Efficacy, Safety, and Tolerability of TC-5619 as Augmentation Therapy to Improve Negative Symptoms and Cognition in Outpatients With Schizophrenia

This is a 30-week, multi-center, double-blind, randomized, placebo-controlled,
parallel-group, fixed-dose titration study. A study overview is in Figure 1. The study has 3
phases: a 4-week Screening phase (Week -4 to Day 1); a 24-week Treatment phase (Day 1 to
Week 24); and a 2-week Follow-up phase (Week 25 to Week 26). Subjects on a stable atypical
antipsychotic will be assessed at screening (Visit 1/Week -4) for stable schizophrenia, as
documented by lack of psychiatric hospitalization for the preceding 8 weeks and stable
dosing of only one approved atypical antipsychotic medication for at least the preceding 8
weeks.

Subjects will continue their prior atypical antipsychotic therapy and therefore TC-5619
(either 5 mg or 50 mg TC-5619) or matching placebo will be evaluated as an add-on therapy
for negative symptoms and cognitive dysfunction in schizophrenia. Since there is no approved
treatment for negative symptoms or cognitive dysfunction in schizophrenia, a
placebo-controlled study is appropriate.

Inclusion Criteria:

1. Diagnosis of schizophrenia, per DSM-IV-TR criteria, as aided by the MINI
International Neuropsychiatric Interview

2. Controlled schizophrenia, on stable dose of an approved atypical antipsychotic for at
least 2 months prior to screening. Approved refers to regulatory approval in the
country of use.

3. Stable schizophrenia as documented by lack of psychiatric hospitalization for 2
months prior to Screening (social admissions for the convenience of the subject
allowed)

4. Clinical history of stable psychotic symptoms for 1 month prior to Screening.

5. Stable positive symptoms of schizophrenia for 4 weeks prior to Day 1, as shown by
score ≤ 4 on PANSS for items related to delusion, hallucination, conceptual
disorganization, and unusual thought content, at Screening and at Day 1.

6. Sum > 20 for the 7 items in the Negative Symptoms subscale of the PANSS.

7. Calgary Depression Schizophrenia Scale (CDSS) score < 6.

8. Simpson Angus Scale score < 12.

9. Outpatient with stable housing, and significant presence of an informant who is not a
group home resident.

Exclusion Criteria:

1. Diagnosis of schizoaffective or schizophreniform disorders within 1 year prior to
Screening.

2. Significant risk of suicide or attempted suicide in the 12 months before screening,
or of danger to themselves or others.

3. Change in dosing of atypical antipsychotic within 2 months of Screening.

4. Treatment with electroconvulsive therapy (ECT) within 12 months of Screening.

5. Treatment with mood stabilizers, antidepressants, anxiolytics (short-acting hypnotics
permitted), anticholinergics, or more than 1 antipsychotic within 1 month prior to
Screening.

6. Treatment within 1 month prior to Screening with cognition-affecting agents other
than the above (e.g. CNS stimulants).

7. History within past 6 months of screening of alcohol or illicit drug abuse.

8. Use of smoking cessation therapy within 1 month prior to Screening.

9. Positive urine drug screen except when related to prescribed short-acting
benzodiazepines and opiates recently prescribed for an episode of acute pain (e.g.,
dental extraction).

10. History of significant other major or unstable neurological, neurosurgical (e.g. head
trauma), metabolic, hepatic, renal, hematological, pulmonary, cardiovascular,
gastrointestinal, or urological disorder.

11. History of myocardial infarction based on medical history or electrocardiogram (ECG)
findings at screening.

12. History of seizure disorder.

13. Type 1 diabetes mellitus.

14. Type 2 diabetes mellitus that requires medication (diet-controlled allowed, with
HbA1C < 7.3).

15. Body Mass Index (BMI) > 35.

16. Uncontrolled hypothyroidism, vitamin B12 or folic acid deficiency.

17. Current TB or known systemic infection (e.g., HBV, HCV, HIV).

18. Clinically significant lab or ECG abnormality that could be a safety issue in the
study, including QTcF > 450 for males and >470 for females.

19. Men, or women of child-bearing potential, who are unwilling or unable to use accepted
methods of birth control as specified in Section 4.4.4

20. Women with a positive pregnancy test, or who are lactating.

21. Participated in another clinical trial within 3 months prior to Screening.