A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-994 in Healthy Participants

Phase 1

Completed

• Conditions: Healthy Participants
• Interventions: Drug: TAK-994; Drug: TAK-994 Placebo

• Registration Number: NCT03933488
• Lead Sponsor: Takeda

Brief Summary

The purpose of this study is to assess the safety and tolerability of TAK-994 following single and multiple oral doses in healthy non-Japanese and Japanese adult participants and healthy elderly participants.

Detailed Description

The drug being tested in this study is called TAK-994. TAK-994 is being tested to find a safe and well-tolerated dose in healthy participants (non-Japanese and Japanese) and healthy elderly participants. The study will enroll up to approximately 160 healthy participants. The study consists of 6 parts and up to 20 cohorts as mentioned below.

* TAK-994: Part A: Single-rising dose (SRD) design to assess the safety, tolerability, and PK of TAK-994 and effect of food on the PK of the TAK-994

* TAK-994: Part B: MRD design to assess the safety, tolerability, PK and PD of TAK-994

* TAK-994: Part C: MRD design to assess the safety, tolerability, PK and PD of TAK-994 and also central nervous system penetration relative to plasma concentrations of TAK-994

* TAK-994: Part D: MRD design to assess the safety, tolerability, PK and PD of TAK-994 for HE participants

* TAK-994: Part E: SRD and MRD design to assess the safety, tolerability, PK and PD of TAK-994 for Japanese origin participants

* TAK-994: Part F (Optional Cohort): Nonrandomized design to assess orexin (OX) levels in the cerebrospinal fluid (CSF) of untreated healthy adult participants.

Participants in each cohort will be randomized to receive treatment with TAK-994 or matching placebo which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need). Participants in optional Part F will receive no study drug.

This multi-center trial will be conducted in the United States. The overall duration of the study is approximately 10 months. Participants will be followed up for 7 days after the last dose of study drug for a follow-up assessment.

Study Timeline

• Study First Submitted: 2019-04-29
• Study First Submitted QC: 2019-04-29
• Study Start: 2019-05-01
• Study First Posted: 2019-05-01
• Primary Completion: 2020-03-29
• Study Completion: 2020-03-29
• Status Verified: 2020-06
• Last Update Submitted: 2020-06-22
• Last Update Posted: 2020-06-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 121

Inclusion Criteria

1. Be normotensive, with no history of hypertension or use of antihypertensive medication. Blood pressure (BP) must be less than (<) 140 millimeter of mercury (mmHg) (systolic) and <90 mmHg (diastolic).

   Healthy Adult and Elderly Participants (Parts A through D and Part F)

2. Must have a body mass index (BMI) greater than or equal to (>=) 18.0 and less than or equal to (<=) 30.0 kilogram per square meter (kg/m^2) at the screening visit (non-Japanese only).

   Healthy Adult Participants (Parts A, B, C, and F)

3. Must be aged 18 to 55 years, inclusive, at the screening visit.

4. Must have a body weight >=50 kilogram (kg) at the screening visit.

   HE Participants (Part D)

5. Must be aged >=65 years, inclusive, at the time of informed consent.

6. Must have a body weight >=40 kg at the screening visit.

   Healthy Japanese Adult Participants (Part E)

7. Must be aged 18 to 55 years, inclusive, at the screening visit.

8. Must have a BMI >=18.0 and <=26.0 kg/m^2 at the screening visit.

9. Must have been born in Japan to a Japanese mother and father and have maternal and paternal Japanese grandparents.

10. Must have not been away from Japan for more than 10 years at the screening visit.

11. In the opinion of the investigator, must have a lifestyle that has not changed significantly since relocation from Japan.

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Exclusion Criteria

1. Has a known hypersensitivity to any component of the formulation of TAK-994 or related compounds.

2. Has a risk of suicide according to endorsement of Item 4 or 5 of the screening/baseline visit Columbia Suicide Severity Rating Scale (C-SSRS) or has made a suicide attempt in the previous 6 months.

3. Has a lifetime history of major psychiatric disorder, such as bipolar disorder or schizophrenia. Participant who have history of major depressive disorder (MDD) may be included, but participants who have current active MDD or who have had active MDD in the past 6 months are excluded.

4. Has a clinically significant history of head injury or head trauma.

5. Has a history of cerebral ischemia, transient ischemic attack, intracranial aneurysm, or arteriovenous malformation.

6. Screening electrocardiogram (ECG) reveals a QT interval with the Fridericia's correction method (QTcF) greater than (>) 450 millisecond (ms) (men) or >470 ms (women).

7. Has a resting heart rate outside of the range of 45 to 100 beats per minute, confirmed on repeat testing within a maximum of 30 minutes).

