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 prior to study Screening and agrees to comply with the study protocol requirements, or the subject has a Legally Authorized Representative (LAR) who can provide consent to be enrolled into the study
• •3. If female and not infertile (defined below), the subject must agree for the duration of the study to use one of the following forms of contraception 1) systemic hormonal treatment 2) an Intrauterine device (IUD) which was implanted at least 2 months prior to screening or 3) "double-barrier" contraception (condom, diaphragm and spermicide are each considered a barrier). Females are considered to be infertile if they are either a) surgically sterile or b) have had spontaneous amenorrhea for at least the last 2 years and at least 2 years after the onset of amenorrhea while not receiving hormone replacement therapy and had a Follicle-Stimulating Hormone (FSH) level greater than 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 2 years based on subject's recorded history and confirmed by psychiatric evaluation and MINI International Neuropsychiatric Interview For Schizophrenia and Psychotic Disorders, version 7.0 (MINI, Version 7.0)
• •5. The subjects should have refractory schizophrenia as defined below (should meet at least two: either a and b; or a and c; or a and b and c):
• •1. Prior non-response to at least 2 antipsychotic drugs of two different chemical classes for at least 4-6 weeks each at doses ≥ 400 mg equivalents of chlorpromazine or 4 mg/day risperidone, AND
• •2. No period of good functioning in previous 2 years; OR,
• •3. Moderate to severe psychopathology (total PANSS score equal or more than 70): including persistent psychotic symptoms, recurrent mood symptoms, repeated suicide attempts or suicidal ideation, uncontrolled aggressive behavior, moderate to severe positive or negative symptoms or moderate-severe cognitive impairment
• •6. The subject has been receiving clozapine for a minimum of 6 months with the dose range of 200-900 mg/day. The dose should have remained unchanged for at least 3 months prior to Screening and not expected to change during the study
• •7. The subject is outpatient, and has been consistently symptomatic without significant fluctuation per the Investigator, with no hospitalization for worsening of schizophrenia within 3 months of the Screening. If the subject is hospitalized during the study for worsening of schizophrenia symptoms the subject will be withdrawn from the study
• •8. The subject has a minimum PANSS total score of 70 at the Screening and Baseline Visits (Visits 1 and 2)
• •9. Without clinically significant abnormalities in physical exam, neurological exam and laboratory assessments (urine/blood routine, biochemical tests and ECG) which would exclude the subject from the study in the opinion of the Investigator. For ALT and AST, clinically significant is defined as above two and a half times the upper limit of normal
• •10. Body Mass Index (BMI) between 17 and 38 inclusive
• •11. Subject has a negative routine urine illicit drug screening test (including heroin, amphetamines (including MDMA/ecstasy), cocaine, cannabis or PCP)
• •12. The subject has a caregiver or some other identified responsible person (e.g., family member, social worker, caseworker, or nurse) as determined by the Investigator and per the local regulations. The identified caregiver should be considered reliable by the Investigator and per the local regulations in providing support to the subject to help ensure compliance with study treatment, study visits and protocol procedures who preferably is also able to provide input helpful for completing study rating scales
• •13. The subject must not be a danger to themselves or others per the Investigator's judgment