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| ID | Type | Description | Link |
|---|---|---|---|
| U1111-1170-0452 | Registry Identifier | WHO |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TAK-935 | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TAK-935 | Drug | TAK-935 oral solution. |
| |
| [18F]MNI-792 (tracer) |
| Measure | Description | Time Frame |
|---|---|---|
| Cholesterol 24S-Hydroxylase (CH24H) Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 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. | 45 minutes post-TAK-935 dose |
| CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 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. | 2 hours post-TAK-935 dose |
| CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | |
| Percent Change From Baseline in the AUEC24 for Plasma 24S Hydroxycholesterol (24HC) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director | Takeda | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| New Haven | Connecticut | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37770111 | Derived | Constantinescu CC, Brown T, Wang S, Yin W, Barret O, Jennings D, Tauscher J. Clinical Characterization of [18F]T-008, a Cholesterol 24-Hydroxylase PET Ligand: Dosimetry, Kinetic Modeling, Variability, and Soticlestat Occupancy. J Nucl Med. 2023 Dec 1;64(12):1972-1979. doi: 10.2967/jnumed.123.265912. |
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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.
Participants took part in the study at 1 investigative site in the United States from 01 July 2015 to 04 January 2016.
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| ID | Title | Description |
|---|---|---|
| FG000 | TAK-935 50 mg | 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. |
| FG001 | TAK-935 100 mg | 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. |
| FG002 | TAK-935 200 mg | 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. |
| FG003 | TAK-935 300 mg | 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. |
| FG004 | TAK-935 600 mg | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Safety analysis set included all participants who were enrolled and received investigational drug ([18F]MNI-792 or TAK-935).
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| ID | Title | Description |
|---|---|---|
| BG000 | TAK-935 50 mg | 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. |
| BG001 | TAK-935 100 mg |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Cholesterol 24S-Hydroxylase (CH24H) Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 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. | 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. | Posted | Number | percentage of occupancy | 45 minutes post-TAK-935 dose |
Baseline up to Day 28
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Baseline [18F]MNI-792 | [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. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Tinnitus | Ear and labyrinth disorders | MedDRA (18.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Takeda | Medical Director | +1-877-825-3327 | trialdisclosures@takeda.com |
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| ID | Term |
|---|---|
| D004827 | Epilepsy |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D011356 | Product Labeling |
| ID | Term |
|---|---|
| D019064 | Product Packaging |
| D007221 | Industry |
| D013676 | Technology, Industry, and Agriculture |
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| Drug |
[18F]MNI-792 injection. |
|
| 10 hours post-TAK-935 dose |
| CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 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. | 24 hours post-TAK-935 dose |
Percent change was calculated as = [(Postdose AUEC24(2) - Baseline AUEC24(2))/Baseline AUEC24(2)]*100 percent. |
| 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 |
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. |
| BG002 | TAK-935 200 mg | 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. |
| BG003 | TAK-935 300 mg | 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. |
| BG004 | TAK-935 600 mg | 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. |
| BG005 | Total | Total of all reporting groups |
| years |
|
| Sex/Gender, Customized | Number | participants |
|
| Region of Enrollment | Number | participants |
|
| Ethnicity | Number | participants |
|
| Race | Number | participants |
|
| Height | Mean | Standard Deviation | centimeter (cm) |
|
| Weight | Mean | Standard Deviation | kilogram (kg) |
|
| Body Mass Index (BMI) | Mean | Standard Deviation | kilogram per square meter (kg/m^2) |
|
| ID | Title | Description |
|---|
| OG000 | TAK-935 600 mg | 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. |
|
|
| Primary | CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 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. | 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. | Posted | Number | percentage of occupancy | 2 hours post-TAK-935 dose |
|
|
|
| Primary | CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 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. | 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. | Posted | Number | percentage of occupancy | 10 hours post-TAK-935 dose |
|
|
|
| Primary | CH24H Brain Enzyme Occupancy as a Function of TAK-935 Plasma Concentration at 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. | 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. | Posted | Number | percentage of occupancy | 24 hours post-TAK-935 dose |
|
|
|
| Secondary | Plasma Concentration of TAK-935 During Post-TAK-935 Dosing PET Scan Periods | 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. | Posted | Number | nanogram per milliliter (ng/mL) | 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 |
|
|
|
| Secondary | Percent Change From Baseline in the AUEC24 for Plasma 24S Hydroxycholesterol (24HC) | Percent change was calculated as = [(Postdose AUEC24(2) - Baseline AUEC24(2))/Baseline AUEC24(2)]*100 percent. | 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. | Posted | Number | percent change | 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 |
|
|
|
| 0 |
| 11 |
| 1 |
| 11 |
| EG001 | TAK-935 50 mg | 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. | 0 | 2 | 1 | 2 |
| EG002 | TAK-935 100 mg | 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. | 0 | 2 | 1 | 2 |
| EG003 | TAK-935 200 mg | 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. | 0 | 2 | 1 | 2 |
| EG004 | TAK-935 300 mg | 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. | 0 | 2 | 1 | 2 |
| EG005 | TAK-935 600 mg | 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. | 0 | 3 | 1 | 3 |
| Catheter site haemorrhage | General disorders | MedDRA (18.0) | Systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA (18.0) | Systematic Assessment |
|
| Presyncope | Nervous system disorders | MedDRA (18.0) | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA (18.0) | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA (18.0) | Systematic Assessment |
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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.
| Participant 2 |
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| Participant 3 |
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| Title | Measurements |
|---|---|
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| Participant 2 |
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| Participant 3 |
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| Participant 1: PET Scan 1: 1 hour post-tracer dose |
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| Participant 1:PET Scan 1: 2 hours post-tracer dose |
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| Participant 1: PET Scan 2: pre-tracer dose |
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| Participant 1:PET Scan 2: 1 hour post-tracer dose |
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| Participant 1:PET Scan 2:2 hours post-tracer dose |
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| Participant 2: PET Scan 1: pre-tracer dose |
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| Participant 2: PET Scan 1: 1 hour post-tracer dose |
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| Participant 2:PET Scan 1: 2 hours post-tracer dose |
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| Participant 2: PET Scan 2: pre-tracer dose |
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| Participant 2:PET Scan 2: 1 hour post-tracer dose |
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| Participant 2:PET Scan 2:2 hours post-tracer dose |
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| Participant 3: PET Scan 1: pre-tracer dose |
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| Participant 3: PET Scan 1: 1 hour post-tracer dose |
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| Participant 3:PET Scan 1: 2 hours post-tracer dose |
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| Participant 3: PET Scan 2: pre-tracer dose |
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| Participant 3: PET Scan 2: 1 hour post-tracer dose |
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| Participant 3:PET Scan 2: 2 hours post-tracer dose |
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| Participant 2 |
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| Participant 3 |
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