   Healthy Non-Japanese Adult Participants (Part C and Part F)

8. Has undergone CSF collection within 30 days before check-in (Day -2 [Part C] or Day -1 [Part F]).

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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
TAK-994: Part A	TAK-994 Placebo	TAK-994 tablet or matching placebo, orally, once on Day 1 to healthy non-Japanese participants. Sentinel dosing will be done in the first 2 cohorts of Part A (Cohorts A1 and A2 \[fasted and fed dosing conditions\]). Dose escalation in Cohorts A2 to A6 will be based on emerging safety, tolerability, and PK (pharmacokinetic) data from previous cohorts.
TAK-994: Part B	TAK-994	TAK-994 tablet or matching placebo, orally, once daily or twice daily from Day 1 to Day 14 to healthy non-Japanese participants. Dose escalation will be based on review of the emerging safety, PK, and PD (pharmacodynamic) data from Part A. Fixed-dose titration regimens may also be evaluated based on review of the emerging safety, PK, and tolerability data from previous cohorts.
TAK-994: Part C	TAK-994 Placebo	TAK-994 tablet or matching placebo, orally, once daily or twice daily from Day 1 to Day 7 to healthy non-Japanese participants. Dose will be determined based on previous multiple-rising dose (MRD) cohorts.
TAK-994: Part B	TAK-994 Placebo	TAK-994 tablet or matching placebo, orally, once daily or twice daily from Day 1 to Day 14 to healthy non-Japanese participants. Dose escalation will be based on review of the emerging safety, PK, and PD (pharmacodynamic) data from Part A. Fixed-dose titration regimens may also be evaluated based on review of the emerging safety, PK, and tolerability data from previous cohorts.
TAK-994: Part D	TAK-994	TAK-994 tablet or matching placebo, orally, once daily or twice daily from Day 1 to Day 14 to healthy non-Japanese elderly participants. Dose will be determined based on previous MRD cohorts. Fixed-dose titration regimens may also be evaluated based on review of the emerging safety, PK, and tolerability data from previous cohorts.
TAK-994: Part E	TAK-994	TAK-994 tablet or matching placebo, orally, once or twice on Day 1, followed by a washout period of 2 days and on Day 4 and continue to Day 17 to healthy Japanese participants. Dose will be determined based on previous MRD cohorts. Fixed-dose titration regimens may also be evaluated based on review of the emerging safety, PK, and tolerability data from previous cohorts.
TAK-994: Part C	TAK-994	TAK-994 tablet or matching placebo, orally, once daily or twice daily from Day 1 to Day 7 to healthy non-Japanese participants. Dose will be determined based on previous multiple-rising dose (MRD) cohorts.
TAK-994: Part A	TAK-994	TAK-994 tablet or matching placebo, orally, once on Day 1 to healthy non-Japanese participants. Sentinel dosing will be done in the first 2 cohorts of Part A (Cohorts A1 and A2 \[fasted and fed dosing conditions\]). Dose escalation in Cohorts A2 to A6 will be based on emerging safety, tolerability, and PK (pharmacokinetic) data from previous cohorts.
TAK-994: Part D	TAK-994 Placebo	TAK-994 tablet or matching placebo, orally, once daily or twice daily from Day 1 to Day 14 to healthy non-Japanese elderly participants. Dose will be determined based on previous MRD cohorts. Fixed-dose titration regimens may also be evaluated based on review of the emerging safety, PK, and tolerability data from previous cohorts.
TAK-994: Part E	TAK-994 Placebo	TAK-994 tablet or matching placebo, orally, once or twice on Day 1, followed by a washout period of 2 days and on Day 4 and continue to Day 17 to healthy Japanese participants. Dose will be determined based on previous MRD cohorts. Fixed-dose titration regimens may also be evaluated based on review of the emerging safety, PK, and tolerability data from previous cohorts.

Primary Outcome Measures

Name	Time	Method
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE)	Baseline up to Day 26
Number of Participants With at Least one Markedly Abnormal Laboratory Value	Baseline up to Day 26
Number of Participants With at Least one Markedly Abnormal Laboratory Value for Vital Signs	Baseline up to Day 26
Number of Participants With at Least one Markedly Abnormal Laboratory Value for Electrocardiogram (ECG)	Baseline up to Day 26

Secondary Outcome Measures

Name	Time	Method
Cmax: Maximum Observed Plasma Concentration for TAK-994	Day 1 (Parts A-E), Day 7 (Part C), Day 14 (Parts B and D), Day 17 (Part E) pre-dose and at multiple time points (up to 72 hours) post-dose
T1/2z: Terminal Disposition Phase Half-life for TAK-994	Day 1 (Parts A-E) pre-dose and at multiple time points (up to 72 hours) post-dose
AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to tau over Dosing Interval for TAK-994	Day 7 (Part C), Day 14 (Parts B and D), Day 17 (Part E) pre-dose and at multiple time points (up to 72 hours) post-dose
Part C: Ratio of the Cerebrospinal Fluid (CSF) to plasma AUC From time 0 to 24 hours for TAK-994	Day 7 (Part C) Pre-dose and at multiple time points (up to 24 hours) post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-994	Day 1 (Parts A-E), Day 7 (Part C), Day 14 (Parts B and D), Day 17 (Part E) pre-dose and at multiple time points (up to 72 hours) post-dose
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-994	Day 1 (Parts A-E) pre-dose and at multiple time points (up to 72 hours) post-dose
CLR: Renal Clearance for TAK-994	Day 1 (Parts A, B, D and E), Day 14 (Parts B and D), Day 17 (Part E) pre-dose and at multiple time points (up to 72 hours) post-dose
Rac(AUC): Accumulation ratio based on AUCτ for TAK-994	Day 7 (Part C), Day 14 (Parts B and D), Day 17 (Part E) pre-dose and at multiple time points (up to 72 hours) post-dose
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-994	Day 1 (Parts A-E) pre-dose and at multiple time points (up to 72 hours) post-dose

Trial Locations

Locations (2)

Parexel International; 🇺🇸 Glendale, California, United States

PRA Health Sciences; 🇺🇸 Salt Lake City, Utah, United States