Clinical trial NCT03754959: This Study in Healthy Men Tests How Different Doses of BI 1358894 Are Taken up in the Body and How Well They Are Tolerated. The Study Also Tests How BI 1358894 Affects the Way the Body Breaks Down Midazolam
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2018-11-27
Enrollment: 50
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Number of Subjects With On-treatment Drug-related Adverse Events (AEs).
timeFrame: Midazolam: Up to 1 day, BI 1358894 or Placebo + Midazolam: Up to 1 day and BI 1358894: Up to 13 days.
Secondary outcomes:
measure: 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
timeFrame: 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.
measure: Maximum Measured Concentration of BI 1358894 in Plasma
timeFrame: 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.
measure: Area Under the Concentration-time Curve of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ
timeFrame: 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.
measure: Maximum Measured Concentration of BI 1358894 in Plasma at Steady State Over a Uniform Dosing Interval τ
timeFrame: 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.
measure: Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 1)
timeFrame: 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 .
measure: Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (Day 14)
timeFrame: 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.
measure: Maximum Measured Concentration of Midazolam in Plasma (Day 1)
timeFrame: 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.
measure: Maximum Measured Concentration of Midazolam in Plasma (Day 14)
timeFrame: 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.
Other outcomes:
Locations:
city: Mannheim
country: Germany
facility: CRS Clinical Research Services Mannheim GmbH
Study officials:
References: