E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment for Refractory Schizophrenia in Adults |
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E.1.1.1 | Medical condition in easily understood language |
Treatment for treatment-resistant Schizophrenia in Adults |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The 2 primary objectives for Part 1 of this study are: 1. To evaluate, in terms of dose-response, the effectiveness of NaBen® (1000 and 2000 mg/day) compared to Placebo (0 mg/day), when combined with clozapine, in improving the residual symptoms associated with refractory schizophrenia in adults, and; to determine the optimal dose to be used in Part 2 of this study. 2. Sample size re-assessment to evaluate the final sample size needed to proceed with the Part 2 of the study The primary objective of Part 2 of this study is to evaluate the effectiveness of NaBen® (at the optimal dose determined in Part 1 of this study) compared to Placebo (0 mg/day), when combined with clozapine, in improving the residual symptoms associated with refractory schizophrenia in adults.
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E.2.2 | Secondary objectives of the trial |
The secondary objective of Part 1 of this study is to evaluate the safety and tolerability of NaBen® (1000 and 2000 mg/day) compared to Placebo (0 mg/day), in combination with clozapine. The secondary objective of Part 2 of this study is to evaluate the safety and tolerability of NaBen® (at the optimal dose determined in Part 1 of this study) compared to Placebo (0 mg/day), in combination with clozapine. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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): a.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 b.No period of good functioning in previous 2 years; OR, c.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 (Visit 1 and Visit 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.
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E.4 | Principal exclusion criteria |
1. Meets the DSM-V criteria at Screening for intellectual disability, dissociative disorder, bipolar disorder, major depressive disorder, schizoaffective disorder, schizophreniform disorder, autistic disorder, primary substance-induced psychotic disorder, dementia, or any other comorbid mental disorders that in the opinion of the Investigator 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 other psychotropic medications due to worsening of schizophrenia symptoms or medication side effects within four (4) weeks prior to Screening Exclusion Criteria: Subjects are required to meet NONE of the following criteria for randomization into the study: 1. Meets the DSM-V criteria at Screening for intellectual disability, dissociative disorder, bipolar disorder, major depressive disorder, schizoaffective disorder, schizophreniform disorder, autistic disorder, primary substance-induced psychotic disorder, dementia, or any other comorbid mental disorders that in the opinion of the Investigator 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 other psychotropic medications due to worsening of schizophrenia symptoms or medication side effects 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 than Tourette’s syndrome which might impair the subject’s cognition or psychiatric functioning 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 heart failure that, in the opinion of the Investigator, may interfere with the conduct of the 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 disorder that might affect the ratings on the EPS scales (e.g. Parkinson’s disease) or any movement disorder that is due to antipsychotic medications and is not currently controlled with anti-EPS medications 10. Current substance abuse, or history of meeting criteria for moderate or severe substance abuse and/or substance dependence (including alcohol, but excluding nicotine and caffeine) in the past six (6) months prior to Screening 11. Female subjects who are pregnant (as confirmed by serum pregnancy test performed at Screening Visit) or are breast feeding 12. History of cancer not in remission for the last three (3) years except for basal cell carcinoma and squamous cell carcinoma 13. Participation in a clinical trial within 3 months prior to Screening or more than two clinical 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 other psychiatric condition within the last 3 months prior to Screening (e.g. individual psychotherapy, cognitive behavioral therapy or rehabilitative therapy) 16. The subject’s anti-EPS medications dose or regimen has changed within 2 weeks prior to Screening 17. The subject’s PANSS total score has decreased more than 20 percent using PANSS score evaluations at Visit 1 and Visit 2 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Mean change from baseline in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of randomized treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 8 weeks of treatment |
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E.5.2 | Secondary end point(s) |
• Percent change from baseline in PANSS total score after 8 weeks of treatment • Percentage of subjects with 20% or more reduction from baseline in PANSS total score after 8 weeks of treatment • Percent change in PANSS sub-scales and Marder PANSS factor scores • Percent change in Personal and Social Performance (PSP) scale • Percent change in Schizophrenia Quality of Life Scale (SQLS) • Percent change in Clinical Global Impression-Severity (CGI-S) and -improvement (CGI-I) • Percent change in Hamilton Depression Rating Scale (HDRS) • Serum pharmacokinetic evaluations • Serum DNA evaluations • Serum neurotransmitter markers evaluations |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 8 weeks of randomized treatment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
There will be “DNA” and “SERUM BIOMARKER EVALUATIONS” per protocol. Samples will be collected for DNA testings of the study subjects. This evaluation will be used to find out more about the sub-populations who might be more responsive to the DAAO Inhibitors. for biomarkers, two groups of biomarkers (Monoamines and Amino acids) will be tested.
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Bulgaria |
Canada |
Germany |
Poland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |