Healthy Volunteers
Conditions
Keywords
Drug Therapy
Brief summary
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.
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.
Interventions
DRUGTAK-418
TAK-418 orally.
DRUG[18F]MNI-1054 (radiotracer)
\[18F\]MNI-1054 injection.
Sponsors
Takeda
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | 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. |
| Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | 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. |
| 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 | — |
| Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | 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'. |
| Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | 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'. |
| Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | 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'. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| ED50 PET Enzyme Occupancy | Days 1 to 2 | 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. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in the United States from 18 December 2019 to 19 March 2020.
Pre-assignment details
Healthy participants were enrolled in this study to receive up to 10 millicurie \[mCi\]) of \[18F\]MNI-1054 for 1 positron emission tomography (PET) Scan on Day -1 (Baseline Scan), and then eligible participants entered into 1 of 3 treatment groups in the Treatment Period to receive 10 mCi of \[18F\]MNI-1054 for 2 PET scans after single dose of TAK-418 1.5 milligram (mg), 10 mg, or 30 mg on Day 1 and either Day 2 or 3. Study was prematurely terminated because of administrative reasons.
Participants by arm
| Arm | Count |
|---|---|
| Baseline [18F]MNI-1054 \[18F\]MNI-1054 up to 10 mCi, PET radiotracer injection, intravenously, prior to PET scan on Day -1 (Baseline scan). | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Baseline Scan (Day-1) | Metabolites of [18F]MNI-1054 could not be analyzed | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Baseline [18F]MNI-1054 |
|---|---|
| Age, Continuous | 43.7 years STANDARD_DEVIATION 8.04 |
| Body Mass Index (BMI) | 26.81 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 2.594 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 7 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 2 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 1 / 7 | 0 / 2 | 1 / 2 | 2 / 2 |
| serious Total, serious adverse events | 0 / 7 | 0 / 2 | 0 / 2 | 0 / 2 |
Outcome results
Primary
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-418
Time frame: 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
Population: The PK set included all participants from the safety set who received TAK-418 and had at least 1 measurable plasma concentration for TAK-418. Here overall number of participants analyzed are those who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAK-418 1.5 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-418 | 25.60 h*ng/mL |
| TAK-418 10 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-418 | 230.0 h*ng/mL |
| TAK-418 30 mg | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-418 | 817.0 h*ng/mL |
Primary
AUClast: Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for TAK-418
Time frame: 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
Population: The PK set included all participants from the safety set who received TAK-418 and had at least 1 measurable plasma concentration for TAK-418.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAK-418 1.5 mg | AUClast: Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for TAK-418 | 22.40 hour*nanogram per milliliter(h*ng/mL) |
| TAK-418 10 mg | AUClast: Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for TAK-418 | 227.5 hour*nanogram per milliliter(h*ng/mL) |
| TAK-418 30 mg | AUClast: Area Under the Plasma Concentration-time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for TAK-418 | 812.0 hour*nanogram per milliliter(h*ng/mL) |
Primary
Cmax: Maximum Observed Plasma Concentration for TAK-418
Time frame: 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
Population: The pharmacokinetic (PK) set included all participants from the safety set who received TAK-418 and had at least 1 measurable plasma concentration for TAK-418.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAK-418 1.5 mg | Cmax: Maximum Observed Plasma Concentration for TAK-418 | 4.420 nanogram per milliliter (ng/mL) |
| TAK-418 10 mg | Cmax: Maximum Observed Plasma Concentration for TAK-418 | 43.80 nanogram per milliliter (ng/mL) |
| TAK-418 30 mg | Cmax: Maximum Observed Plasma Concentration for TAK-418 | 130.5 nanogram per milliliter (ng/mL) |
Primary
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.
