Clinical trial NCT02566759: A TAK-831-1001, Single and Multiple Rising Dose Study in Healthy Participants
Official title: A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Safety, Tolerability and Pharmacokinetic Study of Escalating Single and Multiple Doses of TAK-831 in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Schizophrenia, Cerebellar Ataxia
Keywords: Drug therapy
Lead sponsor: Neurocrine Biosciences
Sponsor class: INDUSTRY
Collaborators: name: Takeda
First posted: 2015-10-02
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The purpose of this study is to determine the safety, tolerability and pharmacokinetics (PK) of single and multiple rising doses of TAK-831 in healthy participants.

Detailed description: The drug being tested in this study is called TAK-831. TAK-831 is being tested to treat participant who have schizophrenia and cerebellar ataxia. This study will look at the PK, safety and tolerability of TAK-831 in healthy participants. The study will enroll approximately 120 participants. The study will include 4 parts: Part 1 (single-rising dose \[SRD\]), Part 2 (SRD/multiple-rising dose \[MRD\]), Part 3 (MRD) and Part 4 (relative bioavailability study). Participants will be randomly assigned (by chance, like flipping a coin) to receive either active drug TAK-831 or placebo which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Part 1, Cohort 1: single dose of TAK-831 100 mg
* Part 1, Cohort 2: single dose of TAK-831 250 mg
* Part 1, Cohort 3: single dose of TAK-831 500 mg
* Part 1, Cohort 4: single dose of TAK-831 30 mg
* Part 1, Cohort 5: single dose of TAK-831 750 mg
* Part 1, Cohort 6: single dose of TAK-831 10 mg
* Part 2, Cohort 1: single dose of TAK-831 30 mg
* Part 2, Cohort 2: single dose of TAK-831 100 mg
* Part 2, Cohort 3: single dose of TAK-831 200 mg
* Part 2, Cohort 4: single dose of TAK-831 400 mg
* Part 3, Cohort 1: TAK-831 400 mg
* Part 4: TAK-831 100 mg (Tablet Fasted + Tablet Fed + Suspension Fasted)
* Part 4: TAK-831 100 mg (Tablet Fed + Tablet Fasted + Suspension Fasted)
* Part 4: TAK-831 100 mg (Suspension Fasted+ Tablet Fed + Tablet Fasted)

Dosing with TAK-831 will progress into study Part 2, 3 and 4, only after review of all available safety, tolerability, and PK data collected in Cohorts 1 to 6 of the Study Part 1. This single center trial will be conducted in the United Kingdom. The overall time to participate in this study is approximately up to 58 days. Participants will be admitted in the clinic for the up to 20 days, and will be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

The study was terminated by Takeda due to the discomfort observed in the study participants from the CSF collection procedure in Part 3 of the study, hence it is was not feasible to collect further CSF samples that were required to meet the exploratory objectives of the study. Part 1, 2 and 4 of the study were completed as planned.

Eligibility criteria: Inclusion Criteria:

1. Should be capable of understanding and complying with protocol requirements.
2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. Healthy male or female aged between 18 to 55 years- Weighing 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).
4. 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.
5. Female participant with no childbearing potential, defined as a participant that has been surgically sterilized (hysterectomy, bilateral oophorectomy or tubal ligation) or who is post menopausal (defined as continuous amenorrhea of at least 2 years and follicle-stimulating hormone \[FSH\] greater than \[\>\] 40 international units per liter \[IU/L\]).

Exclusion Criteria:

