * hours per liter | Geometric Coefficient of Variation 37.2 |
| BI 1358894 25 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam | 3000 picomol * hours per liter | Geometric Coefficient of Variation 40.2 |
| BI 1358894 50 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam | 3610 picomol * hours per liter | Geometric Coefficient of Variation 22.1 |
| BI 1358894 50 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam + BI 1358894 or Placebo | 3360 picomol * hours per liter | Geometric Coefficient of Variation 26.3 |
| BI 1358894 100 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam + BI 1358894 or Placebo | 2480 picomol * hours per liter | Geometric Coefficient of Variation 24.1 |
| BI 1358894 100 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1) | Midazolam | 2750 picomol * hours per liter | Geometric Coefficient of Variation 28.2 |
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [90.2, 106.2]
90% CI: [89.9, 102.4]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [96.3, 106.1]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [86.8, 101.1]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [87.3, 99.3]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [83.8, 96.7]
Secondary
Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14)
Area under the concentration-time curve of midazolam in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz).
Time frame: 25.5, 23.83, 23.5, 23, 22, 21.5, 21, 20, 18, 16 and 1 hour before and 0.17, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 311, 312.33, 312.5, 313, 314, 314.5, 315, 316, 318 and 320 hours after administration of BI 1358894.
Population: PKS-Midazolam (PKS-MDZ): all subjects from the TS receiving BI 1358894 or placebo and midazolam who provided at least one secondary PK parameter for midazolam that was not excluded according to the description above. It was used for investigation of relative bioavailability
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam | 3030 picomol * hours per liter | Geometric Coefficient of Variation 28.6 |
| Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam + BI 1358894 or Placebo | 3200 picomol * hours per liter | Geometric Coefficient of Variation 28.9 |
| Placebo + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam | 3790 picomol * hours per liter | Geometric Coefficient of Variation 46 |
| Placebo + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam + BI 1358894 or Placebo | 4450 picomol * hours per liter | Geometric Coefficient of Variation 43.3 |
| BI 1358894 10 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam + BI 1358894 or Placebo | 3360 picomol * hours per liter | Geometric Coefficient of Variation 26 |
| BI 1358894 10 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam | 3090 picomol * hours per liter | Geometric Coefficient of Variation 28.6 |
| BI 1358894 25 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam + BI 1358894 or Placebo | 3440 picomol * hours per liter | Geometric Coefficient of Variation 17.3 |
| BI 1358894 25 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam | 3000 picomol * hours per liter | Geometric Coefficient of Variation 40.2 |
| BI 1358894 50 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam + BI 1358894 or Placebo | 3480 picomol * hours per liter | Geometric Coefficient of Variation 23.6 |
| BI 1358894 50 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam | 3610 picomol * hours per liter | Geometric Coefficient of Variation 22.1 |
| BI 1358894 100 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam | 2750 picomol * hours per liter | Geometric Coefficient of Variation 28.2 |
| BI 1358894 100 mg + Midazolam | Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14) | Midazolam + BI 1358894 or Placebo | 2460 picomol * hours per liter | Geometric Coefficient of Variation 23.4 |
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [95.6, 116.9]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [106.5, 129.6]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [102.9, 123.1]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [90.1, 135.1]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [84.5, 110.1]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA model on the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [74.9, 106.4]
Secondary
Maximum Measured Concentration of BI 1358894 in Plasma
Maximum measured concentration of the analyte BI 1358894 in plasma (Cmax).
Time frame: Within 2 hours before and 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 27, 48, 72, 75, 96, 120, 123, 144, 192, 195, 240, 243, 288, 311, 312.17, 312.33, 312.5, 313, 314, 315, 316, 318, 320, 324, 336, 360, 384, 408, 432, 456, 504 hours after administration.
Population: Pharmacokinetic parameter set (PKS): all subjects in the TS who provided at least 1 PK parameter that was not excluded due to a protocol deviation relevant to the statistical evaluation of PK endpoints or due to PK non-evaluability, only subjects with available data were included in the endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Maximum Measured Concentration of BI 1358894 in Plasma | 78.8 Nanomol per liter | Geometric Coefficient of Variation 16 |
| Placebo + Midazolam | Maximum Measured Concentration of BI 1358894 in Plasma | 152 Nanomol per liter | Geometric Coefficient of Variation 34.7 |
| BI 1358894 10 mg + Midazolam | Maximum Measured Concentration of BI 1358894 in Plasma | 217 Nanomol per liter | Geometric Coefficient of Variation 28.3 |
| BI 1358894 25 mg + Midazolam | Maximum Measured Concentration of BI 1358894 in Plasma | 491 Nanomol per liter | Geometric Coefficient of Variation 17.2 |
| BI 1358894 50 mg + Midazolam | Maximum Measured Concentration of BI 1358894 in Plasma | 634 Nanomol per liter | Geometric Coefficient of Variation 20.8 |
Secondary
Maximum Measured Concentration of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ
Maximum measured concentration of BI 1358894 in plasma at steady state over a uniform dosing interval τ (Cmax,ss)
Time frame: Within 2 hours before and 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 27, 48, 72, 75, 96, 120, 123, 144, 192, 195, 240, 243, 288, 311, 312.17, 312.33, 312.5, 313, 314, 315, 316, 318, 320, 324, 336, 360, 384, 408, 432, 456, 504 hours after administration.
