First-in-Human Study With Single and Multiple Doses of TS-161 in Healthy Participants

Study Overview
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Brief Summary
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This is a Phase 1, first-in-human study involving single and multiple oral doses of TS-161 in healthy male and female participants. The safety, tolerability, pharmacokinetics and pharmacodynamics of TS-161 will be evaluated. The study includes 3 parts; Part A (single ascending dose: Cohorts 1 to 5) , Part B (single dose, cerebrospinal fluid [CSF] collection: Cohort 6), and Part C (multiple ascending dose: Cohorts 7 to 9). Participants will be assigned to one of the 9 Cohorts.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TS-161 Administered Orally to Healthy Male and Female Participants

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: TS-161
* Drug: TS-161 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult male and female participants between 18 and 55 years of age, inclusive Body weight ≥ 45 kg Body Mass Index (BMI) 18 - 30 kg/m^2, inclusive Exclusion Criteria: Significant history or presence of medical disorders or condition capable of significantly affecting the absorption, metabolism, or elimination of drugs History or presence of psychiatric or neurologic disease or condition History of seizures Abnormal EEG observed at screening Abnormal blood pressure Breast cancer within the past 10 years, or any other malignancies within the past 5 years Clinically significant abnormal results in electrocardiogram, blood and urine test History or presence of liver disease Participants using medication or supplements within 14 days prior to dosing Use of N-methyl-D-aspartate (NMDA) receptor modulators (example: dextromethorphan, ketamine, amantadine, memantine) within 90 days of screening Loss of blood or blood products in excess of 450 mL within 60 days prior to screening Used any investigational drug within 60 days prior to screening Recent history of alcohol or drug abuse Any participant who currently uses or has used tobacco products or nicotine-containing products (cigarettes, pipes, e-cigarettes, nicotine patches, etc.) for one month or more prior to screening Exclusion Criteria for Part B only: Significant abnormalities in lumbar spine History of clinically significant back pain, back pathology, and/or back injury History of migraines, and/or frequent, severe headaches History or presence of significant active bleeding or coagulation disorder or use of non-steroidal anti-inflammatory drugs or other drugs that affect coagulation or platelet function within 14 days prior to lumbar catheter insertion Allergy to lidocaine (Xylocaine®) or related drugs History of adverse reaction to lumbar puncture or epidural procedure

