Safety and Tolerability of Multiple Doses of ITI-214 in Healthy Adults and in Adults With Stable Schizophrenia

The drug being tested in this study is called ITI-214. This study will look at how well
different doses of ITI-214 are tolerated in healthy people and in people with stable
schizophrenia. In addition, exploratory neuroimaging will be conducted in participants
with schizophrenia.

This multi-center trial will be conducted in the United States. The study will be comprised
of 2 parts: Multiple-Rising Dose (MRD) and Neuroimaging (NI). Approximately 40 healthy
participants are planned to be enrolled in the MRD part of the study and approximately 36
patients with stable schizophrenia are planned to be enrolled in the Neuroimaging part of
the study.

Participants in the MRD (parallel design) part will be enrolled in cohorts for different
dose levels. In each dose cohort, participants will be randomly assigned to active dose or
placebo—which will remain undisclosed to participants and study doctor during the study
(unless there is an urgent medical need). The following dose cohorts will be enrolled:
Doses A, B, C, and D.

Participants will be asked to take the study drug in oral solution once daily for a total of
14 days while confined at the study site. Participants will be contacted by telephone 22 and
44 days after last dose of study drug for a follow-up assessment.

Participants in the Neuroimaging (NI) part of the study will be randomly assigned to one of
six treatment sequences. Each sequence consists of 3 cross-over treatment periods. The
following doses will be tested: Doses E, F, G, and H.

Each participant will undergo 3 treatment periods of placebo or ITI-214 once daily dosing
for 7 days in each of the periods. There will be a washout period of a minimum of 7 days
between treatment periods. Participants will be confined at the study site for 5 days of
each treatment period and will report to the site on other dosing days for study drug
administration. There will be follow-up assessments on Days 14 and 37 of Period 3.

Inclusion Criteria:

Healthy Participants

1. Is 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. Is a healthy man or woman, aged 18 to 55 years, inclusive (non-elderly) or aged ≥65
years (elderly), at the time of informed consent and first study medication dose.

4. Weighs at least 50 kg and has a body mass index (BMI) between 18.0 and 35.0 kg/m^2,
inclusive at Screening.

5. 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.

6. A female participant with no childbearing potential. The participant has been
surgically sterilized (hysterectomy, bilateral oophorectomy or tubal ligation) or who
are postmenopausal (defined as continuous amenorrhea of at least 2 years and
follicle-stimulating hormone (FSH) >40 IU/L.

Participants with schizophrenia:

1. Is 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. Is capable of consenting. A standard evaluation by a psychiatrist will be implemented
to assess the participant's capacity to consent.

4. Is a man or woman, aged 18 to 60 years (non-elderly), inclusive, or aged ≥65 years
(elderly, if decided to enroll), at the time of informed consent and first study
medication dose.

5. Weighs at least 50 kg and has a body mass index (BMI) between 18.0 and 35.0 kg/m^2,
inclusive at Screening.

6. Is diagnosed with schizophrenia criteria as defined by the Diagnostic & Statistical
Manual of Mental Disorders 4th Edition - Text Revision (DSM-IV-TR) and determined by
the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I),
schizoaffective disorder, or schizophreniform disorder; on a stable dose of one and
only one of the second generation antipsychotics (except olanzapine, clozapine, or
quetiapine) for at least 2 months by medical history and assessed by site staff;
Positive and Negative Syndrome Scale (PANSS) Conceptual Disorganization item score ≤
4 and PANSS Hallucinatory Behavior or Unusual Thought Content item scores ≤ 4. For
the MRD part, the subject is diagnosed with schizophrenia criteria as defined by the
DSM-IV-TR and determined by the SCID-I, schizoaffective disorder, or schizophreniform
disorder; on a stable dose of one and only one of the second generation
antipsychotics (except clozapine) for at least 2 months by medical history and
assessed by site staff; PANSS Conceptual Disorganization item score ≤ 4 and PANSS
Hallucinatory Behavior or Unusual Thought Content item scores ≤ 4.

7. 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.

8. A female subject of childbearing potential* who is sexually active with a
nonsterilized* male partner agrees to use an acceptable method of contraception* from
signing of informed consent and for 12 weeks postdose.

Exclusion Criteria:

Healthy Participants

1. Has received any investigational compound within 30 days prior to the first dose of
study medication.

2. Has received ITI-214 in a previous clinical study or as a therapeutic agent.

3. 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.

4. 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.

5. Has a known hypersensitivity to any component of the formulation of ITI-214 or
Listerine.

6. Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day
-1).

7. 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.

8. Has taken any excluded medication, supplements, or food products.

9. Is pregnant or lactating or intending to become pregnant before, during, or within 12
weeks after participating in this study; or intending to donate ova during such time
period.

10. If male, the participant intends to donate sperm during the course of this study or
for 12 weeks after last dose.

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. 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 ITI-214, 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. Elderly participants may have been
eligible for enrollment if approved by the investigator and Takeda medical monitor.

12. Has mental retardation or medical condition that can cause cognitive impairment.

13. Has current or recent (within 6 months) gastrointestinal disease that would be
expected to influence the absorption of drugs (ie, a history of malabsorption, any
surgical intervention known to impact absorption [eg, bariatric surgery or bowel
resection], esophageal reflux, peptic ulcer disease, erosive esophagitis, or frequent
[more than once per week] occurrence of heartburn).

