NaBen Add-On Therapy for Schizophrenia

Overseen By Guochuan Tsai

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: SyneuRx International (Taiwan) Corp

Must be taking: Clozapine

Must not be taking: Lithium, Antidepressants, Benzodiazepines, others

Disqualifiers: Bipolar, Major depression, Substance abuse, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

287 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called NaBen® (Sodium Benzoate) for individuals with refractory schizophrenia, a form that doesn't respond well to typical medications. The study aims to determine the optimal dose of NaBen® to use with clozapine (a common antipsychotic) to improve lingering symptoms. The trial consists of two parts: the first part identifies the best dose, and the second part confirms its effectiveness and safety. Individuals diagnosed with schizophrenia for over two years and experiencing ongoing symptoms despite clozapine treatment might be suitable candidates for this study. As a Phase 2, Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Do I have to stop taking my current medications for the trial?

The trial requires participants to continue taking clozapine without changing the dose during the study. Other medications like lithium, antidepressants, mood stabilizers, benzodiazepines, or sleep medications should not have been started or had their doses changed recently. The protocol does not specify stopping other medications, but changes to certain medications close to the trial start may affect eligibility.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that NaBen®, when used alongside other treatments for schizophrenia, has generally been well-tolerated. Studies have found that sodium benzoate, the main ingredient in NaBen®, can improve schizophrenia symptoms without causing major side effects. In one study, patients taking sodium benzoate reported feeling better, and no serious negative effects were observed.

Another study focused on the safety of NaBen® in teenagers with schizophrenia and found it safe and effective. This study did not report any severe negative reactions among those taking the treatment. Additionally, a clinical trial with adults showed sodium benzoate to be as safe as a placebo.

Overall, existing research supports NaBen® as a promising and safe additional therapy for schizophrenia, with previous patients experiencing symptom improvements and minimal side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for schizophrenia?

Researchers are excited about NaBen® as an add-on therapy for schizophrenia because it introduces a novel mechanism of action compared to standard treatments like antipsychotics, which typically target dopamine receptors. NaBen® is thought to work by modulating the glutamatergic system, which plays a key role in brain function and could offer a new pathway for managing symptoms. This approach could potentially complement existing therapies and offer benefits to patients who don't fully respond to current medications. Additionally, having two dosage options (1000 mg/day and 2000 mg/day) allows for flexibility in treatment, potentially leading to improved outcomes with fewer side effects.

What evidence suggests that NaBen® might be an effective treatment for schizophrenia?

Research has shown that NaBen®, a treatment in this trial, can help improve symptoms when used alongside other schizophrenia treatments. Studies have found that adding benzoate to treatment significantly enhances various symptom areas and boosts brain function in individuals with long-term schizophrenia. One study found that sodium benzoate effectively lowered the overall score on a test measuring schizophrenia symptoms. These findings suggest that NaBen® could be a useful option for managing schizophrenia symptoms. Participants in this trial may receive NaBen® at different dosages or a placebo as part of the study. ^{3 6 7 8 9}

Are You a Good Fit for This Trial?

Adults aged 18-55 with refractory schizophrenia, who have not responded to at least two antipsychotic drugs and are on a stable dose of clozapine. Participants must be capable of consent or have a representative, agree to use contraception if applicable, and not have significant medical conditions or substance abuse issues.

Inclusion Criteria

I can give my consent or have someone legally allowed to do so for me.

I agree to use birth control as required if I can become pregnant.

I have been diagnosed with schizophrenia for the last 2 years.

Exclusion Criteria

I haven't started or changed the dose of any specified medications recently.

I have a history of certain medical conditions or allergies.

My only cancers in the last 3 years are skin cancers.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

2 visits (in-person)

Treatment Part 1

Participants receive NaBen® (1000 or 2000 mg/day) or Placebo for dose-finding over 8 weeks

8 weeks

Weekly visits (in-person)

Interim Analysis

Data Safety and Monitoring Committee reviews data for safety and efficacy trends to determine optimal dose for Part 2

Not specified

Treatment Part 2

Participants receive NaBen® at the optimal dose or Placebo for hypothesis testing over 8 weeks

8 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• NaBen®
• Placebo

Trial Overview The study tests NaBen® as an add-on therapy with clozapine for adults with refractory schizophrenia. It's in two parts: first finding the best dose (1000 mg/day or 2000 mg/day) compared to placebo, then testing this optimal dose's effectiveness and safety.

