An [^11C]T-773 Positron Emission Tomography (PET) Study to Determine Phosphodiesterase10A Occupancy by TAK-063

Study Overview
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Brief Summary
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The purpose of this study is to estimate phosphodiesterase 10A (PDE10A) occupancy in brain following a single dose of TAK-063.

Detailed Description
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The drug being tested in this study is called TAK-063. TAK-063 is was tested to estimate phosphodiesterase10A (PDE10A) occupancy in the brain following a single dose of TAK-063. This study used positron emission tomography (PET) scans to look at changes in the volume of tissue distribution before and after TAK-063 administration to calculate PDE10A occupancy in the brain. The study enrolled 13 participants. Participants were assigned to a treatment group based on an enrollment schedule. The first 4 participants were assigned to the Pilot Cohort and received one dose of TAK-063 30 mg or 1000 mg tablets. The remaining participants were enrolled into the Main Cohort and received one dose of TAK-063 at 3, 10, 30 or 100 mg. Participants in both cohorts also received 3 separate intravenous infusions of [^11C]T-773 <8 μg; 400MBq ± 10% followed by a PET scan. This single-centre trial was conducted in Sweden. The overall time to participate in this study was 46 days. Participants made 3 visits to the clinic, including one 3-day period of confinement to the clinic. Participants were contacted by phone on Day 16 for follow-up safety assessments.

Official Title
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An Open-Label [^11C]T-773 Positron Emission Tomography Study to Determine Phosphodiesterase10A Occupancy by TAK-063 After a Single Oral Dose in Human Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: TAK-063
* Drug: [^11C]T-773


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has never previously participated in a positron emission tomography (PET) study (lifetime). In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. The participant, informed consent form and any required privacy authorization prior to the initiation of any study procedures. Is a healthy adult male, as determined by a physician based upon medical history and physical examination findings at Screening. Is aged 20 to 45 years, inclusive, at the time of informed consent. Weighs at least 50 kg and less than 100 kg and has a body mass index (BMI) between 18 and 32 kg/m^2 inclusive at Screening. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose. Has clinical laboratory evaluations (including clinical chemistry, hematology and complete urinalysis) within the reference range for the testing laboratory, unless the results are deemed not to be clinically significant (CS) by the investigator or sponsor at screening. Participants must have normal hemoglobin levels. Has a normal magnetic resonance imaging (MRI) scan or findings that are deemed not clinically significant at screening (the MRI scan may be performed on a day after other screening activities have been performed but before dosing). Exclusion Criteria: Has received any investigational compound within 90 days prior to Screening. Has received TAK-063 in a previous clinical study or as a therapeutic agent. Is an immediate family member, study site employee, or in a dependant relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease, or psychiatric disorder, or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results. Has a known hypersensitivity to any component of the formulation of TAK-063 or [^11C]T-773. Has a positive urine drug result for drugs of abuse or a positive breathalyzer test for alcohol at Screening or Day -1. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the screening visit or is unwilling to agree to abstain from alcohol until discharge from the Phase 1 unit and drugs throughout the study. Has taken any excluded medication, supplements, or food products listed in the Excluded Medications and Dietary Products table. Intends to donate sperm during the course of the study or within 12 weeks after last dose. Has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the participant's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking TAK-063 or a similar drug in the same class, or that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias. The participant, in the opinion of the investigator, has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis frequent [more than once per week] occurrence of heartburn, or any surgical intervention [eg, cholecystectomy]). Has a history of cancer, except basal cell carcinoma which has been in remission for at least 5 years prior to Day 1. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV), human immunodeficiency virus (HIV) antibody/antigen, at Screening. Has used nicotine-containing products (including but not limited to cigarettes, pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to Check-In Day -1. Has poor peripheral arterial/venous access or recent arm or wrist trauma. Has donated or lost 450 mL or more of his blood volume (including plasmapheresis), or had a transfusion of any blood product within 3 months prior to Day 1. Has a Screening or Check-in (Day -1) abnormal (clinically significant) electrocardiogram (ECG). Has a supine blood pressure outside the ranges of 90 to 140 mm Hg for systolic and 50 to 90 mm Hg for diastolic, if out of range may be repeated once for eligibility determination within a maximum of 5 minutes, at the Screening Visit or Check-in (Day -1). Has a resting heart rate outside the range 45 to 90 beats per minute (bpm), if out of range may be repeated once for eligibility determination within a maximum of 5 minutes, at the Screening Visit or Check-in (Day -1). Has an increase in pulse of ≥30 beats per minute or an increase in pulse ≥120 beats per minute within 3 minutes of standing at Screening. Has a decrease of ≥20 mm Hg in systolic blood pressure or a decrease of ≥10 mm Hg in diastolic blood pressure within 3 minutes of standing at Screening. Has a QT interval with Fridericia correction method (QTcF) >430 ms or PQ interval outside the range 120 to 220 ms, if out of range may be repeated once for eligibility determination within a maximum of 5 minutes, at the Screening Visit or Check-in (Day -1) Visit. Has abnormal Screening laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >1.5 the upper limits of normal. Has had administration of radioactive substances or exposure to significant radiation (eg, serial x-ray or computed tomography [CT] scans, barium meal) within the past 12 months prior to Day 1 predose. Has any condition that would prevent an MRI from accurately or safely being performed (eg, claustrophobia, cardiac pacemaker, metallic implants or clips) Has any condition that would prevent the performance of a safe or accurate PET scan. Has any clinically significant MRI finding that in the opinion of the investigator would exclude the participant. Is unwilling to refrain from strenuous exercise from 120 hours before Check-in (Day -1) until discharge from the Phase 1 unit. Has a risk of suicide according to the Investigator's clinical judgment (eg, per Columbia-Suicide Severity Rating Scale (C-SSRS) or has made a suicide attempt in the previous 6 months. Has abnormal international normalized ratio (INR) or activated prothrombin time (aPTT) or other risk of bleeding disorder.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pilot Cohort: [^11C]T-773 + TAK-063<br>[^11C]T-773 <8 μg; 400MBq ± 10%, intravenous (IV), once on Days 1 and 2 prior to PET scans and TAK-063 30 mg or 1000 mg, tablets, orally, once on Day 2 and after PET scan #2 and prior to PET scan #3 and [^11C]T-773 IV after TAK-063 and prior to PET scan #3 on Day 2. | Drug: TAK-063<br>* TAK-063 tablets<br>Drug: [^11C]T-773<br>* [^11C]T-773 IV solution<br>|
| Experimental: Main Cohort: TAK-063 + [^11C]T-773<br>TAK-063 3 to 100 mg, tablets, orally, once, on Day 1, and [^11C]T-773 <8 μg; 400MBq ± 10%, intravenously (IV), prior to PET scans, twice on Day 1 (before and after administration of TAK-063) and once on Day 2 . | Drug: TAK-063<br>* TAK-063 tablets<br>Drug: [^11C]T-773<br>* [^11C]T-773 IV solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phosphodiesterase 10A (PDE10A) Occupancy of Brain Regions With [^11C]T-773 at 3 Hours Following a Single Dose of TAK-063 | Volume of tissue distribution (Vt) values will be estimated by several quantitative methods for each positron emission tomography (PET) scan. Based on the change in Vt before and after TAK-063 administration, PDE10A occupancy will be calculated. PET scan #2 in the Pilot Cohort and PET scan #1 in the Main Cohort will be used as a baseline for the occupancy calculation. Occupancy is reported for putamen only. | 3 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phosphodiesterase 10A (PDE10A) Occupancy of Brain Regions With [^11C]T-773 at 23 Hours Following a Single Dose of TAK-063 | Volume of tissue distribution (Vt) values will be estimated by several quantitative methods for each positron emission tomography (PET) scan. Based on the change in Vt before and after TAK-063 administration, PDE10A occupancy will be calculated. PET scan #2 in the Pilot Cohort and PET scan #1 in the Main Cohort will be used as a baseline for the occupancy calculation. Data was not available for participants in the pilot cohort. Occupancy is reported for putamen only. | 23 hours post-dose | 
| Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event | An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event is defined as an adverse event with an onset that occurs after receiving study drug. | First dose of study drug to 30 days after last dose of study drug (up to 46 days) | 