1. Received any investigational compound within 3 months prior to randomization.
2. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (example, spouse, parent, child, sibling) or may consent under duress.
3. Has uncontrolled, clinically significant neurological (including seizure disorders), cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine disease, or psychiatric disorder, or other abnormality.
4. Has a known hypersensitivity to any component of the formulation of TAK-831.
5. Female participant is of childbearing potential.
6. Has a positive urine drug result for drugs of abuse (defined as any illicit drug use) at Screening or Check-in.
7. 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 1 single measure of spirits or 1 small glass of wine.
8. Has taken any excluded medication, supplements, or food products during the time periods listed in the excluded medications and dietary products.
9. Female participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.
10. Male participant intending to donate sperm during the course of this study or for 12 weeks after the last dose of study medication.
11. 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.
12. Has a QT interval with Fridericia's correction method (QTcF) \>450 millisecond (msec) (males) or \>470 msec (females) or PR outside the range of 120 to 220 msec, confirmed with one repeat testing, at the screening visit or check-in (Day -2).
13. Has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (that is, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent \[more than once per week\] occurrence of heartburn, or any surgical intervention.
14. Has a history of cancer, except basal cell carcinoma which has been in remission for at least 5 years prior to Day 1.
15. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody/antigen at Screening.
16. 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. Cotinine test is positive at Screening or Check-in.
17. Has poor peripheral venous access.
18. Has donated or lost 450 milliliter (mL) or more of his or her blood volume (including plasmapheresis), or had a transfusion of any blood product within 45 days prior to first dose of medication.
19. Has a Screening or Check-in abnormal (clinically significant) electrocardiogram (ECG). Entry of any participant with an abnormal (not clinically significant) ECG must be approved, and documented by signature by the principal investigator or designee.
20. Has a supine blood pressure outside the ranges of 90 to 140 millimeter of mercury (mm Hg) for systolic and 50 to 90 mm Hg for diastolic, confirmed on repeat testing within a maximum of 30 minutes, at the Screening Visit or Check-in.
21. Has a resting heart rate outside the range 40 to 100 bpm confirmed on repeat testing within a maximum of 30 minutes, at the Screening Visit or Check-in.
22. Has abnormal Screening or check-in laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities: Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) \>1.5 the upper limits of normal.
23. Has a risk of suicide according to the Investigator's clinical judgment (example, per The Columbia Suicide Severity Rating Scale \[C-SSRS\]), or has scored "yes" on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or "yes" on any item of the Suicidal Behavior section, except for the "Non-Suicidal Self-Injurious Behavior", if this behaviour occurred in the past 2 years.
24. Has received TAK-831 in a previous clinical study.
25. Participant is vegan or vegetarian (Part 4 only - food effect).

Primary outcomes:
measure: Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE)
timeFrame: Baseline up to 30 days after the last dose of study drug (Part 1 Day 31, Part 2 Day 46, Part 3 Day 44 and Part 4 Day 43)
measure: Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at Least Once Post Dose
timeFrame: Baseline up to Day 15 in Part 1, Day 30 in Part 2, Day 28 in Part 3 and Day 25 in Part 4
measure: Percentage of Participants Who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at Least Once Post Dose
timeFrame: Baseline up to Day 15 in Part 1, Day 30 in Part 2, Day 28 in Part 3 and Day 25 in Part 4
measure: Percentage of Participants Who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Post Dose
timeFrame: Baseline up to Day 15 in Part 1, Day 30 in Part 2, Day 28 in Part 3 and Day 25 in Part 4
Secondary outcomes:
measure: Part 1, 2 and 4: Cmax: Maximum Observed Plasma Concentration for TAK-831
timeFrame: Day 1 pre-dose and at multiple time points (up to 96 hours in Part 1 and up to 72 hours in Part 2 and 4) post-dose
measure: Part 2 and 3: Cmax, ss: Maximum Observed Plasma Concentration at Steady State for TAK-831
timeFrame: Day 16 (Part 2) and Day 14 (Part 3) pre-dose and at multiple time points (up to 24 hours) post-dose
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-831
timeFrame: Day 1 pre-dose and at multiple time points (up to 96 hours in Part 1 and up to 72 hours in Part 2 and 4) post-dose; Day 16 (Part 2) and Day 14 (Part 3) pre-dose and at multiple time points (up to 24 hours) post-dose
measure: Part 1, 2 and 4: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-831
timeFrame: Day 1 pre-dose and at multiple time points (up to 96 hours in Part 1 and up to 72 hours in Part 2 and 4) post-dose
measure: Part 1, 2 and 4: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-831
timeFrame: Day 1 pre-dose and at multiple time points (up to 96 hours in Part 1 and up to 72 hours in Part 2 and 4) post-dose
measure: Part 2 and 3: AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for TAK-831
timeFrame: Day 16 (Part 2) and Day 14 (Part 3) pre-dose and at multiple time points (up to 24 hours) post-dose
Other outcomes:
Locations:
city: London
country: United Kingdom
Study officials:
References: