An Adaptive Phase II/III, Two-Part, Double-Blind, Randomized, Placebo-controlled, Dose-Finding, Multi-center Study of the Safety and Efficacy of NaBen®, as an Add-on Therapy With Clozapine, for Residual Symptoms of Refractory Schizophrenia in Adults

Inclusion Criteria:

1. Male or female subjects who are between 18 and 55 years of age inclusive
2. Subject is capable of providing informed consent and is willing to sign the ICF priorto study Screening and agrees to comply with the study protocol requirements, or thesubject has a Legally Authorized Representative (LAR) who can provide consent to beenrolled into the study
3. If female and not infertile (defined below), the subject must agree for the durationof the study to use one of the following forms of contraception 1) systemic hormonaltreatment 2) an Intrauterine device (IUD) which was implanted at least 2 months priorto screening or 3) "double-barrier" contraception (condom, diaphragm and spermicideare each considered a barrier). Females are considered to be infertile if they areeither a) surgically sterile or b) have had spontaneous amenorrhea for at least thelast 2 years and at least 2 years after the onset of amenorrhea while not receivinghormone replacement therapy and had a Follicle-Stimulating Hormone (FSH) level greaterthan 40 mIU/mL and an estradiol level less than 30 pg/mL
4. The subject has Physician confirmed DSM-V diagnosis of schizophrenia for the past 2years based on subject's recorded history and confirmed by psychiatric evaluation andMINI International Neuropsychiatric Interview For Schizophrenia and PsychoticDisorders, version 7.0 (MINI, Version 7.0)
5. The subjects should have refractory schizophrenia as defined below (should meet atleast two: either a and b; or a and c; or a and b and c):
6. Prior non-response to at least 2 antipsychotic drugs of two different chemicalclasses for at least 4-6 weeks each at doses ≥ 400 mg equivalents ofchlorpromazine or 4 mg/day risperidone, AND
7. No period of good functioning in previous 2 years; OR,
8. Moderate to severe psychopathology (total PANSS score equal or more than 70):including persistent psychotic symptoms, recurrent mood symptoms, repeatedsuicide attempts or suicidal ideation, uncontrolled aggressive behavior, moderateto severe positive or negative symptoms or moderate-severe cognitive impairment
9. The subject has been receiving clozapine for a minimum of 6 months with the dose rangeof 200-900 mg/day. The dose should have remained unchanged for at least 3 months priorto Screening and not expected to change during the study
10. The subject is outpatient, and has been consistently symptomatic without significantfluctuation per the Investigator, with no hospitalization for worsening ofschizophrenia within 3 months of the Screening. If the subject is hospitalized duringthe study for worsening of schizophrenia symptoms the subject will be withdrawn fromthe study
11. The subject has a minimum PANSS total score of 70 at the Screening and Baseline Visits (Visits 1 and 2)
12. Without clinically significant abnormalities in physical exam, neurological exam andlaboratory assessments (urine/blood routine, biochemical tests and ECG) which wouldexclude the subject from the study in the opinion of the Investigator. For ALT andAST, clinically significant is defined as above two and a half times the upper limitof normal
13. Body Mass Index (BMI) between 17 and 38 inclusive
14. Subject has a negative routine urine illicit drug screening test (including heroin,amphetamines (including MDMA/ecstasy), cocaine, cannabis or PCP)
15. The subject has a caregiver or some other identified responsible person (e.g., familymember, social worker, caseworker, or nurse) as determined by the Investigator and perthe local regulations. The identified caregiver should be considered reliable by theInvestigator and per the local regulations in providing support to the subject to helpensure compliance with study treatment, study visits and protocol procedures whopreferably is also able to provide input helpful for completing study rating scales
16. The subject must not be a danger to themselves or others per the Investigator'sjudgment

Exclusion Criteria:

1. Meets the DSM-V criteria at Screening for intellectual disability, dissociativedisorder, bipolar disorder, major depressive disorder, schizoaffective disorder,schizophreniform disorder, autistic disorder, primary substance-induced psychoticdisorder, dementia, or any other comorbid mental disorders that in the opinion of theInvestigator may interfere with study conduct and results interpretation
2. Initiation or dose change of lithium, antidepressant or other mood stabilizers within 16 weeks prior to Screening
3. Initiation or dose change of benzodiazepines or sleep medications, or any otherpsychotropic medications due to worsening of schizophrenia symptoms or medication sideeffects within four (4) weeks prior to Screening
4. The subject has previously received NaBen®
5. History of epilepsy, major head trauma, or any neurological illness other thanTourette's syndrome which might impair the subject's cognition or psychiatricfunctioning per the Investigator's judgment
6. History of allergic reaction to sodium benzoate
7. Serious medical illnesses such as end-stage renal disease, liver failure or heartfailure that, in the opinion of the Investigator, may interfere with the conduct ofthe study
8. Any significant gastrointestinal disorders that, in the opinion of the Investigator,markedly alter the absorption, metabolism or elimination of sodium benzoate
9. Any movement disorders with a total score higher than 6 on SAS scale, or more than 2on any items of the AIMS scale
10. Current substance abuse, or history of meeting criteria for moderate or severesubstance abuse (including alcohol, but excluding nicotine and caffeine) in the pastsix (6) months prior to Screening
11. Female subjects who are pregnant (as confirmed by serum pregnancy test performed atScreening Visit) or are breast feeding
12. History of cancer not in remission for the last three (3) years except for basal cellcarcinoma and squamous cell carcinoma
13. Participation in a clinical trial within 3 months prior to Screening or more than twoclinical trials within 12 months
14. Electroconvulsive Therapy (ECT) within 6 months prior to Screening
15. The subject started a new non-medication treatment for schizophrenia or otherpsychiatric condition within the last 3 months prior to Screening (e.g. individualpsychotherapy, cognitive behavioral therapy or rehabilitative therapy)
16. The subject's anti-EPS medications dose or regimen has changed within 2 weeks prior toScreening
17. The subject's PANSS total score has decreased more than 20 percent using PANSS scoreevaluations at Visit 1 and Visit 2