Time frame: Day 1
Population: The PD set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Cerebellum | 68.5 percentage of occupancy | Standard Deviation 10.61 |
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Frontal Lobe | 19.5 percentage of occupancy | Standard Deviation 10.61 |
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Hippocampus | 33.0 percentage of occupancy | Standard Deviation 5.66 |
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Occipital Lobe | 37.0 percentage of occupancy | Standard Deviation 14.14 |
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Pons | 25.0 percentage of occupancy | Standard Deviation 39.6 |
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Striatum | 8.0 percentage of occupancy | Standard Deviation 16.97 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Striatum | 50.5 percentage of occupancy | Standard Deviation 3.54 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Cerebellum | 87.0 percentage of occupancy | Standard Deviation 1.41 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Occipital Lobe | 54.5 percentage of occupancy | Standard Deviation 4.95 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Pons | 37.5 percentage of occupancy | Standard Deviation 4.95 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Frontal Lobe | 44.0 percentage of occupancy | Standard Deviation 9.9 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Hippocampus | 59.5 percentage of occupancy | Standard Deviation 26.16 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Frontal Lobe | 38.0 percentage of occupancy | Standard Deviation 9.9 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Hippocampus | 40.0 percentage of occupancy | Standard Deviation 0 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Striatum | 39.0 percentage of occupancy | Standard Deviation 0 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Occipital Lobe | 43.5 percentage of occupancy | Standard Deviation 6.36 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Cerebellum | 79.5 percentage of occupancy | Standard Deviation 2.12 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 1 | Pons | 31.0 percentage of occupancy | Standard Deviation 1.41 |
Primary
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.
Time frame: Day 2
Population: The PD set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Cerebellum | 42.5 percentage of occupancy | Standard Deviation 13.44 |
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Frontal Lobe | 0.5 percentage of occupancy | Standard Deviation 19.09 |
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Hippocampus | 13.0 percentage of occupancy | Standard Deviation 21.21 |
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Occipital Lobe | 16.0 percentage of occupancy | Standard Deviation 19.8 |
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Pons | 25.0 percentage of occupancy | Standard Deviation 28.28 |
| TAK-418 1.5 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Striatum | -9.0 percentage of occupancy | Standard Deviation 35.36 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Striatum | 42.0 percentage of occupancy | Standard Deviation 19.8 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Cerebellum | 71.5 percentage of occupancy | Standard Deviation 4.95 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Occipital Lobe | 47.0 percentage of occupancy | Standard Deviation 11.31 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Pons | 32.5 percentage of occupancy | Standard Deviation 16.26 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Frontal Lobe | 42.0 percentage of occupancy | Standard Deviation 9.9 |
| TAK-418 10 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Hippocampus | 44.5 percentage of occupancy | Standard Deviation 6.36 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Frontal Lobe | 51.0 percentage of occupancy | Standard Deviation 9.9 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Hippocampus | 50.5 percentage of occupancy | Standard Deviation 4.95 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Striatum | 56.5 percentage of occupancy | Standard Deviation 6.36 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Occipital Lobe | 53.5 percentage of occupancy | Standard Deviation 7.78 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Cerebellum | 82.0 percentage of occupancy | Standard Deviation 1.41 |
| TAK-418 30 mg | Percent Enzyme Occupancy Based on Quantitative Estimates of Binding for TAK-418 on Day 2 | Pons | 55.0 percentage of occupancy | Standard Deviation 2.83 |
Primary
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'.