Population: Pharmacokinetic parameter set (PKS): all subjects in the TS who provided at least 1 PK parameter that was not excluded due to a protocol deviation relevant to the statistical evaluation of PK endpoints or due to PK non-evaluability, only subjects with available data were included in the endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Midazolam | Maximum Measured Concentration of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | 138 nanomol per liter | Geometric Coefficient of Variation 14.5 |
| Placebo + Midazolam | Maximum Measured Concentration of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | 225 nanomol per liter | Geometric Coefficient of Variation 18.8 |
| BI 1358894 10 mg + Midazolam | Maximum Measured Concentration of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | 383 nanomol per liter | Geometric Coefficient of Variation 26.7 |
| BI 1358894 25 mg + Midazolam | Maximum Measured Concentration of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | 843 nanomol per liter | Geometric Coefficient of Variation 19.8 |
| BI 1358894 50 mg + Midazolam | Maximum Measured Concentration of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ | 1150 nanomol per liter | Geometric Coefficient of Variation 13.8 |
Secondary
Maximum Measured Concentration of Midazolam in Plasma (Day 1)
Maximum measured concentration of midazolam in plasma (Cmax).
Time frame: 25.5, 23.83, 23.5, 23, 22, 21.5, 21, 20, 18, 16 and 1 hour before and 0.17, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 311, 312.33, 312.5, 313, 314, 314.5, 315, 316, 318 and 320 hours after administration of BI 1358894.
Population: PKS-Midazolam (PKS-MDZ): all subjects from the TS receiving BI 1358894 or placebo and midazolam who provided at least one secondary PK parameter for midazolam that was not excluded according to the description above. It was used for investigation of relative bioavailability
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam (R) | 929 picomole per liter | Geometric Coefficient of Variation 25.6 |
| Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam + BI 1358894 or placeobo (T) | 913 picomole per liter | Geometric Coefficient of Variation 26.2 |
| Placebo + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam (R) | 1120 picomole per liter | Geometric Coefficient of Variation 34.1 |
| Placebo + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam + BI 1358894 or placeobo (T) | 1090 picomole per liter | Geometric Coefficient of Variation 32.1 |
| BI 1358894 10 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam (R) | 963 picomole per liter | Geometric Coefficient of Variation 42 |
| BI 1358894 10 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam + BI 1358894 or placeobo (T) | 1130 picomole per liter | Geometric Coefficient of Variation 30.5 |
| BI 1358894 25 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam (R) | 974 picomole per liter | Geometric Coefficient of Variation 35 |
| BI 1358894 25 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam + BI 1358894 or placeobo (T) | 920 picomole per liter | Geometric Coefficient of Variation 32.8 |
| BI 1358894 50 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam + BI 1358894 or placeobo (T) | 1150 picomole per liter | Geometric Coefficient of Variation 19 |
| BI 1358894 50 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam (R) | 1170 picomole per liter | Geometric Coefficient of Variation 8.89 |
| BI 1358894 100 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam + BI 1358894 or placeobo (T) | 812 picomole per liter | Geometric Coefficient of Variation 19.7 |
| BI 1358894 100 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 1) | Midazolam (R) | 828 picomole per liter | Geometric Coefficient of Variation 30.6 |
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [84.2, 114.8]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [87.9, 109.3]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [102.6, 134.6]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [85.5, 104.4]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [87.3, 99.3]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [84.3, 114]
Secondary
Maximum Measured Concentration of Midazolam in Plasma (Day 14)
Maximum measured concentration of midazolam in plasma (Cmax).
Time frame: 25.5, 23.83, 23.5, 23, 22, 21.5, 21, 20, 18, 16 and 1 hour before and 0.17, 0.5, 1, 2, 2.5, 3, 4, 6, 8, 311, 312.33, 312.5, 313, 314, 314.5, 315, 316, 318 and 320 hours after administration of BI 1358894.
Population: PKS-Midazolam (PKS-MDZ): all subjects from the TS receiving BI 1358894 or placebo and midazolam who provided at least one secondary PK parameter for midazolam that was not excluded according to the description above. It was used for investigation of relative bioavailability
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam + BI 1358894 or placeobo (T) | 887 picomole per liter | Geometric Coefficient of Variation 27.1 |
| Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam (R) | 929 picomole per liter | Geometric Coefficient of Variation 25.6 |
| Placebo + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam + BI 1358894 or placeobo (T) | 1180 picomole per liter | Geometric Coefficient of Variation 28.2 |
| Placebo + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam (R) | 1120 picomole per liter | Geometric Coefficient of Variation 34.1 |
| BI 1358894 10 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam (R) | 963 picomole per liter | Geometric Coefficient of Variation 42 |
| BI 1358894 10 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam + BI 1358894 or placeobo (T) | 1070 picomole per liter | Geometric Coefficient of Variation 31 |
| BI 1358894 25 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam + BI 1358894 or placeobo (T) | 1090 picomole per liter | Geometric Coefficient of Variation 27.3 |
| BI 1358894 25 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam (R) | 974 picomole per liter | Geometric Coefficient of Variation 35 |
| BI 1358894 50 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam + BI 1358894 or placeobo (T) | 985 picomole per liter | Geometric Coefficient of Variation 29.3 |
| BI 1358894 50 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam (R) | 1170 picomole per liter | Geometric Coefficient of Variation 8.89 |
| BI 1358894 100 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam (R) | 828 picomole per liter | Geometric Coefficient of Variation 30.6 |
| BI 1358894 100 mg + Midazolam | Maximum Measured Concentration of Midazolam in Plasma (Day 14) | Midazolam + BI 1358894 or placeobo (T) | 722 picomole per liter | Geometric Coefficient of Variation 18.8 |
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [81.3, 112.1]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [91.5, 122]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [90.9, 148.7]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [92.4, 123.4]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [71.2, 98.9]
Comparison: The statistical model used for the analysis of the secondary endpoints was an ANOVA mode lon the logarithmic scale including 'treatment' ('midazolam' and 'midazolam + Placebo/BI') as fixed effect and 'subject' as random effect. The analysis was performed separately for Day 1 and Day 14.90% CI: [73.5, 103.5]