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Cohort 1: TS-161 15 mg<br>Single dose of TS-161 15 mg or placebo in a fasted condition. | Drug: TS-161<br>* TS-161 capsules<br>Drug: TS-161 Placebo<br>* TS-161 matching placebo capsules<br>|
| Experimental: Part A: Cohort 2: TS-161 50 mg<br>Single dose of TS-161 50 mg or placebo which will be dosed first in a fasted condition, and then in a fed condition, with a washout period in between 2 dosing. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts. | Drug: TS-161<br>* TS-161 capsules<br>Drug: TS-161 Placebo<br>* TS-161 matching placebo capsules<br>|
| Experimental: Part A: Cohort 3: TS-161 100 mg<br>Single dose of TS-161 100 mg or placebo in a fasted condition. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts. | Drug: TS-161<br>* TS-161 capsules<br>Drug: TS-161 Placebo<br>* TS-161 matching placebo capsules<br>|
| Experimental: Part A: Cohort 4: TS-161 200 mg<br>Single dose of TS-161 200 mg or placebo in a fasted condition. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts. | Drug: TS-161<br>* TS-161 capsules<br>Drug: TS-161 Placebo<br>* TS-161 matching placebo capsules<br>|
| Experimental: Part A: Cohort 5: TS-161 400 mg<br>Single dose of TS-161 400 mg or placebo in a fasted condition. Although planned, all subsequent dose levels after Cohort 1 will be determined based on the results from the preceding cohorts. | Drug: TS-161<br>* TS-161 capsules<br>Drug: TS-161 Placebo<br>* TS-161 matching placebo capsules<br>|
| Experimental: Part B: Cohort 6: TS-161 TBD<br>Single dose of TS-161 in a fasted condition. The dose level will be determined based on the results from the preceding cohorts. | Drug: TS-161<br>* TS-161 capsules<br>|
| Experimental: Part C: Cohort 7: TS-161 TBD<br>Daily doses of TS-161 or placebo for 10 days in a fed condition. The dose level will be determined based on the results from the preceding cohorts. | Drug: TS-161<br>* TS-161 capsules<br>Drug: TS-161 Placebo<br>* TS-161 matching placebo capsules<br>|
| Experimental: Part C: Cohort 8: TS-161 TBD<br>Daily doses of TS-161 or placebo for 10 days in a fed condition. The dose level will be determined based on the results from the preceding cohorts. | Drug: TS-161<br>* TS-161 capsules<br>Drug: TS-161 Placebo<br>* TS-161 matching placebo capsules<br>|
| Experimental: Part C: Cohort 9: TS-161 TBD<br>Daily doses of TS-161 or placebo for 10 days in a fed condition. The dose level will be determined based on the results from the preceding cohorts. | Drug: TS-161<br>* TS-161 capsules<br>Drug: TS-161 Placebo<br>* TS-161 matching placebo capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of Adverse Events |  | Parts A and B: Day 1 to Day 8; Part C: Day 1 to Day 17 | 
| TS-161 Plasma Pharmacokinetic Profile - Cmax | Maximum plasma concentration | Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose; Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose | 
| TS-161 Plasma Pharmacokinetic Profile - Tmax | Time to maximum plasma concentration | Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose; Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose | 
| TS-161 Plasma Pharmacokinetic Profile - AUC(0-last) | Area under the plasma concentration versus time curve from time zero to last measurable concentration | Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose | 
| TS-161 Plasma Pharmacokinetic Profile - AUC(0-tau) | Area under the plasma concentration versus time curve over a dosing interval | Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose | 
| TS-161 Plasma Pharmacokinetic Profile - T1/2 | Apparent terminal elimination half-life | Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose; Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose | 
| TS-161 Plasma Pharmacokinetic Profile - CL/F | Apparent clearance following oral administration | Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose; Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose | 
| TS-161 Plasma Pharmacokinetic Profile - Vd,z/F | Apparent volume of distribution following oral administration | Parts A and B: Day 1 predose and at multiple time points (up to 48 hours) postdose; Part C: Day 1 predose and at multiple time points (up to 12 hours) postdose, Day 2 to Day 9 predose, Day 10 predose and at multiple time points (up to 48 hours) postdose | 
| TS-161 Urine Pharmacokinetic Profile - Ae | Amount excreted in urine | Part A: Day 1 predose and pooled for multiple intervals (up to 48 hours) postdose; Part C: Day 1 predose and pooled for multiple intervals (up to 48 hours after last dose) postdose | 
| TS-161 Urine Pharmacokinetic Profile - Fe% | Percent of dose excreted in urine | Part A: Day 1 predose and pooled for multiple intervals (up to 48 hours) postdose; Part C: Day 1 predose and pooled for multiple intervals (up to 48 hours after last dose) postdose | 
| TS-161 Urine Pharmacokinetic Profile - CLr | Renal Clearance | Part A: Day 1 predose and pooled for multiple intervals (up to 48 hours) postdose; Part C: Day 1 predose and pooled for multiple intervals (up to 48 hours after last dose) postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TS-161 CSF Pharmacokinetic Profile - Cmax | Maximum CSF concentration | Part B: Day 1 predose and at multiple time points (up to 24 hours) postdose | 
| TS-161 CSF Pharmacokinetic Profile - Tmax | Time to maximum CSF concentration | Part B: Day 1 predose and at multiple time points (up to 24 hours) postdose | 
| TS-161 CSF Pharmacokinetic Profile - AUC(0-last) | Area under the CSF concentration versus time curve from time zero to last | Part B: Day 1 predose and at multiple time points (up to 24 hours) postdose | 
| TS-161 CSF Pharmacokinetic Profile - T1/2 | Apparent terminal elimination half-life | Part B: Day 1 predose and at multiple time points (up to 24 hours) postdose | 
| Changes from baseline in relative and absolute powers of the delta, theta, alpha, beta and gamma bands using quantitative electroencephalogram (qEEG) compared to placebo |  | Part A: predose and at multiple time points (up to 8 hours) postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TS-161, CSF, first-in-human