Time frame: Day -1
Population: The pharmacodynamics (PD) set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Cerebellum | 0.03405 mL/cm^3/min | Standard Deviation 0.002192 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Frontal Lobe | 0.01930 mL/cm^3/min | Standard Deviation 0.004525 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Hippocampus | 0.01900 mL/cm^3/min | Standard Deviation 0.000141 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Occipital Lobe | 0.02140 mL/cm^3/min | Standard Deviation 0.002404 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Pons | 0.01685 mL/cm^3/min | Standard Deviation 0.000071 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Striatum | 0.01575 mL/cm^3/min | Standard Deviation 0.004031 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Striatum | 0.01930 mL/cm^3/min | Standard Deviation 0.00495 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Cerebellum | 0.03515 mL/cm^3/min | Standard Deviation 0.005869 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Occipital Lobe | 0.02225 mL/cm^3/min | Standard Deviation 0.003606 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Pons | 0.01855 mL/cm^3/min | Standard Deviation 0.004313 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Frontal Lobe | 0.02070 mL/cm^3/min | Standard Deviation 0.004384 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Hippocampus | 0.01935 mL/cm^3/min | Standard Deviation 0.005303 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Frontal Lobe | 0.02140 mL/cm^3/min | Standard Deviation 0.002263 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Hippocampus | 0.01960 mL/cm^3/min | Standard Deviation 0.001414 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Striatum | 0.01995 mL/cm^3/min | Standard Deviation 0.003323 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Occipital Lobe | 0.02365 mL/cm^3/min | Standard Deviation 0.002616 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Cerebellum | 0.03560 mL/cm^3/min | Standard Deviation 0.003394 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models At Baseline Scan on Day -1 | Pons | 0.01870 mL/cm^3/min | Standard Deviation 0.004667 |
Primary
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'.
Time frame: Day 1
Population: The PD set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Cerebellum | 0.01020 mL/cm^3/min | Standard Deviation 0.003536 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Frontal Lobe | 0.01295 mL/cm^3/min | Standard Deviation 0.001768 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Hippocampus | 0.01260 mL/cm^3/min | Standard Deviation 0.00099 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Occipital Lobe | 0.01245 mL/cm^3/min | Standard Deviation 0.002758 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Pons | 0.01265 mL/cm^3/min | Standard Deviation 0.006718 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Striatum | 0.01185 mL/cm^3/min | Standard Deviation 0.002192 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Striatum | 0.00785 mL/cm^3/min | Standard Deviation 0.000495 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Cerebellum | 0.00405 mL/cm^3/min | Standard Deviation 0.000495 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Occipital Lobe | 0.00910 mL/cm^3/min | Standard Deviation 0.00099 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Pons | 0.00970 mL/cm^3/min | Standard Deviation 0.000707 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Frontal Lobe | 0.00980 mL/cm^3/min | Standard Deviation 0.001697 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Hippocampus | 0.00635 mL/cm^3/min | Standard Deviation 0.004031 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Frontal Lobe | 0.01435 mL/cm^3/min | Standard Deviation 0.002333 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Hippocampus | 0.01240 mL/cm^3/min | Standard Deviation 0 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Striatum | 0.01365 mL/cm^3/min | Standard Deviation 0.000071 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Occipital Lobe | 0.01430 mL/cm^3/min | Standard Deviation 0.001556 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Cerebellum | 0.00760 mL/cm^3/min | Standard Deviation 0.000849 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 1 | Pons | 0.01515 mL/cm^3/min | Standard Deviation 0.000212 |
Primary
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'.