| Percentage of Participants With Markedly Abnormal Safety Laboratory Findings | The percentage of participants with any markedly abnormal standard safety laboratory values was collected throughout study. | From Day 1 to Day 16 | 
| Percentage of Participants With Markedly Abnormal Vital Sign Measurements | The percentage of participants with any markedly abnormal standard vital sign measurements was collected throughout study. BL=baseline. bpm=beats per minute. | From Day 1 to Day 16 | 
| Percentage of Participants With Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters | The percentage of participants with any markedly abnormal standard 12-lead ECG measurements. QTc - Bazett's Interval (msec) is ≥500 msec OR ≥30 msec change from Baseline and ≥450 msec | From Day 1 to Day 16 | 
| Cmax: Maximum Observed Plasma Concentration for TAK-063 and TAK-063 Metabolite M-I | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. | Pilot Cohort: Day 2 predose and at multiple time points (up to 24 hours) post-dose. Main Cohort: Day 1 predose and at multiple time points (up to 24 hours) post-dose. | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-063 and TAK-063 Metabolite M-I | Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax. | Pilot Cohort: Day 2 predose and at multiple time points (up to 24 hours) post-dose. Main Cohort: Day 1 predose and at multiple time points (up to 24 hours) post-dose. | 
| AUC(0-tlqc): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-063 and TAK-063 Metabolite M-I | (AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc]). | Pilot Cohort: Day 2 predose and at multiple time points (up to 24 hours) post-dose. Main Cohort: Day 1 predose and at multiple time points (up to 24 hours) post-dose. | 
| AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Postdose for TAK-063 and TAK-063 Metabolite M-I | AUC(0-24) is a measure of total plasma exposure to the drug from Time 0 to 24 hours post-dose. | Pilot Cohort: Day 2 predose and at multiple time points (up to 24 hours) post-dose. Main Cohort: Day 1 predose and at multiple time points (up to 24 hours) post-dose. | 
| Average Plasma Concentration on Day 1 (Cavg) for TAK-063 and TAK-063 Metabolite M-I | Cavg is the average plasma concentration on Day 1, calculated as AUC(0-24)/24. | Pilot Cohort: Day 2 predose and at multiple time points (up to 24 hours) post-dose. Main Cohort: Day 1 predose and at multiple time points (up to 24 hours) post-dose. | 
| CL/F: Oral Clearance of TAK-063 | CL/F is apparent clearance of the drug from the plasma, calculated as the drug dose divided by area under the curve from time 0 to 24 hours post-dose, after multiple dosing (at steady state). | Pilot Cohort: Day 2 predose and at multiple time points (up to 24 hours) post-dose. Main Cohort: Day 1 predose and at multiple time points (up to 24 hours) post-dose. | 
| Ratio of TAK-063 Metabolite Cmax to TAK-063 Cmax | Cmax Ratio is the ratio of Cmax values of the metabolite compared to the parent calculated by dividing Cmax values of metabolite M-I with those of the parent drug TAK-063. | Pilot Cohort: Day 2 predose and at multiple time points (up to 24 hours) post-dose. Main Cohort: Day 1 predose and at multiple time points (up to 24 hours) post-dose. | 
| Ratio of TAK-063 Metabolite M-I AUC( 0-24) to TAK-063 AUC (0-24) | AUC Ratio is the ratio of AUC values of the metabolite compared to the parent calculated by dividing AUC values of metabolite M-I with those of the parent drug TAK-063. | Pilot Cohort: Day 2 predose and at multiple time points (up to 24 hours) post-dose. Main Cohort: Day 1 predose and at multiple time points (up to 24 hours) post-dose. | 
| AUC During the Positron Emission Tomography (PET) Scan Period (AUC(Scan)) at 3 Hours Post-dose for TAK-063 and TAK-063 Metabolite M-I | AUC values of TAK-063 and TAK-063 metabolite M-I during the PET scan at approximately 3 hours post TAK-063 administration. | 3 hours post-dose | 
| Cavg During the Positron Emission Tomography (PET) Scan Period (AUC(Scan)) at 3 Hours Post-dose for TAK-063 and TAK-063 Metabolite M-I | Cavg values of TAK-063 and TAK-063 metabolite M-I during the PET scan at approximately 3 hours post TAK-063 administration. | 3 hours post-dose | 
| AUC During the Positron Emission Tomography (PET) Scan Period (AUC(Scan)) at 23 Hours Post-dose for TAK-063 and TAK-063 Metabolite M-I | AUC values of TAK-063 and TAK-063 metabolite M-I during the PET scan at approximately 23 hours post TAK-063 administration. Data was not available for participants in the pilot cohort. | 23 hours post-dose | 
| Cavg During the Positron Emission Tomography (PET) Scan Period (AUC(Scan)) at 23 Hours Post-dose for TAK-063 and TAK-063 Metabolite M-I | Cavg values of TAK-063 and TAK-063 metabolite M-I during the PET scan at approximately 23 hours post TAK-063 administration. Data is not available for the pilot cohort. | 23 hours post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy