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

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03927209
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arms: 2
• Actual Duration (Months): 5.6
• Patients Per Site Per Month: 1.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: BI 1467335	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: Jun 6, 2019
• Actual Primary Completion Date: Nov 22, 2019
• Actual Study Completion Date: Nov 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BI 1467335 (low dose)	Drug: BI 1467335; tablet
Experimental: BI 1467335 (high dose)	Drug: BI 1467335; tablet

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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).

4. 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).

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwick Park Hospital	Harrow		United Kingdom	HA1 3UJ

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jun 24, 2019
• Statistical Analysis Plan - Jan 17, 2020

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT03927209
• Other Study ID Numbers: 1386-0022; 2018-003745-41
• First Posted: Apr 25, 2019
• Last Update Posted: Jun 22, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Study Results

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 Detail	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.

Arm/Group Title	BI 1467335 10 Milligram (mg)	BI 1467335 3 Milligram (mg)
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	5	5
COMPLETED	5	5
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	BI 1467335 10 Milligram (mg)	BI 1467335 3 Milligram (mg)	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	5	5	10
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43.8 (7.7)	39.0 (11.4)	41.4 (9.5)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	5 100%	5 100%	10 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	5 100%	5 100%	10 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	2 40%	2 20%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 20%	1 10%
White	3 60%	2 40%	5 50%
More than one race	2 40%	0 0%	2 20%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage Reduction in Whole Brain Monoamine Oxidase (MAO)-B Availability Assessed by Positron Emission Tomography (PET) Imaging
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 1467335 10 Milligram (mg)	BI 1467335 3 Milligram (mg)
Arm/Group Description	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.	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.
Measure Participants	5	4
Mean (Standard Deviation) [Percent reduction]	72.58 (11.81)	2.43 (6.05)

2. Secondary Outcome

Title	Percent Reduction in MAO-B Availability on Day 14 of Treatment With 10 mg BI 1467335 Compared With Baseline
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 1467335 10 Milligram (mg)
Arm/Group Description	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.
Measure Participants	5
Mean (Standard Deviation) [Percent reduction]	44.56 (16.20)

3. Secondary Outcome

Title	Reduction in MAO-B Availability on Day 28 of Treatment With 3 mg BI 1467335 Compared With Baseline
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 1467335 3 Milligram (mg)
Arm/Group Description	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.
Measure Participants	3
Mean (Standard Deviation) [Percent reduction]	-1.43 (6.29)

4. Secondary Outcome

Title	MAO-B Inhibition in Platelet Rich Plasma Compared With Baseline
Description	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).

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	BI 1467335 10 Milligram (mg)	BI 1467335 3 Milligram (mg)
Arm/Group Description	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.	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.
Measure Participants	0	0

5. Secondary Outcome

Title	Maximum Measured Concentration of BI 1467335 in Plasma
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 1467335 10 Milligram (mg)	BI 1467335 3 Milligram (mg)
Arm/Group Description	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.	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.
Measure Participants	5	5
Day 14	36.4 (65.2)
Day 28	48.4 (85.3)	2.28 (76.0)
Day 42	3.60 (146)

6. Secondary Outcome

Title	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)
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	BI 1467335 10 Milligram (mg)	BI 1467335 3 Milligram (mg)
Arm/Group Description	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.	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.
Measure Participants	5	5
Day 14	85.7 (75.5)
Day 28	235 (148.0)	4.65 (54.9)
Day 42	4.34 (132)

Adverse Events

Time Frame	From the date/time of first administration of BI 1467335 until 12 a.m. on the day after subjects end of participation date. (Up to 36 days for 10mg group, up to 50 days for 3mg group)
Adverse Event Reporting Description	Treated set (TS): The TS included all subjects who were randomized and treated with at least one dose of study drug.
Arm/Group Title	BI 1467335 10 Milligram (mg)		BI 1467335 3 Milligram (mg)		Total on Treatment
Arm/Group Description	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.		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.		Total of the over all on-treatment phases of BI 1467335.
All Cause Mortality
	BI 1467335 10 Milligram (mg)		BI 1467335 3 Milligram (mg)		Total on Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		0/10 (0%)
Serious Adverse Events
	BI 1467335 10 Milligram (mg)		BI 1467335 3 Milligram (mg)		Total on Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/5 (0%)		0/5 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	BI 1467335 10 Milligram (mg)		BI 1467335 3 Milligram (mg)		Total on Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		3/5 (60%)		8/10 (80%)
Ear and labyrinth disorders
Ear discomfort	0/5 (0%)		1/5 (20%)		1/10 (10%)
Gastrointestinal disorders
Abdominal discomfort	1/5 (20%)		0/5 (0%)		1/10 (10%)
Abdominal distension	0/5 (0%)		1/5 (20%)		1/10 (10%)
Abdominal pain	0/5 (0%)		1/5 (20%)		1/10 (10%)
Constipation	1/5 (20%)		0/5 (0%)		1/10 (10%)
Diarrhoea	0/5 (0%)		1/5 (20%)		1/10 (10%)
General disorders
Catheter site bruise	1/5 (20%)		1/5 (20%)		2/10 (20%)
Catheter site erythema	0/5 (0%)		1/5 (20%)		1/10 (10%)
Catheter site pain	1/5 (20%)		0/5 (0%)		1/10 (10%)
Fatigue	1/5 (20%)		0/5 (0%)		1/10 (10%)
Feeling hot	1/5 (20%)		0/5 (0%)		1/10 (10%)
Injury, poisoning and procedural complications
Injury	1/5 (20%)		0/5 (0%)		1/10 (10%)
Metabolism and nutrition disorders
Decreased appetite	0/5 (0%)		1/5 (20%)		1/10 (10%)
Musculoskeletal and connective tissue disorders
Back pain	0/5 (0%)		1/5 (20%)		1/10 (10%)
Musculoskeletal pain	1/5 (20%)		0/5 (0%)		1/10 (10%)
Pain in extremity	1/5 (20%)		0/5 (0%)		1/10 (10%)
Nervous system disorders
Dysgeusia	1/5 (20%)		0/5 (0%)		1/10 (10%)
Lethargy	0/5 (0%)		1/5 (20%)		1/10 (10%)
Psychiatric disorders
Euphoric mood	0/5 (0%)		1/5 (20%)		1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Nasal congestion	1/5 (20%)		0/5 (0%)		1/10 (10%)
Oropharyngeal pain	1/5 (20%)		0/5 (0%)		1/10 (10%)
Sneezing	0/5 (0%)		1/5 (20%)		1/10 (10%)
Skin and subcutaneous tissue disorders
Dry skin	1/5 (20%)		0/5 (0%)		1/10 (10%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.