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

Trial Summary

What is the purpose of this trial?

This is an adaptive, Phase II/III study in 2 parts (i.e. Part 1 (dose ranging) and Part 2 (Hypothesis testing)). NaBen® is granted Breakthrough Therapy Designation by US FDA as treatment for refractory schizophrenia. Part 1 Objectives: There are two primary objectives for Part 1 of this study: 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 Part 2 of the study The secondary objective of the 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. Part 2 Objectives: The primary objective of the Part 2 of this study is to evaluate the effectiveness of NaBen® (at the optimal dose determined in the 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. The secondary objective of the Part 2 of this study is to evaluate the safety and tolerability of NaBen® (at the optimal dose determined in the Part 1 of this study) compared to Placebo (0 mg/day), in combination with clozapine.

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.

What data supports the idea that NaBen Add-On Therapy for Schizophrenia is an effective drug?

The available research shows that drugs, in general, have greater effectiveness than placebo in reducing negative symptoms in schizophrenia, although the effect size is small. This suggests that NaBen Add-On Therapy, as a drug, may also be effective in treating schizophrenia, but the data does not specifically highlight its effectiveness compared to other treatments. ^{1 2 3 4 5}

What safety data is available for NaBen Add-On Therapy for Schizophrenia?

The provided research does not contain specific safety data for NaBen Add-On Therapy, Sodium Benzoate, or NaBen®. The studies focus on other antipsychotic drugs and placebo responses in schizophrenia trials, but do not mention NaBen or Sodium Benzoate. Therefore, no relevant safety data for NaBen is available in the given research. ^{3 6 7 8 9}

Is the placebo a promising treatment for schizophrenia?

The placebo is not a promising treatment for schizophrenia. Studies show that actual drugs are more effective than placebos in reducing symptoms, even though placebos can sometimes show some effect. Overall, drugs have a greater impact on improving the condition. ^{1 2 3 10 11}

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

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]

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]

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]

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 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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Schizophrenia: do we really need placebo-controlled studies? [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Early onset of antipsychotic action in schizophrenia: evaluating the possibility of shorter acute efficacy trials. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Predictors of Placebo Response in Pharmacological Clinical Trials of Negative Symptoms in Schizophrenia: A Meta-regression Analysis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Placebo response in clinical trials with schizophrenia patients. [2011]

5. United States pubmed.ncbi.nlm.nih.gov

Placebo effects in adult and adolescent patients with schizophrenia: combined analysis of nine RCTs. [2020]

6. United States 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. [2022]

7. Switzerland 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. [2022]

8. Japan pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of oral blonanserin for schizophrenia: A review of Japanese post-marketing surveillances. [2021]

9. Netherlands pubmed.ncbi.nlm.nih.gov

The risk of death among adult participants in trials of antipsychotic drugs in schizophrenia. [2010]

10. England 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? [2021]

11. United States pubmed.ncbi.nlm.nih.gov

Control group bias in randomized atypical antipsychotic medication trials for schizophrenia. [2007]