A Phase 1 Positron Emission Tomography Study to Measure Cholesterol 24S-Hydroxylase Target Occupancy of TAK-935

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02497235
• Collaborator: (none)
• Enrollment: 11
• Location: 1
• Arm: 1
• Duration (Months): 6
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the brain cholesterol 24S-hydroxylase (CH24H) enzyme occupancy of TAK-935 after single oral dose in healthy participants using the positron emission tomography (PET) ligand [18F]MNI-792 and PET imaging and to determine the relationship of occupancy to TAK-935 exposure.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy, Molecular Mechanisms of Pharmalogical Action, Protective Agents	Drug: TAK-935; Drug: [18F]MNI-792 (tracer)	Phase 1

Detailed Description

The drug being tested in this study is called TAK-935. TAK-935 is being tested to examine the degree and duration of brain CH24H enzyme occupancy/target engagement as a function of TAK-935 plasma concentration in order to guide dosing and schedule for future clinical trials with TAK-935. This study will utilize the PET ligand [18F]MNI-792 to evaluate the brain CH24H occupancy of TAK-935 after single dose oral administration in healthy adult participants. The study will evaluate up to 16 participants. The first 2 participants will take TAK-935 600 mg oral solution and undergo PET imaging using tracer [18F]MNI-792 up to 5 mcg (up to 370 MBq), injection, intravenously prior to each PET scan at Baseline, 45 minutes and 10 hours post-TAK-935 dose. TAK-935 dose and timing of post-dose scans for subsequent participants will be based on the data from the previous participants. This single-center trial will be conducted in the United States. The overall time to participate in this study is up to 55 days. Participants will make 4 visits to the clinic, including 2 confinement periods to the clinic for PET imaging. Participants will be contacted by phone on Day 28 for follow-up safety assessments.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: An Open-Label, Positron Emission Tomography, Phase 1 Study With [18F]MNI-792 to Determine Cholesterol 24S-Hydroxylase Target Occupancy of TAK-935 After Single-Dose Oral Administration in Healthy Subjects.
• Study Start Date: Jul 1, 2015
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: TAK-935 A single dose of TAK-935 600 milligram (mg), oral solution on Day 1 as a starting dose and up to 370 megabecquerel (MBq) (10 millicurie [mCi]) of [18F]MNI-792 with a mass of up to 5 microgram (mcg), injection intravenously (IV), prior to each PET imaging at Baseline, 45 minutes and 10 hours post-TAK-935 dose. Subsequent dose of TAK-935 oral solution and timing of PET imaging will be based on safety, tolerability and occupancy data from previous level participants.

Drug: TAK-935; TAK-935 oral solution.; Drug: [18F]MNI-792 (tracer); [18F]MNI-792 injection.

Outcome Measures

Primary Outcome Measures

1. Cholesterol 24S-Hydroxylase (CH24H) Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 45 Minutes Post-TAK-935 Dose [45 minutes post-TAK-935 dose]

   CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: total volume of distribution [VT] (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT [Baseline] - non-displaceable volume of distribution [VND]), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept. Data was reported only for TAK-935 600 mg because only first two participants were analyzed at 45 minutes post-TAK-935 dose.

2. CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 2 Hours Post-TAK-935 Dose [2 hours post-TAK-935 dose]

   CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT [Baseline] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept.

3. CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 10 Hours Post-TAK-935 Dose [10 hours post-TAK-935 dose]

   CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT [Baseline] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept. Data was reported only for TAK-935 600 mg because only first two participants were analyzed at 10 hour post-TAK-935 dose.

4. CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 24 Hours Post-TAK-935 Dose [24 hours post-TAK-935 dose]

   CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT [Baseline] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept.

Secondary Outcome Measures

1. Plasma Concentration of TAK-935 During Post-TAK-935 Dosing PET Scan Periods [At time 0 (just after tracer injection), 1 hour after tracer injection and 2 hours after tracer injection for each post-TAK-935 dosing PET scan period]

2. Percent Change From Baseline in the AUEC24 for Plasma 24S Hydroxycholesterol (24HC) [Baseline (Day -1): 1 hour and at multiple timepoints (up to 12 hours) post check in and Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-TAK-935 dose]

   Percent change was calculated as = [(Postdose AUEC24(2) - Baseline AUEC24(2))/Baseline AUEC24(2)]*100 percent.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. In the opinion of the investigator, is capable of understanding and complying with protocol requirements.

2. Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures including requesting that a participant fast for any laboratory evaluations.

3. Is a healthy male or female and aged 19 to 55 years, inclusive, at the time of informed consent and first study medication dose.

4. Weighs at least 45 kilogram (kg) and has a body mass index (BMI) from 18.0 to 30.0 kilogram per square meter (kg/m^2), inclusive at Screening.

5. A female of non-bearing potential (example post-menopausal by history; or history of hysterectomy, bilateral salpingectomy, or oophorectomy).

Exclusion Criteria:

1. Have a known history or evidence of a clinically significant disorder (including neurologic and psychiatric), or disease that in the opinion of the study investigator would pose a risk to the participant safety or interfere with the study evaluation, procedures or completion.

2. Contraindication to magnetic resonance imaging (MRI) based on the standard MRI radiography screening questionnaire.

3. Had exposure to any radiation greater than (>) 15 millisievert (mSv)/year (example, occupational or radiation therapy) within the previous year prior to Baseline imaging.

4. Has a known hypersensitivity to any component of the formulation of TAK-935 or related compounds, or to [18F]MNI-792 or to any of its components.

5. Clinically significant abnormal findings on brain MRI scan or findings on brain MRI that may interfere with the interpretation of the PET imaging.

6. Use of any over-the-counter, herbal, or prescription medications or supplements within 30 days prior to baseline imaging.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		New Haven	Connecticut	United States

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02497235
• Other Study ID Numbers: TAK-935_1003; U1111-1170-0452
• First Posted: Jul 14, 2015
• Last Update Posted: Apr 11, 2017
• Last Verified: Feb 1, 2017

• Keywords provided by Takeda: Drug therapy, Positron Emission Tomography, Brain enzyme occupancy, Cholesterol 24S-hydroxylase, CH24H
• Additional relevant MeSH terms: Epilepsy

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in the United States from 01 July 2015 to 04 January 2016.
Pre-assignment Detail	Healthy participants received up to 370 megabecquerel (MBq) (10 millicurie [mCi]) of [18F]MNI-792 with a mass of up to 5 microgram (mcg) at baseline and were enrolled to 1 of 5 treatment groups: TAK-935 50 milligram (mg), 100 mg, 200 mg, 300 mg, and 600 mg.

Arm/Group Title	TAK-935 50 mg	TAK-935 100 mg	TAK-935 200 mg	TAK-935 300 mg	TAK-935 600 mg
Arm/Group Description	TAK-935 50 mg, solution, orally, once on Day 1 and up to 370 MBq (10 mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at 2 hours and 24 hours post-TAK-935 dose.	TAK-935 100 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 200 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 300 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 600 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to first PET imaging at Baseline, 45 minutes and 10 hours post-TAK-935 dose for the first 2 enrolled participants and at Baseline, 2 hours and 24 hours post-TAK-935 dose for the participant enrolled later.
Period Title: Overall Study
STARTED	2	2	2	2	3
COMPLETED	2	2	2	2	3
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	TAK-935 50 mg	TAK-935 100 mg	TAK-935 200 mg	TAK-935 300 mg	TAK-935 600 mg	Total
Arm/Group Description	TAK-935 50 mg, solution, orally, once on Day 1 and up to 370 MBq (10 mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at 2 hours and 24 hours post-TAK-935 dose.	TAK-935 100 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 200 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 300 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 600 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to first PET imaging at Baseline, 45 minutes and 10 hours post-TAK-935 dose for the first 2 enrolled participants and at Baseline, 2 hours and 24 hours post-TAK-935 dose for the participant enrolled later.	Total of all reporting groups
Overall Participants	2	2	2	2	3	11
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.0 (7.07)	25.5 (2.12)	42.0 (2.83)	48.5 (2.12)	36.7 (6.11)	38.4 (8.48)
Sex/Gender, Customized (participants) [Number]
Male	2 100%	2 100%	2 100%	2 100%	3 100%	11 100%
Region of Enrollment (participants) [Number]
United States	2 100%	2 100%	2 100%	2 100%	3 100%	11 100%
Ethnicity (participants) [Number]
Hispanic or Latino	1 50%	2 100%	0 0%	0 0%	1 33.3%	4 36.4%
Not Hispanic or Latino	1 50%	0 0%	2 100%	2 100%	2 66.7%	7 63.6%
Race (participants) [Number]
Black or African American	2 100%	1 50%	2 100%	0 0%	1 33.3%	6 54.5%
White	0 0%	1 50%	0 0%	2 100%	2 66.7%	5 45.5%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	171.5 (4.95)	181.5 (3.54)	177.0 (4.24)	180.0 (0.00)	183.0 (16.09)	179.0 (8.69)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	86.05 (7.283)	93.60 (10.748)	79.40 (12.869)	87.05 (5.162)	84.83 (23.692)	86.06 (13.009)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	29.22 (0.789)	28.37 (2.157)	25.46 (5.327)	26.87 (1.593)	24.95 (4.275)	26.79 (3.212)

