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

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ClinicalTrials.gov Identifier: NCT02497235
Recruitment Status : Completed
First Posted : July 14, 2015
Results First Posted : April 11, 2017
Last Update Posted : April 11, 2017
Sponsor:
Information provided by (Responsible Party):
Takeda

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
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 : July 2015
Actual Primary Completion Date : December 2015
Actual Study Completion Date : January 2016


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.




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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ 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 ]
  2. Percent Change From Baseline in the AUEC24 for Plasma 24S Hydroxycholesterol (24HC) [ 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 ]
    Percent change was calculated as = [(Postdose AUEC24(2) - Baseline AUEC24(2))/Baseline AUEC24(2)]*100 percent.



Information from the National Library of Medicine

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Ages Eligible for Study:   19 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02497235


Locations
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United States, Connecticut
New Haven, Connecticut, United States
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Medical Director Takeda

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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02497235     History of Changes
Other Study ID Numbers: TAK-935_1003
U1111-1170-0452 ( Registry Identifier: WHO )
First Posted: July 14, 2015    Key Record Dates
Results First Posted: April 11, 2017
Last Update Posted: April 11, 2017
Last Verified: February 2017
Keywords provided by Takeda:
Drug therapy, Positron Emission Tomography, Brain enzyme occupancy, Cholesterol 24S-hydroxylase, CH24H
Additional relevant MeSH terms:
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Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases