This Study Tests How Healthy Men Tolerate Different Doses of BI 730357 and How the Metabolism of Midazolam is Affected by BI 730357

Study Overview
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Brief Summary
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Phase Ib evaluation of the safety, tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) properties of Multiple Rising Dose (MRD) administration of BI 730357 to healthy volunteers for up to 28 days.

Official Title
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Phase Ib Evaluation of the Safety and Tolerability and Effect on Midazolam Metabolism of the Administration of Multiple Rising Doses of BI 730357 to Healthy Volunteers

Conditions
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Healthy, Psoriasis

Intervention / Treatment
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* Drug: BI 730357
* Drug: Placebo
* Drug: Midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subjects according to the assessment of the Investigator, based on a complete medical history, physical examination, vital signs (blood pressure, pulse rate), 12-lead Electrocardiogram (ECG), and clinical laboratory tests Subjects with a partner who is a woman of childbearing potential (WOCBP) must be willing to use male contraception (condom or sexual abstinence) from the first administration of trial medication until 30 days after last administration of trial medication Age of 18 to 45 years (incl.) at screening Body Mass Index (BMI) of 18.5 to 29.9 kg/m2 (incl.) at screening Signed and dated written informed consent prior to admission to the study in accordance with International Conference on Harmonisation - Good Clinical Practice (ICH-GCP) and local legislation Exclusion criteria Any finding in the medical examination (including blood pressure, pulse rate or Electrocardiogram (ECG)) 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) 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 (except appendectomy and simple hernia repair) that could interfere with the PK of the trial medication Diseases of the Central Nervous System (CNS) (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 acute infections which are of relevance in the opinion of the Investigator 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 (corrected QT interval) 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 Tobacco usage (more than 10 cigarettes or 3 cigars or 3 pipes per day) 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 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, is considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study Unwillingness to adhere to the rules of UV-light protection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 730357 25 mg fast<br>Subjects were orally administered BI 730357 25 mg, film-coated tablet once daily over 14 days after a fasting period of at least 6 hours | Drug: BI 730357<br>* BI 730357 film-coated tablet<br>|
| Placebo Comparator: Placebo fast<br>Subjects were orally administered matching Placebo to BI 730357, film-coated tablet after a fasting period of at least 6 hours. | Drug: Placebo<br>* Placebo<br>|
| Placebo Comparator: Placebo fed<br>Subjects were orally administered matching Placebo to BI 730357, film-coated tablet after the intake of a standard continental breakfast. | Drug: Placebo<br>* Placebo<br>|
| Experimental: BI 730357 50 mg fast<br>Subjects were orally administered BI 730357 50 mg, film-coated tablet once daily over 14 days after a fasting period of at least 6 hours. | Drug: BI 730357<br>* BI 730357 film-coated tablet<br>|
| Experimental: BI 730357 50mg/Placebo<br>Subject was orally administered mixed treatment of BI 730357 50 mg and placebo, film-coated tablet once daily over 14 days after a fasting period of at least 6 hours | Drug: BI 730357<br>* BI 730357 film-coated tablet<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: BI 730357 50 mg fed<br>Subjects were orally administered BI 730357 50 mg, film-coated tablet once daily over 14 days after the intake of a standard continental breakfast. | Drug: BI 730357<br>* BI 730357 film-coated tablet<br>|
| Experimental: BI 730357 100 mg fast<br>Subjects were orally administered BI 730357 100 mg, film-coated tablet once daily over 14 days after a fasting period of at least 6 hours | Drug: BI 730357<br>* BI 730357 film-coated tablet<br>|
| Experimental: BI 730357 200 mg fast<br>Subjects were orally administered BI 730357 200 mg, film-coated tablet once daily over 28 days after a fasting period of at least 6 hours | Drug: BI 730357<br>* BI 730357 film-coated tablet<br>|
| Experimental: BI 730357 200 mg fed<br>Subjects were orally administered a microdose of midazolam 75 microgram (75 μg) solution for injection, orally on Day -1, and prior receiving BI 730357 on Days 3, and 14. Subjects were orally administered BI 730357 200 mg, film-coated tablet once daily over 28 days after the intake of a standard continental breakfast. | Drug: BI 730357<br>* BI 730357 film-coated tablet<br>Drug: Midazolam<br>* Once per day (QD) on Days -1, 3, and 14. Dose groups BI 730357 200 mg fed and BI 730357 400 mg fed<br>|
| Experimental: BI 730357 400 mg fed<br>Subjects were orally administered a microdose of midazolam 75 microgram (75 μg) solution for injection, orally on Day -1, and prior receiving BI 730357 on Days 3, and 14. Subjects were orally administered BI 730357 400 mg, film-coated tablet once daily over 28 days after the intake of a standard continental breakfast. | Drug: BI 730357<br>* BI 730357 film-coated tablet<br>Drug: Midazolam<br>* Once per day (QD) on Days -1, 3, and 14. Dose groups BI 730357 200 mg fed and BI 730357 400 mg fed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Drug-related Adverse Events (AEs) | Number of subjects with drug-related Adverse Events (AEs) assessed by the investigator. | From first drug administration until 7 days after last dose, up to 21 days (for 25, 50 and 100 mg dose groups) and up to 35 days (for 200 and 400 mg dose groups) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve of the Analyte BI 730357 in Plasma Over a Uniform Dosing Interval Tau After Administration of the First Dose (AUCtau,1) | Area under the concentration-time curve of the analyte BI 730357 in plasma over a uniform dosing interval tau after administration of the first dose (AUCtau,1). In this study AUCtau,1 = AUC0-24 | -0.5h before dosing and 0.25h, 0.5h, 1h, 1.5h, 2 h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h and 23.5h after first dosing on Day1. | 
| Maximum Measured Concentration of the Analyte BI 730357 in Plasma After Administration of the First Dose (Cmax) | Maximum measured concentration of the analyte BI 730357 in plasma after administration of the first dose (Cmax) | -0.5h before dosing and 0.25h, 0.5h, 1h, 1.5h, 2 h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h and 23.5h after first dosing on Day1. | 
| Area Under the Concentration-time Curve of BI 730357 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss) After Last Dose Administration. | Area under the concentration-time curve of BI 730357 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) after last dose administration is reported. τ for 25, 50, 100 , 200 and 400 mg dose groups is: 24 hours (h). Time Frame: For 25, 50, and 100 mg dose groups: -0.5h before dosing and 0.25h, 0.5h, 1h, 1.5h, 2 h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 23.5h, 47.5 and 71.5 h after last dose on Day14. For 200 and 400 mg dose groups: -0.5h before last dose and 1.0h, 2.0h, 3.0h, 4.0h and 24.0h after last dose on Day28. | Day 14 and Day 28 (Please refer description for the time frame in detail) | 
| Maximum Measured Concentration of the Analyte BI 730357 in Plasma at Steady State Over a Uniform Dosing Interval τ After the Last Dose (Cmax,ss) | Maximum measured concentration of BI 730357 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) after last dose administration is reported. τ for 25, 50, 100 , 200 and 400 mg dose groups is: 24 hours (h). Time Frame: For 25, 50, and 100 mg dose groups:-0.5h before dosing and 0.25h, 0.5h, 1h, 1.5h, 2 h, 2.5h, 3h, 3.5h, 4h, 6h, 8h, 12h, 23.5h, 47.5 and 71.5 h after last dose on Day14. For 200 and 400 mg dose groups: -0.5h before last dose and 1.0h, 2.0h, 3.0h, 4.0h and 24.0h after last dose on Day28. | Day 14 and Day 28 (Please refer description for the time frame in detail) |