Outcome Measures

1. Primary Outcome

Title	Cholesterol 24S-Hydroxylase (CH24H) Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 45 Minutes Post-TAK-935 Dose
Description	CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: total volume of distribution [VT] (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT [Baseline] - non-displaceable volume of distribution [VND]), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept. Data was reported only for TAK-935 600 mg because only first two participants were analyzed at 45 minutes post-TAK-935 dose.
Time Frame	45 minutes post-TAK-935 dose

Outcome Measure Data

Analysis Population Description

PET target occupancy set where 45 minutes post-TAK-935-dose assessment were available. PET target occupancy set included all participants who received study drug (TAK-935) and had a technically adequate Baseline PET scan and at least 1 technically adequate post-TAK-935 dose PET scan.

Arm/Group Title	TAK-935 600 mg
Arm/Group Description	TAK-935 600 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to first PET imaging at Baseline, 45 minutes and 10 hours post-TAK-935 dose for the first 2 enrolled participants.
Measure Participants	2
Participant 1	NA
Participant 2	98
Participant 3	NA

2. Primary Outcome

Title	CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 2 Hours Post-TAK-935 Dose
Description	CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT [Baseline] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept.
Time Frame	2 hours post-TAK-935 dose

Outcome Measure Data

Analysis Population Description

PET target occupancy set where 2 hour post-TAK-935-dose assessment were available. PET target occupancy set included all participants who received study drug (TAK-935) and had a technically adequate Baseline PET scan and at least 1 technically adequate post-TAK-935 dose PET scan.

Arm/Group Title	TAK-935 50 mg	TAK-935 100 mg	TAK-935 200 mg	TAK-935 300 mg	TAK-935 600 mg
Arm/Group Description	TAK-935 50 mg, solution, orally, once on Day 1 and up to 370 MBq (10 mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at 2 hours and 24 hours post-TAK-935 dose.	TAK-935 100 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 200 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 300 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 600 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to first PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose for the participant enrolled later.
Measure Participants	2	2	2	2	1
Participant 1	70	79	96	91	NA
Participant 2	64	85	89	89	NA
Participant 3	NA	NA	NA	NA	96

3. Primary Outcome

Title	CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 10 Hours Post-TAK-935 Dose
Description	CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT [Baseline] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept. Data was reported only for TAK-935 600 mg because only first two participants were analyzed at 10 hour post-TAK-935 dose.
Time Frame	10 hours post-TAK-935 dose

Outcome Measure Data

Analysis Population Description

PET target occupancy set where 10 hour post-TAK-935-dose assessment were available. PET target occupancy set included all participants who received study drug (TAK-935) and had a technically adequate Baseline PET scan and at least 1 technically adequate post-TAK-935 dose PET scan.

Arm/Group Title	TAK-935 600 mg
Arm/Group Description	TAK-935 600 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to first PET imaging at Baseline, 45 minutes and 10 hours post-TAK-935 dose for the first 2 enrolled participants.
Measure Participants	2
Participant 1	92
Participant 2	87
Participant 3	NA

4. Primary Outcome

Title	CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 24 Hours Post-TAK-935 Dose
Description	CH24H brain enzyme occupancy was obtained by graphical analysis of global occupancy plot. Global occupancy plot was calculated as: VT (Baseline) - VT (Day 1) = Occupancy (Day 1) * (VT [Baseline] - VND), where VT (Baseline) and VT (Day 1) are the total distribution volumes obtained at Baseline and after TAK-935 administration, respectively and VND is the non-displaceable volume of distribution. The occupancy is determined as the slope of the linear regression of the plot, and the VND as the x-intercept.
Time Frame	24 hours post-TAK-935 dose

Outcome Measure Data

Analysis Population Description

PET target occupancy set where 24 hour post-TAK-935-dose assessment were available. PET target occupancy set included all participants who received study drug (TAK-935) and had a technically adequate Baseline PET scan and at least 1 technically adequate post-TAK-935 dose PET scan.

