TAK-935 Multiple Rising Dose Study in Healthy Participants

Phase 1

Completed

• Conditions: Epilepsy
• Interventions: Drug: TAK-935; Drug: Placebo

• Registration Number: NCT02539134
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study is to assess the safety, tolerability and pharmacokinetics (PK) of multiple rising doses of TAK-935 in healthy participants.

Detailed Description

The drug being tested in this study is called TAK-935. This study will look at the pharmacokinetics, safety and tolerability of TAK-935 in healthy participants. The study will enroll approximately 56 participants. Participants will be randomly assigned (by chance, like flipping a coin) to 1 of the 5 cohorts in Part 1, which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Part 1, Cohort 1: TAK-935 100 mg QD

* Part 1, Cohort 2: TAK-935 300 mg QD

* Part 1, Cohort 3: TAK-935 300 mg BID

* Part 1, Cohort 4: TAK-935 600 mg QD

* Part 1, Cohort 5: TAK-935 400 mg QD Participants will be asked to take the oral solution once or twice a day at the same time for 14 days. An optional Part 2 may be conducted for collecting data to assess the engagement by TAK-935 of the central molecular target cholesterol 24S-hydroxylase (CH24H) by measuring the changes of levels of the metabolite 24S-hydroxycholesterol (24HC). In Part 2, participants will be assigned to up to 2 treatment groups at doses based on the data from other ongoing TAK-935 trials, combined with the safety and tolerability data from Cohorts 1-4 of Part 1.

This single center trial will be conducted in the United States. The overall time to participate in this study will be approximately 30 days. Participants will be admitted in the clinic for the first 14 days, and will be contacted by telephone on Day 28 for a follow-up assessment.

Study Timeline

• Study First Submitted: 2015-08-31
• Study First Submitted QC: 2015-08-31
• Study Start: 2015-09
• Study First Posted: 2015-09-02
• Primary Completion: 2016-04
• Study Completion: 2016-04
• Status Verified: 2017-04
• Results First Submitted: 2017-04-19
• Results First Submitted QC: 2017-04-19
• Last Update Submitted: 2017-04-19
• Results First Posted: 2017-07-12
• Last Update Posted: 2017-07-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

All Cohorts

1. 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 aged 18 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 and Day -1.

5. Male participant who is non-sterilized 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 30 days after last dose.

6. Female participant of childbearing potential who is sexually active with a non-sterilized male partner agrees to use routinely adequate contraception from signing of informed consent and throughout the duration of the study, and for 30 days after the last dose.

7. Can complete the CogState Battery at Screening.

   Additional Inclusion Criteria for Participants undergoing cerebrospinal fluid (CSF) Sampling (Part 2 only):

8. Agrees to spinal tap procedures for CSF collection.

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Exclusion Criteria

All Cohorts

1. Has received any investigational compound within 30 days prior to randomization.

2. Has received TAK-935 in a previous clinical study or as a therapeutic agent.

3. Has a significant history of uncontrolled, clinically significant neurologic (including seizure disorders), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease or psychiatric disorder or endocrine disease or other abnormality or any significant results from physical examinations, or clinical laboratory results which may impact the ability of the participant to participate or potentially confound the study results. It is the responsibility of the investigator to assess the clinical significance; however, consultation with the Takeda Medical Monitor may be warranted.

4. Has a known hypersensitivity to any component of the formulation of TAK-935.

5. 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 and drugs throughout the study. One unit is equivalent to a half-pint of beer or a single measure of spirits or 1 small glass of wine.

6. Has taken any excluded medication, supplements, or food products during the time periods listed in the Excluded Medications and Dietary Products table.

   Additional Exclusion Criteria for Participants undergoing CSF sampling (Part 2)

7. Has CSF collection performed within 30 days prior to check-in (Day -3).

8. Has a known hypersensitivity to the anesthetic or its derivatives used during CSF collection, or any medication used to prepare the area of lumbar puncture.

9. Has significant vertebral deformities (scoliosis or kyphosis) which, in the opinion of the investigator, may interfere with lumbar puncture procedure.

10. Has a history of clinically significant back pain and/or injury.

11. Has local infection at the puncture site.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1, Cohort 2: TAK-935 300 mg QD	TAK-935	TAK-935 300 mg, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days.
Part 1, Cohort 3: TAK-935 300 mg BID	Placebo	TAK-935 300 mg, solution, orally, twice daily (BID) or TAK-935 placebo-matching solution, orally, BID for up to 10 days.
Part 1, Cohort 4: TAK-935 600 mg QD	TAK-935	TAK-935 600 mg, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 10 days.
Part 1, Cohort 4: TAK-935 600 mg QD	Placebo	TAK-935 600 mg, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 10 days.
Part 2, Cohort 6: TAK-935 Dose 1	Placebo	TAK-935 first decided dose as determined from other TAK-935 trials and Cohorts 1 to 4 of Part 1, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days.
Part 1, Cohort 1: TAK-935 100 mg QD	TAK-935	TAK-935 100 milligram (mg), solution, orally, once daily (QD) or TAK-935 placebo-matching solution, orally, QD for up to 14 days.
Part 1, Cohort 5: TAK-935 400 mg QD	TAK-935	TAK-935 400 mg, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days.
Part 2, Cohort 6: TAK-935 Dose 1	TAK-935	TAK-935 first decided dose as determined from other TAK-935 trials and Cohorts 1 to 4 of Part 1, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days.
Part 2, Cohort 7: TAK-935 Dose 2	Placebo	TAK-935 second decided dose as determined from other TAK-935 trials and Cohorts 1 to 4 of Part 1, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days.
Part 1, Cohort 1: TAK-935 100 mg QD	Placebo	TAK-935 100 milligram (mg), solution, orally, once daily (QD) or TAK-935 placebo-matching solution, orally, QD for up to 14 days.
Part 1, Cohort 2: TAK-935 300 mg QD	Placebo	TAK-935 300 mg, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days.
Part 1, Cohort 5: TAK-935 400 mg QD	Placebo	TAK-935 400 mg, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days.
Part 2, Cohort 7: TAK-935 Dose 2	TAK-935	TAK-935 second decided dose as determined from other TAK-935 trials and Cohorts 1 to 4 of Part 1, solution, orally, QD or TAK-935 placebo-matching solution, orally, QD for up to 14 days.
Part 1, Cohort 3: TAK-935 300 mg BID	TAK-935	TAK-935 300 mg, solution, orally, twice daily (BID) or TAK-935 placebo-matching solution, orally, BID for up to 10 days.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Experience at Least One Treatment-emergent Adverse Event (TEAE)	Day 1 up to Day 28
Percentage of Participants Who Meet the Takeda Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose	Baseline up to Day 15
Percentage of Participants Who Meet the Takeda Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose	Baseline up to Day 15
Percentage of Participants Who Meet the Takeda Markedly Abnormal Criteria for Safety 12-lead Electrocardiogram (ECG) Parameters at Least Once Post Dose	Baseline up to Day 15

Secondary Outcome Measures

Name	Time	Method
Cmax: Maximum Observed Plasma Concentration for TAK-935	Day 1 and Day 14: Pre-dose and at multiple time points (up to 24 hours for Cohorts 1, 2, 4, and 5; up to 12 hours for Cohort 3) post-dose
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-935	Day 1 and Day 14: Pre-dose and at multiple time points (up to 24 hours for Cohorts 1, 2, 4, and 5; up to 12 hours for Cohort 3) post-dose
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-935	Day 1: Pre-dose and at multiple time points (up to 24 hours for Cohorts 1, 2, 4, and 5; up to 12 hours for Cohort 3) post-dose
AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Over the Dosing Interval for TAK-935	Day 14: Pre-dose and at multiple time points (up to 24 hours for Cohorts 1, 2, 4, and 5; up to 12 hours for Cohort 3) post-dose