Healthy
Conditions
Brief summary
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.
Interventions
DRUGBI 1467335
tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
21 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Reduction in Whole Brain Monoamine Oxidase (MAO)-B Availability Assessed by Positron Emission Tomography (PET) Imaging | 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). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Reduction in MAO-B Availability on Day 14 of Treatment With 10 mg BI 1467335 Compared With Baseline | Baseline (day -14 to -2) and Day 14 of treatment. | 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. |
| Reduction in MAO-B Availability on Day 28 of Treatment With 3 mg BI 1467335 Compared With Baseline | Baseline (day -14 to -2) and Day 28 of treatment. | 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. |
| MAO-B Inhibition in Platelet Rich Plasma Compared With Baseline | 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). | 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). |
| Maximum Measured Concentration of BI 1467335 in Plasma | 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. | Maximum measured concentration of BI 1467335 in Plasma (Cmax). |
| 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) | 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. |
Countries
United Kingdom
Participant flow
Recruitment details
This phase I trial was conducted using a non-randomised, non-controlled, open-label, parallel-group, multiple-dose design.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| BI 1467335 10 Milligram (mg) Oral administration of 10 milligram (mg) BI 1467335 (2 film-coated tablet of 5 mg) per day for 28 days together with 240 milliliter (mL) of water. | 5 |
| BI 1467335 3 Milligram (mg) Oral administration of 3 milligram (mg) BI 1467335 (3 film-coated tablet of 1 mg) per day for 42 days together with 240 milliliter (mL) of water. | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | BI 1467335 3 Milligram (mg) | Total | BI 1467335 10 Milligram (mg) |
|---|---|---|---|
| Age, Continuous | 39.0 Years STANDARD_DEVIATION 11.4 | 41.4 Years STANDARD_DEVIATION 9.5 | 43.8 Years STANDARD_DEVIATION 7.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 10 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 | 0 / 10 |
| other Total, other adverse events | 5 / 5 | 3 / 5 | 8 / 10 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 10 |
Outcome results
Primary
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.
Time frame: 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).
Population: PET set (PETS): This set included all subjects who were randomized and treated with at least one dose of study drug for whom at least 1 PET scan at baseline and 1 on-treatment scan were provided.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BI 1467335 10 Milligram (mg) | Percentage Reduction in Whole Brain Monoamine Oxidase (MAO)-B Availability Assessed by Positron Emission Tomography (PET) Imaging | 72.58 Percent reduction | Standard Deviation 11.81 |
| BI 1467335 3 Milligram (mg) | Percentage Reduction in Whole Brain Monoamine Oxidase (MAO)-B Availability Assessed by Positron Emission Tomography (PET) Imaging | 2.43 Percent reduction | Standard Deviation 6.05 |
Secondary
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.
Time frame: 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.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the TS for whom at least 1 PK endpoint was provided, and who were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| BI 1467335 10 Milligram (mg) | 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) | Day 14 | 85.7 nanomol * hours per liter | Geometric Coefficient of Variation 75.5 |
| BI 1467335 10 Milligram (mg) | 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) | Day 28 | 235 nanomol * hours per liter | Geometric Coefficient of Variation 148 |
| BI 1467335 3 Milligram (mg) | 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) | Day 28 | 4.65 nanomol * hours per liter | Geometric Coefficient of Variation 54.9 |
| BI 1467335 3 Milligram (mg) | 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) | Day 42 | 4.34 nanomol * hours per liter | Geometric Coefficient of Variation 132 |
Secondary
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).
Time frame: 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).
Population: Due to missing baseline values, processing errors and errors in the conduct of the analytical assay most subjects were excluded. The small amount of available data precluded accurate evaluation of the pharmacokinetic - pharmacodynamic (PK-PD) relationship.
Secondary
Maximum Measured Concentration of BI 1467335 in Plasma
Maximum measured concentration of BI 1467335 in Plasma (Cmax).
Time frame: 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.
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the TS for whom at least 1 PK endpoint was provided, and who were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| BI 1467335 10 Milligram (mg) | Maximum Measured Concentration of BI 1467335 in Plasma | Day 14 | 36.4 nanomol per liter | Geometric Coefficient of Variation 65.2 |
| BI 1467335 10 Milligram (mg) | Maximum Measured Concentration of BI 1467335 in Plasma | Day 28 | 48.4 nanomol per liter | Geometric Coefficient of Variation 85.3 |
| BI 1467335 3 Milligram (mg) | Maximum Measured Concentration of BI 1467335 in Plasma | Day 28 | 2.28 nanomol per liter | Geometric Coefficient of Variation 76 |
| BI 1467335 3 Milligram (mg) | Maximum Measured Concentration of BI 1467335 in Plasma | Day 42 | 3.60 nanomol per liter | Geometric Coefficient of Variation 146 |
Secondary
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.
Time frame: Baseline (day -14 to -2) and Day 14 of treatment.
Population: PET set (PETS): This set included all subjects who were randomized and treated with at least one dose of study drug for whom at least 1 PET scan at baseline and 1 on-treatment scan were provided
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BI 1467335 10 Milligram (mg) | Percent Reduction in MAO-B Availability on Day 14 of Treatment With 10 mg BI 1467335 Compared With Baseline | 44.56 Percent reduction | Standard Deviation 16.2 |
Secondary
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.
Time frame: Baseline (day -14 to -2) and Day 28 of treatment.
Population: PET set (PETS): This set included all subjects who were randomized and treated with at least one dose of study drug for whom at least 1 PET scan at baseline and 1 on-treatment scan were provided. One subject in the 3 mg dose group was excluded from the PET analysis because had no measurement of MAO-B availability on Day 28.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BI 1467335 10 Milligram (mg) | Reduction in MAO-B Availability on Day 28 of Treatment With 3 mg BI 1467335 Compared With Baseline | -1.43 Percent reduction | Standard Deviation 6.29 |