Evaluation of Sodium Benzoate as an Adjunct to Clozapine for Residual Symptoms in Refractory Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2024-519237-34-00
- Protocol
- SNR-05
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **effectiveness** of NaBen® as an add-on therapy with clozapine in improving the residual symptoms associated with refractory schizophrenia in adults. In Part 1, the study aims to assess the dose-response relationship of NaBen® at doses of 1000 mg/day and 2000 mg/day compared to placebo, and to determine the optimal dose for use in Part 2. This is clinically relevant as it seeks to enhance treatment outcomes for patients with refractory schizophrenia, a condition characterized by persistent symptoms despite standard treatment. In Part 2, the primary objective is to confirm the effectiveness of NaBen® at the optimal dose identified in Part 1, again compared to placebo, in combination with clozapine.
Secondary objectives include evaluating the **safety** and **tolerability** of NaBen® at the specified doses in Part 1, and at the optimal dose in Part 2, compared to placebo, when used alongside clozapine. These assessments are crucial for ensuring that the therapeutic benefits of NaBen® do not come at the cost of increased adverse effects, thereby supporting its potential use as a safe adjunctive treatment for refractory schizophrenia.
Participants
The clinical trial involves a total of **228 participants** diagnosed with **refractory schizophrenia**. The study population comprises both male and female subjects, aged between 18 and 55 years. Participants are required to have a **Body Mass Index (BMI)** ranging from 17 to 38. All subjects must have a negative routine urine illicit drug screening test and must not pose a danger to themselves or others. The trial population was selected based on their confirmed diagnosis of schizophrenia for at least two years, as verified by psychiatric evaluation and the MINI International Neuropsychiatric Interview. Participants must have been on a stable dose of clozapine for a minimum of six months prior to the study. The study excludes individuals with clinically significant abnormalities in physical, neurological, or laboratory assessments. Participants are required to have a caregiver or responsible person to ensure compliance with study protocols. The trial does not include a vulnerable population, and all participants are outpatients with consistent symptoms without significant fluctuation. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.
Plans and Procedures
The clinical trial is designed as an **adaptive Phase II/III**, double-blind, randomized, placebo-controlled, two-part, dose-finding, multi-center study. The primary objective is to evaluate the safety and efficacy of **NaBen**, a D-amino acid oxidase inhibitor, as an add-on therapy with clozapine for residual symptoms of refractory schizophrenia in adults. The trial is expected to run until December 31, 2029, with recruitment having started on February 27, 2020. Participants will be involved for a maximum treatment period of 8 weeks, during which they will receive either NaBen at doses of 1000 mg or 2000 mg per day or a placebo, all administered orally in the form of film-coated tablets.
The study includes several key visits: an initial screening visit to determine eligibility based on inclusion criteria such as age, body mass index, and a confirmed diagnosis of schizophrenia, followed by a baseline visit to establish initial health parameters. Participants will then undergo regular follow-up visits to monitor their response to the treatment and any adverse effects. The primary endpoint is the mean change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of treatment. Secondary endpoints include percent changes in PANSS sub-scales, Personal and Social Performance scale, Schizophrenia Quality of Life Scale, and other clinical assessments.
Participants are expected to remain in the study for the full 8-week treatment period unless conditions arise that necessitate early termination, such as hospitalization for worsening schizophrenia symptoms or significant non-compliance with the study protocol. The study aims to determine the optimal dose of NaBen for further investigation in Part 2 of the trial, with a focus on improving the residual symptoms associated with refractory schizophrenia when combined with clozapine.
Treatment
The clinical trial involves the administration of **NaBen F.C.T.II**, which is a film-coated tablet containing the active substance **sodium benzoate**. This experimental medication is provided by SyneuRx International (Taiwan) Corp. The pharmaceutical form of NaBen is a film-coated tablet, and it is administered orally. The dosing regimen includes a daily dose of either 1000 mg or 2000 mg, with a maximum treatment period of 8 weeks. The trial aims to evaluate the dose-response effectiveness of NaBen when used as an add-on therapy with clozapine for the treatment of residual symptoms in adults with refractory schizophrenia. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.
The study also includes a **placebo** group, which receives a placebo for NaBen. The placebo is designed to match the experimental medication in appearance and is administered in the same manner, orally, with a dosage of 0 mg per day. The placebo serves as a comparator treatment to assess the efficacy of NaBen in improving the residual symptoms associated with refractory schizophrenia. The use of a placebo control allows for a double-blind, randomized study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias in the evaluation of the treatment outcomes.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the effectiveness of NaBen® as an add-on therapy with clozapine for residual symptoms of refractory schizophrenia in adults. The primary endpoint is the mean change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of randomized treatment. This scale is a widely used tool in schizophrenia research to measure symptom severity.
Secondary endpoints include the percent change from baseline in PANSS total score after 8 weeks of treatment, the percentage of subjects achieving a 20% or more reduction in PANSS total score, and percent changes in PANSS sub-scales and Marder PANSS factor scores. Additional secondary measures involve the Personal and Social Performance (PSP) scale, Schizophrenia Quality of Life Scale (SQLS), Clinical Global Impression-Severity (CGI-S) and -Improvement (CGI-I), and the Hamilton Depression Rating Scale (HDRS). Serum pharmacokinetic evaluations will also be conducted to assess drug levels.
These efficacy parameters will be collected and analyzed at specified timepoints throughout the study, with the primary analysis occurring after 8 weeks of treatment. The use of validated scales such as PANSS, PSP, SQLS, CGI, and HDRS ensures the reliability and accuracy of the efficacy assessments. The trial is structured to determine the optimal dose of NaBen® in Part 1, which will then be used in Part 2 to further evaluate its efficacy compared to placebo.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female subjects who are between 18 and 55 years of age inclusive
- 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.
- 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
- 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).
- 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
- 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
- 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.
- The subject has a minimum PANSS total score of 70 at the Screening and Baseline Visits (Visit 1 and Visit 2)
- 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
- Body Mass Index (BMI) between 17 and 38 inclusive
- Subject has a negative routine urine illicit drug screening test (including heroin, amphetamines (including MDMA/ecstasy), cocaine, cannabis or PCP)
- 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.
- The subject must not be a danger to themselves or others per the Investigator’s judgment.
Exclusion Criteria
- 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
- Initiation or dose change of lithium, antidepressant or other mood stabilizers within 16 weeks prior to Screening
- 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
- The subject has previously received NaBen®
- 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
- History of allergic reaction to sodium benzoate
- 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
- Any significant gastrointestinal disorders that, in the opinion of the Investigator, markedly alter the absorption, metabolism or elimination of sodium benzoate
- 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
- 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
- Female subjects who are pregnant (as confirmed by serum pregnancy test performed at Screening Visit) or are breast feeding
- History of cancer not in remission for the last three (3) years except for basal cell carcinoma and squamous cell carcinoma
- Participation in a clinical trial within 3 months prior to Screening or more than two clinical trials within 12 months
- Electroconvulsive Therapy (ECT) within 6 months prior to Screening
- 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)
- The subject’s anti-EPS medications dose or regimen has changed within 2 weeks prior to Screening
- The subject’s PANSS total score has decreased more than 20 percent using PANSS score evaluations at Visit 1 and Visit 2
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Recruiting | 27 Feb 2020 | 50 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo for NaBen | Placebo | N/A | — | — | — | N/A |
NaBen F.C.T.II | Test | FILM COATED TABLET | ORAL USE | 2000 | 8 | PRD11780912 |