14. Has a history of cancer, except basal cell carcinoma which has not been in remission
for at least 5 years prior to Check-in (Day -1)

15. Has a positive test result for hepatitis B surface antigen (HBsAg), antibody to
hepatitis C (anti-HCV) or a known history of human immunodeficiency virus infection
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 (Day -1). Cotinine test is positive at Screening or Check-in (Day -1).
The participant has poor peripheral venous access.

17. Has donated or lost 450 mL or more of his or her blood volume (including
plasmapheresis), or had a transfusion of any blood product within 45 days prior the
first dose of study medication.

18. Has a Screening or Check-in (Day -1) 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.

19. Has a supine blood pressure outside the ranges of 90 to 140 mm Hg for systolic and 60
to 90 mm Hg for diastolic, confirmed on repeat testing within a maximum of 30
minutes, at the Screening Visit or Check-in (Day -1).

20. Has a resting heart rate outside the range 50 to 100 bpm, confirmed on repeat testing
within a maximum of 30 minutes, at the Screening Visit or Check-in (Day -1).

21. Has a QTcF >440 ms (males) or >460 ms (females) or PR outside the range 120 to 220
ms, confirmed on repeat testing within a maximum of 30 minutes, at the Screening
Visit or Check-in (Day -1).

22. Has abnormal Screening or Check-in (Day -1) 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.

23. 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).

Participants with schizophrenia:

1. Has received any investigational compound within 30 days prior to the first dose of
study medication.

2. 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.

3. 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.

4. Has a known hypersensitivity to any component of the formulation of ITI-214 or
Listerine.

5. Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -2
of Periods 1).

6. 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.

7. Has taken any excluded medication, supplements, or food products.

8. Iis pregnant or lactating or intending to become pregnant before, during, or within
12 weeks after participating in this study; or intending to donate ova during such
time period.

9. If male, the participant intends to donate sperm during the course of this study or
for 12 weeks after last dose.

10. 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 ITI-214, 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.

11. Has mental retardation.

12. Has current or recent (within 6 months) gastrointestinal disease that would be
expected to influence the absorption of drugs (ie, a history of malabsorption, any
surgical intervention known to impact absorption [eg, bariatric surgery or bowel
resection], esophageal reflux, peptic ulcer disease, erosive esophagitis, or frequent
[more than once per week] occurrence of heartburn).

13. Subject has a history of cancer, except basal cell carcinoma which has not been in
remission for at least 5 years prior to Check-in Day -1 for MRD part) and Day -2 of
Period 1 for Neuroimaging part ).

14. Has a positive test result for hepatitis B surface antigen (HBsAg), antibody to
hepatitis C (anti-HCV) or a known history of human immunodeficiency virus infection
at Screening.

15. Participants who currently use nicotine-containing products but will not maintain
their nicotine use habit throughout the study.

16. Has poor peripheral venous access.

17. Has donated or lost 450 mL or more of his or her blood volume (including
plasmapheresis), or had a transfusion of any blood product within 45 days prior the
first dose of study medication.

18. The subject has a Screening or Check-in (Day -1 for MRD part) and Check-in (Day -2 of
Period 1 for Neuroimaging part) abnormal (clinically significant) ECG. Entry of any
subject with an abnormal (not clinically significant) ECG must be approved and
documented by signature by the principal investigator or medically qualified
sub-investigator.

19. The subject has a supine blood pressure outside the ranges of 90 to 140 mm Hg for
systolic and 60 to 90 mm Hg for diastolic, confirmed on repeat testing within a
maximum of 30 minutes, at the Screening Visit or Check-in (Day -1 for MRD part) and
Check-in (Day -2 of Period 1 for Neuroimaging part).

20. The subject has a resting heart rate outside the range 50 to 100 bpm, confirmed on
repeat testing within a maximum of 30 minutes, at the Screening Visit or Check-in
(Day -1 for MRD part) and Check-in (Day -2 of Period 1 for Neuroimaging part).

21. The subject has a QTcF >440 ms (males) or >460 ms (females) or PR outside the range
120 to 220 ms, confirmed on repeat testing within a maximum of 30 minutes, at the
Screening Visit or Check-in (Day -1 for MRD part) and Check-in (Day -2 of Period 1
for Neuroimaging part).

22. The subject has abnormal Screening or Check-in (Day -1 for MRD part) and Check-in
(Day -2 of Period 1 for Neuroimaging part) laboratory values that suggest a
clinically significant underlying disease or has the following lab abnormalities: ALT
and/or AST >1.5 the upper limits of normal.

23. Has a risk of suicide according to the Investigator's clinical judgment (eg, per
C-SSRS) or has made a suicide attempt in the previous 6 months.

24. Has a current diagnosis of significant psychiatric illness other than schizophrenia,
per DSM-IV.

25. For subjects enrolled in the neuroimaging part at the site performing fMRI, the
subject has a personal history of claustrophobia or inability to tolerate mock
scanner environment during habituation/screening session; surgery involving metal
implants, non-removable body metal objects (metal body piercing, dentures, dental
plates or bridges, any implanted device that is electrically, magnetically, and
mechanically activated); a personal history of seizures, other neurologic disease, or
increased intracranial pressure; history of open head injury or significant closed
head injury; or hearing loss.