This Study in Healthy Men Tests How Different Doses of BI... | NCT03754959

ID	Type	Description	Link
2018-000389-12	EudraCT Number

Label	Type	Intervention Names
Dose Group 1	Experimental	Drug: BI 1358894 Drug: Placebo Drug: Midazolam
Dose Group 2	Experimental	Drug: BI 1358894 Drug: Placebo Drug: Midazolam
Dose Group 3	Experimental	Drug: BI 1358894 Drug: Placebo Drug: Midazolam
Dose Group 4	Experimental	Drug: BI 1358894 Drug: Placebo Drug: Midazolam
Dose Group 5	Experimental	Drug: BI 1358894 Drug: Placebo Drug: Midazolam

Name	Type	Description	Arm Group Labels	Other Names
BI 1358894	Drug	Film-coated tablet	Dose Group 1 Dose Group 2 Dose Group 3 Dose Group 4 Dose Group 5

Measure	Description	Time Frame
Number of Subjects With On-treatment Drug-related Adverse Events (AEs).	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.

Measure	Description	Time Frame
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).	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.

Eligibility Module

Eligibility Criteria

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

Facility	Status	City	State	ZIP	Country	Contacts
CRS Clinical Research Services Mannheim GmbH		Mannheim		68167	Germany

PubMed Identifier	Type	Citation	Retractions
38019355	Derived	Fuertig R, Goettel M, Herich L, Hoefler J, Wiebe ST, Sharma V. Effects of Single and Multiple Ascending Doses of BI 1358894 in Healthy Male Volunteers on Safety, Tolerability and Pharmacokinetics: Two Phase I Partially Randomised Studies. CNS Drugs. 2023 Dec;37(12):1081-1097. doi: 10.1007/s40263-023-01041-4. Epub 2023 Nov 29.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Apr 3, 2019	Feb 4, 2025

Arm/Group Information

ID	Title	Description
BG000	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.
BG001	BI 1358894 10 Milligram (mg) Dose Group	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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.
BG002	BI 1358894 25 Milligram (mg) Dose Group	Oral administration of 25 milligram (mg) BI 1358894 film-coated tablet (125 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)/mL1.5 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.
BG003	BI 1358894 50 Milligram (mg) Dose Group	Oral administration of 50 milligram (mg) BI 1358894 film-coated tablet (225 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)/mL1.5 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.
BG004	BI 1358894 100 Milligram (mg) Dose Group	Oral administration of 100 milligram (mg) BI 1358894 film-coated tablet (1100 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)/mL1.5 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.
BG005	BI 1358894 200 Milligram (mg) Dose Group	Oral administration of 200 milligram (mg) BI 1358894 film-coated tablet (2100 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)/mL1.5 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.
BG006	Total	Total of all reporting groups

Units	Counts
Participants	BG00010 BG0018 BG0028 BG0038 BG0048 BG0058 BG00650

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Subjects With On-treatment Drug-related Adverse Events (AEs).

Number of subjects with on-treatment drug-related Adverse Events (AEs).

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.

Posted

Number

Participants

Midazolam: Up to 1 day, BI 1358894 or Placebo + Midazolam: Up to 1 day and BI 1358894: Up to 13 days.

