A Study in Healthy Men to Test the Effects of Different Doses of BI 1467335 on MAO-B Activity in the Brain.

Study Overview
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Brief Summary
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The main objective of this trial is to investigate the effect of multiple oral dosing of high dose BI 1467335 over 28 days and multiple oral dosing of low dose BI 1467335 over 42 days on MAO-B occupancy in the brain compared to baseline using [11C]-L-deprenyl-D2 PET tracer in healthy male subjects.

Official Title
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A Phase I, Open-label, Positron Emission Tomography Study in Healthy Male Subjects to Explore the Inhibition of Monoamine Oxidase B in the Brain After Multiple Oral Doses of BI 1467335 (Non-randomized, Open-label, Parallel-group Study)

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 1467335


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Healthy male subjects according to the assessment of the investigator, as 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 21 to 55 years (inclusive) Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation Non-smoker with no history of smoking Subjects who are sexually active must use, with their partner, highly effective contraception from the time of administration of trial medication until 4 months after administration of trial medication. Adequate methods are: Condoms plus use of hormonal contraception by the female partner that started at least 2 months prior to administration of trial medication (e.g., implants, injectables, combined oral or vaginal contraceptives, intrauterine device) or Condoms plus surgical sterilization (vasectomy at least 1 year prior to enrolment) or Condoms plus surgically sterilised partner (including hysterectomy) or Condoms plus intrauterine device or Condoms plus partner of non-childbearing potential (including homosexual men) Subjects are required to use condoms to prevent unintended exposure of the partner to the study drug via seminal fluid. Alternatively, true abstinence is acceptable when it is in line with the subject's preferred and usual lifestyle. If a subject is usually not sexually active but becomes active, with their partner, they must comply with the contraceptive requirements detailed above. Exclusion criteria: Any finding in the medical examination (including Blood pressure (BP), Pulse rate (PR) or Electrocardiogram (ECG)) deviating from normal and assessed as clinically relevant by the investigator Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 bpm Any laboratory value outside the reference range that the investigator considers to be of clinical relevance Any evidence of a concomitant disease assessed as clinically relevant by the investigator Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or 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 of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause QT/QTc interval prolongation) Intake of an investigational drug in another clinical trial within 90 days or within 5 half-lives, whichever is longer, of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administered Alcohol abuse (consumption of more than 30 g per day for males) within the 24 months prior to dosing Drug abuse within the 24 months prior to dosing or positive drug screening Blood donation of more than 100 mL within 30 days of planned administration of trial medication or intended blood donation during the trial Intention to perform excessive physical activities within one week prior to the administration of trial medication or during the trial Inability to comply with the dietary regimen of the trial site A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms) or any other relevant ECG finding at screening A history of additional risk factors for Torsade 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 the subject is not considered able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study Structural brain abnormality has been shown on an Magnetic Resonance Imaging (MRI) Severe anxiety of enclosed spaces Contraindication for arterial cannulation: Allen's test indicating potential risk in placement of the arterial cannula. Contraindication to MRI as determined by screening and safety questionnaire including but not limited to significant tattoos (as determined by the radiographer), cardiac pacemakers, aneurysm clips and cochlear implants. Unable to lie flat on the MRI or Positron emission tomography (PET) scanner for a prolonged period of time. Prior participation in other research protocols in the past year such that the total effective dose including this study would exceed 10 mSv.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 1467335 (low dose)<br> | Drug: BI 1467335<br>* tablet<br>|
| Experimental: BI 1467335 (high dose)<br> | Drug: BI 1467335<br>* tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Reduction in Whole Brain Monoamine Oxidase (MAO)-B Availability Assessed by Positron Emission Tomography (PET) Imaging | The primary endpoint of the trial was the percent reduction in whole brain MAO-B availability, as assessed by PET imaging, on the last day of treatment with BI 1467335 (Day 28 for the 10 mg dose group and Day 42 for the 3 mg dose group) compared with baseline. Image analysis was used to generate the outcome parameter for the PET data (proportional to the target availability at each PET scan) using the PET emission and the metabolite corrected arterial plasma input function in an appropriate kinetic model. | Baseline (day -14 to -2) and last day of treatment (Day 28 for the 10 mg dose group and Day 42 for the 3 mg dose group). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Reduction in MAO-B Availability on Day 14 of Treatment With 10 mg BI 1467335 Compared With Baseline | Percent reduction in MAO-B availability on Day 14 of treatment with 10 mg BI 1467335 compared with baseline. Image analysis was used to generate the outcome parameter for the PET data (proportional to the target availability at each PET scan) using the PET emission and the metabolite corrected arterial plasma input function in an appropriate kinetic model. | Baseline (day -14 to -2) and Day 14 of treatment. | 
| Reduction in MAO-B Availability on Day 28 of Treatment With 3 mg BI 1467335 Compared With Baseline | Reduction in MAO-B availability on Day 28 of treatment with 3 mg BI 1467335 compared with baseline. Image analysis was used to generate the outcome parameter for the PET data (proportional to the target availability at each PET scan) using the PET emission and the metabolite corrected arterial plasma input function in an appropriate kinetic model. | Baseline (day -14 to -2) and Day 28 of treatment. | 
| MAO-B Inhibition in Platelet Rich Plasma Compared With Baseline | MAO-B activity in plasma was assessed after 14 days of dosing with BI 1467335 (10 mg dose group only), 28 days of dosing (10 and 3 mg dose groups), and 42 days of dosing (3 mg dose group only). | Baseline (day -14 to -2) and last day of treatment (Day 28 for the 10 mg dose group and Day 42 for the 3 mg dose group). | 
| Maximum Measured Concentration of BI 1467335 in Plasma | Maximum measured concentration of BI 1467335 in Plasma (Cmax). | Within 3 hours (h) before and 20 minutes (min), 45 min, 1h, 1h 30 min, 3h, 4h, 7h, 11h, 24h ( 30 min before next scheduled dosing where applicable) after administration of BI 1467335. | 
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time 24 h (AUC 0-24) | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time 24 h. | Within 3 hours (h) before and 20 minutes (min), 45 min, 1h, 1h 30 min, 3h, 4h, 7h, 11h, 24h ( 30 min before next scheduled dosing where applicable) after administration of BI 1467335. |