Arm/Group Title	TAK-935 50 mg	TAK-935 100 mg	TAK-935 200 mg	TAK-935 300 mg	TAK-935 600 mg
Arm/Group Description	TAK-935 50 mg, solution, orally, once on Day 1 and up to 370 MBq (10 mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at 2 hours and 24 hours post-TAK-935 dose.	TAK-935 100 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 200 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 300 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 600 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to first PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose for the participant enrolled later.
Measure Participants	2	2	2	2	1
Participant 1	22	13	79	46	NA
Participant 2	11	NA	47	27	NA
Participant 3	NA	NA	NA	NA	52

5. Secondary Outcome

Title	Plasma Concentration of TAK-935 During Post-TAK-935 Dosing PET Scan Periods
Time Frame	At time 0 (just after tracer injection), 1 hour after tracer injection and 2 hours after tracer injection for each post-TAK-935 dosing PET scan period

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all participants who received TAK-935 and had at least 1 measurable plasma concentration for either TAK-935 or its M-1 metabolite. Data was reported for Participant 1 and 2 of each of TAK-935 50, 100, 200, and 300 mg arms and Participant 1, 2, and 3 of TAK-935 600 mg arm.

Arm/Group Title	TAK-935 50 mg	TAK-935 100 mg	TAK-935 200 mg	TAK-935 300 mg	TAK-935 600 mg
Arm/Group Description	TAK-935 50 mg, solution, orally, once on Day 1 and up to 370 MBq (10 mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at 2 hours and 24 hours post-TAK-935 dose.	TAK-935 100 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 200 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 300 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 600 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to first PET imaging at Baseline, 45 minutes and 10 hours post-TAK-935 dose for the first 2 enrolled participants and at Baseline, 2 hours and 24 hours post-TAK-935 dose for the participant enrolled later.
Measure Participants	2	2	2	2	3
Participant 1: PET Scan 1: pre-tracer dose	9.16	11.3	158	56.2	6.83
Participant 1: PET Scan 1: 1 hour post-tracer dose	3.79	5.02	72.7	19.4	200
Participant 1:PET Scan 1: 2 hours post-tracer dose	2.98	2.45	30.3	12.9	379
Participant 1: PET Scan 2: pre-tracer dose	NA	NA	14.2	NA	22.3
Participant 1:PET Scan 2: 1 hour post-tracer dose	NA	NA	9.16	NA	16
Participant 1:PET Scan 2:2 hours post-tracer dose	NA	NA	8.08	NA	14.4
Participant 2: PET Scan 1: pre-tracer dose	6.92	23.9	34.8	50.9	569
Participant 2: PET Scan 1: 1 hour post-tracer dose	2.97	12.3	16.8	15.7	257
Participant 2:PET Scan 1: 2 hours post-tracer dose	1.95	6.46	7.52	14.6	90.8
Participant 2: PET Scan 2: pre-tracer dose	NA	1.83	NA	NA	7.99
Participant 2:PET Scan 2: 1 hour post-tracer dose	NA	1.28	NA	NA	6.27
Participant 2:PET Scan 2:2 hours post-tracer dose	NA	NA	NA	NA	5.12
Participant 3: PET Scan 1: pre-tracer dose	NA	NA	NA	NA	589
Participant 3: PET Scan 1: 1 hour post-tracer dose	NA	NA	NA	NA	236
Participant 3:PET Scan 1: 2 hours post-tracer dose	NA	NA	NA	NA	155
Participant 3: PET Scan 2: pre-tracer dose	NA	NA	NA	NA	3.04
Participant 3: PET Scan 2: 1 hour post-tracer dose	NA	NA	NA	NA	2.58
Participant 3:PET Scan 2: 2 hours post-tracer dose	NA	NA	NA	NA	2.24

6. Secondary Outcome

Title	Percent Change From Baseline in the AUEC24 for Plasma 24S Hydroxycholesterol (24HC)
Description	Percent change was calculated as = [(Postdose AUEC24(2) - Baseline AUEC24(2))/Baseline AUEC24(2)]*100 percent.
Time Frame	Baseline (Day -1): 1 hour and at multiple timepoints (up to 12 hours) post check in and Day 1: pre-dose and at multiple timepoints (up to 24 hours) post-TAK-935 dose

Outcome Measure Data

Analysis Population Description

PK set included all participants who received TAK-935 and had at least 1 measurable plasma concentration for either TAK-935 or its M-1 metabolite. Data was reported for Participant 1 and 2 of each of TAK-935 50, 100, 200, and 300 mg arms and Participant 1, 2, and 3 of TAK-935 600 mg arm.