Time frame: Day 2
Population: The PD set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Cerebellum | 0.01865 mL/cm^3/min | Standard Deviation 0.004455 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Frontal Lobe | 0.01610 mL/cm^3/min | Standard Deviation 0.003111 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Hippocampus | 0.01650 mL/cm^3/min | Standard Deviation 0.00396 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Occipital Lobe | 0.01665 mL/cm^3/min | Standard Deviation 0.003889 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Pons | 0.01265 mL/cm^3/min | Standard Deviation 0.004738 |
| TAK-418 1.5 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Striatum | 0.01410 mL/cm^3/min | Standard Deviation 0.004667 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Striatum | 0.00915 mL/cm^3/min | Standard Deviation 0.003182 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Cerebellum | 0.00875 mL/cm^3/min | Standard Deviation 0.001485 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Occipital Lobe | 0.01045 mL/cm^3/min | Standard Deviation 0.002192 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Pons | 0.01045 mL/cm^3/min | Standard Deviation 0.002475 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Frontal Lobe | 0.01020 mL/cm^3/min | Standard Deviation 0.001838 |
| TAK-418 10 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Hippocampus | 0.00865 mL/cm^3/min | Standard Deviation 0.001061 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Frontal Lobe | 0.01130 mL/cm^3/min | Standard Deviation 0.002404 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Hippocampus | 0.01015 mL/cm^3/min | Standard Deviation 0.000919 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Striatum | 0.00965 mL/cm^3/min | Standard Deviation 0.001344 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Occipital Lobe | 0.01180 mL/cm^3/min | Standard Deviation 0.00198 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Cerebellum | 0.00690 mL/cm^3/min | Standard Deviation 0.000566 |
| TAK-418 30 mg | Quantitative Estimates of Binding of [18F]MNI-1054 Based on PET Radiotracer Kinetic Models on Day 2 | Pons | 0.00985 mL/cm^3/min | Standard Deviation 0.000636 |
Secondary
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.
Time frame: Days 1 to 2
Population: The PD set included all participants who received TAK-418 and have at least 1 analyzable PET Scan following TAK-418
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| TAK-418 1.5 mg | ED50 PET Enzyme Occupancy | Cerebellum | 0.756 milligram (mg) |
| TAK-418 1.5 mg | ED50 PET Enzyme Occupancy | Frontal Lobe | 4.328 milligram (mg) |
| TAK-418 1.5 mg | ED50 PET Enzyme Occupancy | Hippocampus | 1.639 milligram (mg) |
| TAK-418 1.5 mg | ED50 PET Enzyme Occupancy | Occipital Lobe | 1.416 milligram (mg) |
| TAK-418 1.5 mg | ED50 PET Enzyme Occupancy | Pons | 1.112 milligram (mg) |
| TAK-418 1.5 mg | ED50 PET Enzyme Occupancy | Striatum | 7.496 milligram (mg) |
Secondary
Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: From first dose of [18F]MNI-1054 radiotracer injection up to Day 14
Population: The safety set included all enrolled participants who received at least 1 dose of \[18F\]MNI-1054 or TAK-418
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TAK-418 1.5 mg | Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 Participants |
| TAK-418 1.5 mg | Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| TAK-418 10 mg | Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| TAK-418 10 mg | Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 0 Participants |
| TAK-418 30 mg | Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 1 Participants |
| TAK-418 30 mg | Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| TAK-418 30 mg | Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 Participants |
| TAK-418 30 mg | Number of Participants Reporting One or More Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormal Laboratory Values
Time frame: From first dose of [18F]MNI-1054 radiotracer injection up to Day 14
Population: The safety set included all enrolled participants who received at least 1 dose of \[18F\]MNI-1054 or TAK-418
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TAK-418 1.5 mg | Number of Participants With Clinically Significant Abnormal Laboratory Values | 0 Participants |
| TAK-418 10 mg | Number of Participants With Clinically Significant Abnormal Laboratory Values | 0 Participants |
| TAK-418 30 mg | Number of Participants With Clinically Significant Abnormal Laboratory Values | 0 Participants |
| TAK-418 30 mg | Number of Participants With Clinically Significant Abnormal Laboratory Values | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormal Vital Signs
Time frame: From first dose of [18F]MNI-1054 radiotracer injection up to Day 14
Population: The safety set included all enrolled participants who received at least 1 dose of \[18F\]MNI-1054 or TAK-418.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TAK-418 1.5 mg | Number of Participants With Clinically Significant Abnormal Vital Signs | 0 Participants |
| TAK-418 10 mg | Number of Participants With Clinically Significant Abnormal Vital Signs | 0 Participants |
| TAK-418 30 mg | Number of Participants With Clinically Significant Abnormal Vital Signs | 0 Participants |
| TAK-418 30 mg | Number of Participants With Clinically Significant Abnormal Vital Signs | 0 Participants |