ID	Title	Description
OG000	Midazolam	Oral administration of midazolam as solution for injection (5 mg/5 mL) diluted to 50 microgram (μg)/mL*1.5 mL with 240 milliliter (mL) water after a standard continental breakfast on Day -1 before administration of BI 1358894/ Placebo
OG001	Placebo + Midazolam	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.
OG002	BI 1358894 10 mg + Midazolam	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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.
OG003	BI 1358894 25 mg + Midazolam	Oral administration of 25 milligram (mg) BI 1358894 film-coated tablet (125 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)/mL1.5 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 1358894was administered immediately prior to midazolam.
OG004	BI 1358894 50 mg + Midazolam	Oral administration of 50 milligram (mg) BI 1358894 film-coated tablet (225 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)/mL1.5 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.
OG005	BI 1358894 100 mg + Midazolam	Oral administration of 100 milligram (mg) BI 1358894 film-coated tablet (1100 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)/mL1.5 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.
OG006	BI 1358894 200 mg + Midazolam	Oral administration of 200 milligram (mg) BI 1358894 film-coated tablet (2100 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)/mL1.5 mL 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.
OG007	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 BI 1358894 was administered immediately prior to midazolam.
OG008	BI 1358894 10 Milligram (mg) Dose Group	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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.
OG009	BI 1358894 25 Milligram (mg) Dose Group	Oral administration of 25 milligram (mg) BI 1358894 film-coated tablet (125 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)/mL1.5 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.
OG010	BI 1358894 50 Milligram (mg) Dose Group	Oral administration of 50 milligram (mg) BI 1358894 film-coated tablet (225 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)/mL1.5 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.
OG011	BI 1358894 100 Milligram (mg) Dose Group	Oral administration of 100 milligram (mg) BI 1358894 film-coated tablet (1100 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)/mL1.5 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.
OG012	BI 1358894 200 Milligram (mg) Dose Group	Oral administration of 200 milligram (mg) BI 1358894 film-coated tablet (2100 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)/mL1.5 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.

Units	Counts
Participants	OG00050 OG00110 OG0028 OG003

Title

Denominators

Categories

Title	Measurements
	OG0000 OG0011 OG0024 OG003

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).

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

nanomols * hours per liter

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.

ID	Title	Description
OG000	BI 1358894 10 Milligram (mg) Dose Group	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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.
OG001	BI 1358894 25 Milligram (mg) Dose Group

Secondary

Maximum Measured Concentration of BI 1358894 in Plasma

Maximum measured concentration of the analyte BI 1358894 in plasma (Cmax).

Posted

Geometric Mean

Geometric Coefficient of Variation

Nanomol per liter

ID	Title	Description
OG000	BI 1358894 10 Milligram (mg) Dose Group	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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.
OG001	BI 1358894 25 Milligram (mg) Dose Group	Oral administration of 25 milligram (mg) BI 1358894 film-coated tablet (125 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)/mL1.5 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.

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)

Posted

Geometric Mean

Geometric Coefficient of Variation

nanomol * hours per liter

ID	Title	Description
OG000	BI 1358894 10 Milligram (mg) Dose Group	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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.
OG001	BI 1358894 25 Milligram (mg) Dose Group

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)

Posted

Geometric Mean

Geometric Coefficient of Variation

nanomol per liter

ID	Title	Description
OG000	BI 1358894 10 Milligram (mg) Dose Group	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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.
OG001	BI 1358894 25 Milligram (mg) Dose Group

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).

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

Posted

Geometric Mean

Geometric Coefficient of Variation

picomol * hours per liter

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 .

ID	Title	Description
OG000	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 BI 1358894 was administered immediately prior to midazolam.
OG001	BI 1358894 10 Milligram (mg) Dose Group

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).

Posted

Geometric Mean

Geometric Coefficient of Variation

picomol * hours per liter

ID	Title	Description
OG000	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 BI 1358894 was administered immediately prior to midazolam.
OG001	BI 1358894 10 Milligram (mg) Dose Group

Secondary

Maximum Measured Concentration of Midazolam in Plasma (Day 1)

Maximum measured concentration of midazolam in plasma (Cmax).

Posted

Geometric Mean

Geometric Coefficient of Variation

picomole per liter

ID	Title	Description
OG000	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 BI 1358894 was administered immediately prior to midazolam.
OG001	BI 1358894 10 Milligram (mg) Dose Group	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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.

Secondary

Maximum Measured Concentration of Midazolam in Plasma (Day 14)

Maximum measured concentration of midazolam in plasma (Cmax).