How Is the Trial Designed?

Group I: NaBen® - 2000 mg/day Active Control 1 Intervention

Two NaBen® ( 500 mg) will be taken twice daily at a total dose of 2000 mg/day during this study.

Group II: NaBen® - 1000 mg/day Active Control 1 Intervention

One NaBen® (500 mg) and one placebo will be taken twice daily at a total dose of 1000 mg/day during this study.

Group III: Placebo - 0 mg/day Placebo Group 1 Intervention

The control treatment is placebo.

Who Is Running the Clinical Trial?

SyneuRx International (Taiwan) Corp

Lead Sponsor

Trials

4

Recruited

720+

Amarex Clinical Research

Collaborator

Trials

28

Recruited

1,700+

Published Research Related to This Trial

In a review of 32 studies involving 7264 patients, atypical antipsychotic medications showed nearly double the improvement in active-controlled trials compared to placebo-controlled trials, indicating a significant control group bias.

The findings suggest that the assumption that new medications will perform similarly in active-controlled studies as they would in placebo-controlled trials is not valid, highlighting the need for caution when using active controls to establish efficacy in schizophrenia treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Control group bias in randomized atypical antipsychotic medication trials for schizophrenia. Woods, SW., Gueorguieva, RV., Baker, CB., et al.[2007]

Placebo responses in clinical trials for schizophrenia are similar in magnitude and impact to those seen in major depression trials, and these responses have increased in recent years.

To address the challenge of high placebo responses in schizophrenia trials, a multipronged strategy is recommended, as no single factor has been identified as the primary cause.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo response in clinical trials with schizophrenia patients. Kinon, BJ., Potts, AJ., Watson, SB.[2011]

Placebo-controlled studies are essential for demonstrating the efficacy of treatments in schizophrenia, as they provide a clearer picture of responder rates compared to non-placebo-controlled studies.

The study found that responder rates in the treatment arms of non-placebo-controlled studies were similar to those in placebo arms, highlighting the variability in placebo responses and the need for standardized definitions of responders in future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Schizophrenia: do we really need placebo-controlled studies? Storosum, JG., Elferink, AJ., van Zwieten, BJ.[2019]

In a review of 23 short-term placebo-controlled trials involving 7553 patients with schizophrenia, the risk of death was found to be significantly higher in the placebo group compared to those receiving active treatment, with a crude odds ratio of 7.92, indicating a potential safety concern with placebo use.

Despite the higher mortality risk associated with placebo, the study emphasizes the necessity of short-term placebo-controlled trials to ensure that new antipsychotic drugs are effective and safe before they are licensed for use, suggesting that without such trials, ineffective drugs could be approved and cause harm.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The risk of death among adult participants in trials of antipsychotic drugs in schizophrenia. Isaac, M., Koch, A.[2010]

In a pooled analysis of two 6-week trials involving 422 patients with schizophrenia, early response to antipsychotic treatment (low-dose olanzapine or haloperidol) significantly distinguished active drug from placebo, with a greater mean reduction in psychiatric symptoms observed at 2 weeks.

The study suggests that shortening the duration of placebo-controlled trials from 6 weeks to 2-4 weeks is feasible for identifying efficacy in acutely ill patients, as early treatment response was predictive of overall treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early onset of antipsychotic action in schizophrenia: evaluating the possibility of shorter acute efficacy trials. Kinon, BJ., Chen, L., Stauffer, VL., et al.[2021]

In a meta-regression analysis of 18 double-blind, randomized, placebo-controlled trials involving 998 patients with stable schizophrenia, drugs were found to be more effective than placebo in reducing negative symptoms, although the effect size was small (Cohen's d: 0.208).

The study revealed a significant placebo response (Cohen's d: 2.909), indicating that factors like the number of trial arms, study sites, and industry sponsorship can influence the placebo effect, suggesting a need for improved trial designs to accurately assess treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of Placebo Response in Pharmacological Clinical Trials of Negative Symptoms in Schizophrenia: A Meta-regression Analysis. Fraguas, D., Díaz-Caneja, CM., Pina-Camacho, L., et al.[2022]

In a 12-week study involving 1,018 patients with schizophrenia in China, blonanserin (BNS) demonstrated a safety profile with a 20.1% incidence of adverse drug reactions (ADRs), including extrapyramidal symptoms (16.6%) and akathisia (8.8%).

Blonanserin was effective in reducing symptoms of schizophrenia, with a significant improvement in Brief Psychiatric Rating Scale (BPRS) scores over time and a response rate of 53.5% by week 12.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of Blonanserin in Chinese Patients with Schizophrenia: An Interim Analysis of a 12-Week Open-Label Prospective Multi-Center Post-marketing Surveillance. Wu, H., Wang, X., Liu, X., et al.[2022]

Blonanserin, a second-generation antipsychotic approved in Japan, has shown effectiveness in reducing symptoms of schizophrenia, including cognitive dysfunction, with sustained benefits observed over a year of treatment in post-marketing surveillances involving diverse patient populations.

While common side effects like akathisia and extrapyramidal symptoms were noted, serious adverse effects typically associated with second-generation antipsychotics, such as significant weight gain and metabolic issues, were rarely reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of oral blonanserin for schizophrenia: A review of Japanese post-marketing surveillances. Inoue, Y., Tsuchimori, K., Nakamura, H.[2021]

Brexpiprazole at doses of 2 mg and 4 mg significantly reduced symptoms of acute schizophrenia compared to placebo, as measured by the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions Scale (CGI) after 6 weeks.

The treatment was generally well-tolerated, with akathisia being the most common side effect, and only moderate weight gain observed, indicating that brexpiprazole is a viable option for managing acute schizophrenia exacerbations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Brexpiprazole for the Treatment of Acute Schizophrenia: A 6-Week Randomized, Double-Blind, Placebo-Controlled Trial. Correll, CU., Skuban, A., Ouyang, J., et al.[2022]

The placebo effect in schizophrenia clinical trials is becoming a significant challenge, making it harder to detect the effectiveness of new treatments and increasing development costs.

Understanding the central nervous system mechanisms behind the placebo effect and improving study designs could help mitigate this issue and enhance the reliability of clinical trial results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-related effects in clinical trials in schizophrenia: what is driving this phenomenon and what can be done to minimize it? Alphs, L., Benedetti, F., Fleischhacker, WW., et al.[2021]

In a study of 672 patients with schizophrenia, early improvement in symptoms (measured by a 10% reduction in PANSS score at week 1) was strongly predictive of a subsequent placebo response by week 6.

Lower baseline scores for disorganized thoughts also correlated with a higher likelihood of responding to placebo, suggesting that these factors can help identify potential placebo responders early in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo effects in adult and adolescent patients with schizophrenia: combined analysis of nine RCTs. Kubo, K., Fleischhacker, WW., Suzuki, T., et al.[2020]

Citations

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Effect of Sodium Benzoate vs Placebo Among Individuals With ... In this randomized clinical trial of 100 participants with early psychosis, there was no significant improvement in the total Positive and ...

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Add-on treatment of benzoate for schizophrenia Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia.

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Adaptive Phase II Study to Evaluate the Safety & Efficacy of ... The purpose of this study is to determine if NaBen® is a safe and effective add-on treatment for schizophrenia in adolescents. Detailed Description. This is a ...

4. jamanetwork.com jamanetwork.com/journals/jamapsychiatry/fullarticle/1746121

Add-on Treatment of Benzoate for Schizophrenia Conclusions and Relevance Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic ...

5. frontiersin.org frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2024.1370431/full

Effects of sodium benzoate on cognitive function in ... Our results were mostly consistent with theirs, with a notable exception. In our study, sodium benzoate demonstrated efficacy in reducing the total PANSS score.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34890931/

Efficacy and safety of add-on sodium benzoate, a D-amino ... Results: Add-on sodium benzoate can improve positive symptoms of schizophrenia significantly (MD: -1.87; 95%CI: -3.25 to -0.48; p = 0.008) but had no ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01908192

Adaptive Phase II Study to Evaluate the Safety & Efficacy of ... Study Overview. Brief Summary. The purpose of this study is to determine if NaBen® is a safe and effective add-on treatment for schizophrenia in adolescents.

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Add-on Sodium Benzoate and N-Acetylcysteine in Patients ... ... safety of NaB, for adults with schizophrenia ... Effect of sodium benzoate vs placebo among individuals with early psychosis: a randomized clinical trial.

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1876201821004032

Efficacy and safety of add-on sodium benzoate, a D-amino ... Add-on sodium benzoate can improve positive symptoms of schizophrenia significantly (MD: -1.87; 95%CI: -3.25 to -0.48; p = 0.008) but had no significant ...