Arm/Group Title	TAK-935 50 mg	TAK-935 100 mg	TAK-935 200 mg	TAK-935 300 mg	TAK-935 600 mg
Arm/Group Description	TAK-935 50 mg, solution, orally, once on Day 1 and up to 370 MBq (10 mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at 2 hours and 24 hours post-TAK-935 dose.	TAK-935 100 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 200 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 300 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at Baseline, 2 hours and 24 hours post-TAK-935 dose.	TAK-935 600 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to first PET imaging at Baseline, 45 minutes and 10 hours post-TAK-935 dose for the first 2 enrolled participants and at Baseline, 2 hours and 24 hours post-TAK-935 dose for the participant enrolled later.
Measure Participants	2	2	2	2	3
Participant 1	-6.79	-14.82	-10.50	-12.41	-7.23
Participant 2	-13.38	-15.04	-9.30	-18.55	-12.79
Participant 3	NA	NA	NA	NA	-6.81

Adverse Events

Time Frame	Baseline up to Day 28
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Adverse events were summarized separately for Baseline period and TAK-935 dosing groups.
Arm/Group Title	Baseline [18F]MNI-792		TAK-935 50 mg		TAK-935 100 mg		TAK-935 200 mg		TAK-935 300 mg		TAK-935 600 mg
Arm/Group Description	[18F]MNI-792 up to 370 MBq (10mCi) with a mass of up to 5 mcg, injection, intravenously, prior to Positron Emission Tomography (PET) imaging at Baseline.		TAK-935 50 mg, solution, orally, once on Day 1 and up to 370 MBq (10 mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at 2 hours and 24 hours post-TAK-935 dose.		TAK-935 100 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at 2 hours and 24 hours post-TAK-935 dose.		TAK-935 200 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at 2 hours and 24 hours post-TAK-935 dose.		TAK-935 300 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to PET imaging at 2 hours and 24 hours post-TAK-935 dose.		TAK-935 600 mg, solution, orally, once on Day 1 and up to 370 MBq (10mCi) of [18F]MNI-792 with a mass of up to 5 mcg, injection, intravenously, prior to first PET imaging at 45 minutes and 10 hours post-TAK-935 dose for the first 2 enrolled participants and at 2 hours and 24 hours post-TAK-935 dose for the participant enrolled later.
All Cause Mortality
	Baseline [18F]MNI-792		TAK-935 50 mg		TAK-935 100 mg		TAK-935 200 mg		TAK-935 300 mg		TAK-935 600 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Baseline [18F]MNI-792		TAK-935 50 mg		TAK-935 100 mg		TAK-935 200 mg		TAK-935 300 mg		TAK-935 600 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	Baseline [18F]MNI-792		TAK-935 50 mg		TAK-935 100 mg		TAK-935 200 mg		TAK-935 300 mg		TAK-935 600 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/11 (9.1%)		1/2 (50%)		1/2 (50%)		1/2 (50%)		1/2 (50%)		1/3 (33.3%)
Ear and labyrinth disorders
Tinnitus	0/11 (0%)		1/2 (50%)		0/2 (0%)		0/2 (0%)		0/2 (0%)		0/3 (0%)
General disorders
Catheter site haemorrhage	0/11 (0%)		0/2 (0%)		0/2 (0%)		1/2 (50%)		0/2 (0%)		0/3 (0%)
Investigations
Blood creatine phosphokinase increased	0/11 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)		1/3 (33.3%)
Nervous system disorders
Presyncope	0/1 (0%)		0/2 (0%)		1/2 (50%)		0/2 (0%)		0/2 (0%)		0/3 (0%)
Syncope	1/11 (9.1%)		0/2 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)		0/3 (0%)
Vascular disorders
Hypertension	0/11 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)		1/2 (50%)		0/3 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.