Posted

Geometric Mean

Geometric Coefficient of Variation

picomole per liter

ID	Title	Description
OG000	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 BI 1358894 was administered immediately prior to midazolam.
OG001	BI 1358894 10 Milligram (mg) Dose Group	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Midazolam	Oral administration of midazolam as solution for injection (5 mg/5 mL) diluted to 50 microgram (μg)/mL*1.5 mL with 240 milliliter (mL) water after a standard continental breakfast on Day -1 before administration of BI 1358894/ Placebo	50	50	2	50
EG001	Placebo + Midazolam	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	10	1	10
EG002	BI 1358894 10 mg + Midazolam	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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	8	4	8
EG003	BI 1358894 25 mg + Midazolam	Oral administration of 25 milligram (mg) BI 1358894 film-coated tablet (125 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)/mL1.5 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 1358894was administered immediately prior to midazolam.	8	8	4	8
EG004	BI 1358894 50 mg + Midazolam	Oral administration of 50 milligram (mg) BI 1358894 film-coated tablet (225 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)/mL1.5 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	8	3	8
EG005	BI 1358894 100 mg + Midazolam	Oral administration of 100 milligram (mg) BI 1358894 film-coated tablet (1100 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)/mL1.5 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	8	4	8
EG006	BI 1358894 200 mg + Midazolam	Oral administration of 200 milligram (mg) BI 1358894 film-coated tablet (2100 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)/mL1.5 mL 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	8	5	8
EG007	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 BI 1358894 was administered immediately prior to midazolam.	10	10	7	10
EG008	BI 1358894 10 Milligram (mg) Dose Group	Oral administration of 10 milligram (mg) BI 1358894 film-coated tablet (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)/mL1.5 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	8	3	8
EG009	BI 1358894 25 Milligram (mg) Dose Group	Oral administration of 25 milligram (mg) BI 1358894 film-coated tablet (125 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)/mL1.5 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	8	6	8
EG010	BI 1358894 50 Milligram (mg) Dose Group	Oral administration of 50 milligram (mg) BI 1358894 film-coated tablet (225 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)/mL1.5 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	8	1	8
EG011	BI 1358894 100 Milligram (mg) Dose Group	Oral administration of 100 milligram (mg) BI 1358894 film-coated tablet (1100 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)/mL1.5 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	8	4	8
EG012	BI 1358894 200 Milligram (mg) Dose Group	Oral administration of 200 milligram (mg) BI 1358894 film-coated tablet (2100 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)/mL1.5 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	8	5	8

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Headache	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0001 affected50 at risk EG0011 affected10 at risk EG0023 affected8 at risk EG0033 affected8 at risk EG0042 affected8 at risk EG0052 affected8 at risk EG0063 affected8 at risk EG0074 affected10 at risk EG0080 affected8 at risk EG0095 affected8 at risk EG0101 affected8 at risk EG0111 affected8 at risk EG0125 affected8 at risk
Orthostatic intolerance	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0011 affected10 at risk EG0021 affected8 at risk EG003
Disturbance in attention	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Dizziness	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0021 affected8 at risk EG003
Head discomfort	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Muscle contractions involuntary	Nervous system disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0021 affected8 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Dry mouth	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Flatulence	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0001 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0011 affected10 at risk EG0020 affected8 at risk EG003
Ocular discomfort	Eye disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Vision blurred	Eye disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Fatigue	General disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Procedural dizziness	Injury, poisoning and procedural complications	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Skin injury	Injury, poisoning and procedural complications	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Dermatitis acneiform	Skin and subcutaneous tissue disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Blood creatine phosphokinase increased	Investigations	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003
Thrombophlebitis superficial	Vascular disorders	MedDRA 22.0	Systematic Assessment	EG0000 affected50 at risk EG0010 affected10 at risk EG0020 affected8 at risk EG003

ID	Term
D001569	Benzodiazepines
D001552	Benzazepines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds