A Study With [18F]MNI-1054 to Determine Lysine -Specific Demethylase 1A (LSD1) Brain Enzyme Occupancy of TAK-418 After Single-Dose Oral Administration in Healthy Participants

A Phase 1, Open-label, Positron Emission Tomography Study With [18F]MNI-1054 to Determine Lysine-Specific Demethylase 1A Brain Enzyme Occupancy of TAK-418 After Single-Dose Oral Administration in Healthy Subjects

The purpose of this study is to determine brain LSD1 enzyme occupancy and the relationship of occupancy to TAK-418 dose and plasma exposure after single oral dosing of TAK-418 in healthy participants using [18F]MNI-1054 positron emission tomography (PET) imaging.

Study Overview

• Status: Terminated
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: TAK-418; Drug: [18F]MNI-1054 (radiotracer)

Detailed Description

The drug being tested in this study is called TAK-418. TAK-418 is being tested to determine the relationship between brain LSD1 enzyme occupancy and TAK-418 plasma concentration. This study will utilize the PET radiotracer [18F]MNI-1054 to evaluate the brain LSD1 enzyme occupancy of TAK-418 after single dose oral administration in healthy adult participants.

The study will enroll approximately 16 participants. The TAK-418 starting dose is 1.5 mg, given on Day 1. Each participant will receive one dose of TAK-418 and up to 3 dynamic [18F]MNI-1054 PET scans to assess enzyme occupancy on baseline, Day 1 and Day 2 or 3 post-TAK-418 dosing.

This single center trial will be conducted in the United States. The overall time to participate in this study is 62 days. Participants will be followed up on Day 14 for follow-up safety assessments.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Invicro, a Konica Minolta company

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. The participant must have a body mass index (BMI) greater than or equal to (>=) 18.5 and less than or equal to (<=) 30.0 kilogram per square meter (kg/m^2) at the screening visit.
2. The participant must be a current nonsmoker at screening as demonstrated by negative cotinine test.
3. The participant has adequate circulation to both hands for safe placement of arterial lines (as determined by Allen's test).

Exclusion Criteria:

1. Has a known hypersensitivity to any component of the formulation of TAK-418 or related compounds, including [18F]MNI-1054.
2. The participant has a positive alcohol or drug screen.
3. The participant has a history of alcohol consumption exceeding 2 standard drinks per day on average (1 glass is approximately equivalent to the following: beer [354 milliliter (mL)/12 ounce (oz)], wine [118 mL/4 oz], or distilled spirits [29.5 mL/1 oz] per day).
4. The participant consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day.
5. The participant has a substance abuse disorder.
6. The participant cannot tolerate venipuncture or has poor venous access that would cause difficulty in collecting blood samples.
7. The participant has contraindications to undergoing magnetic resonance imaging (MRI) examination including but not limited to implants, such as implanted cardiac pacemakers or defibrillators, insulin pumps, cochlear implants, metallic ocular foreign body, implanted neural stimulators, central nervous system aneurysm clips, and other medical implants that have not been certified for MRI, or history of claustrophobia in MRI.
8. The participant has clinically significant abnormal findings on brain MRI scan that in the opinion of the investigator may interfere with the interpretation of the PET imaging.
9. The participant has experienced an acute illness within 10 days before the screening visit.
10. The participant has a risk of suicide according to the investigator's clinical judgement per the Columbia-Suicide Severity Rating Scale at screening or has made a suicide attempt in the 12 months before screening.
11. The participant has luteinizing hormone, follicle stimulating hormone (FSH), or estradiol levels that are clinically abnormal.
12. The participant has existing skin rashes that can be diagnosed as dermatitis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TAK-418 1.5 mg; TAK-418 1.5 milligram (mg), orally, once on Day 1. Participants will also receive 10 millicurie (mCi) of [18F]MNI-1054 injection intravenously, prior to each PET scans on Day -1, Day 1, and either on Day 2 or 3. Dose levels for subsequent participants may vary based on available review of imaging and pharmacokinetics (PK) data.	Drug: TAK-418; TAK-418 orally.; Drug: [18F]MNI-1054 (radiotracer); [18F]MNI-1054 injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1	Enzyme binding parameter [Ki] was obtained from irreversible 2-tissue compartment model (mL/cm^3/min). Data is reported for the following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. Here, mL/cm^3/min signifies 'milliliter per cubic centimeter per minute'.	Day -1
Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1	Enzyme binding parameter [Ki] was obtained from irreversible 2-tissue compartment model (mL/cm^3/min). Data is reported for the following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. Here, mL/cm^3/min signifies 'milliliter per cubic centimeter per minute'.	Day 1
Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2	Enzyme binding parameter [Ki] was obtained from irreversible 2-tissue compartment model (mL/cm^3/min). Data is reported for the following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. Here, mL/cm^3/min signifies 'milliliter per cubic centimeter per minute'.	Day 2
Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1	Lysine-Specific Demethylase 1A (LSD1) enzyme occupancy (%) in region of interest (ROI) after a single dose of TAK-418 was obtained from the baseline and postdose Ki values as follows: occupancy (1st postdose) = 100*(Ki [baseline] - Ki [1st postdose]) / Ki (baseline). Data is reported for following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum.	Day 1
Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2	LSD1 enzyme occupancy (%) in ROI after a single dose of TAK-418 was obtained from the baseline and postdose Ki values as follows: occupancy (2nd postdose) = 100*(Ki [baseline] - Ki [2nd postdose]) / Ki (baseline). Data is reported for following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum.	Day 2
Cmax: Maximum Observed Plasma Concentration for TAK-418		Day 1: pre-dose and at multiple time points (up to 3 hours) post-dose, immediately before and after the Day 1 PET scan, and within 30 minutes before and 30 minutes after Day 2 or 3 PET scan
AUClast: Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for TAK-418		Day 1: pre-dose and at multiple time points (up to 3 hours) post-dose, immediately before and after the Day 1 PET scan, and within 30 minutes before and 30 minutes after Day 2 or 3 PET scan
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-418		Day 1: pre-dose and at multiple time points (up to 3 hours) post-dose, immediately before and after the Day 1 PET scan, and within 30 minutes before and 30 minutes after Day 2 or 3 PET scan

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ED50 PET Enzyme Occupancy	The relationship between PET enzyme occupancy and TAK-418 dose level was investigated using an Emax model containing the regression parameters maximal target occupancy (Emax) and dose that gives 50 percent (%) of Emax (ED50). ED50 values are reported for following brain regions: cerebellum, frontal lobe, hippocampus, occipital Lobe, pons, and striatum. The data tabulated are the estimated value and confidence intervals of the ED50 value derived from an Emax model fit across all data points from all arms. ED50 is the dose at which 50% enzyme occupancy is expected.	Days 1 to 2
Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs)		From first dose of [18F]MNI-1054 radiotracer injection up to Day 14
Number of Participants With Clinically Significant Abnormal Laboratory Values		From first dose of [18F]MNI-1054 radiotracer injection up to Day 14
Number of Participants With Clinically Significant Abnormal Vital Signs		From first dose of [18F]MNI-1054 radiotracer injection up to Day 14

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2019
• Primary Completion (Actual): March 5, 2020
• Study Completion (Actual): March 19, 2020

Study Registration Dates

• First Submitted: December 12, 2019
• First Submitted That Met QC Criteria: December 16, 2019
• First Posted (Actual): December 17, 2019

Study Record Updates

• Last Update Posted (Actual): July 30, 2021
• Last Update Submitted That Met QC Criteria: July 9, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy
• Other Study ID Numbers: TAK-418-0004; U1111-1242-8485 (Registry Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No