Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000327886
Ethics application status
Approved
Date submitted
15/02/2021
Date registered
23/03/2021
Date last updated
28/04/2024
Date data sharing statement initially provided
23/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Dose finding clinical trial of sodium benzoate in people with treatment refractory schizophrenia
Scientific title
Dose finding clinical trial of sodium benzoate in people with treatment refractory schizophrenia
Secondary ID [1] 303471 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment refractory schizophrenia 320780 0
Schizophrenia 320781 0
Condition category
Condition code
Mental Health 318603 318603 0 0
Schizophrenia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will include 52 individuals with treatment refractory schizophrenia who will be randomised to receive 1000mg daily (500mg twice daily) or 2000mg daily (1000mg twice daily) or 4000mg daily (2000mg twice daily) of Sodium Benzoate or placebo for 6 weeks, in addition to their normal routine care.

Participants will be requested to return all unused study medication (i.e. capsules not taken) to the delegated research assistants. All unused supplies of study medication will be accounted for and documented by the designated Research Pharmacist. Compliance with study medication will be calculated at each visit by means of self-report and a capsule count

Face to face clinical assessments will be at baseline (week 0) and weeks 2, 4 and 6. Weekly phone contact will occur in between face to face visits.
Intervention code [1] 319760 0
Treatment: Drugs
Comparator / control treatment
This study will use a placebo (microcrystalline cellulose gelatine capsules) adjunct to routine care as a comparator condition
Control group
Placebo

Outcomes
Primary outcome [1] 326564 0
Positive and Negative Syndrome Scale (PANSS) total score
Timepoint [1] 326564 0
baseline (week 0), and weeks 2, 4, and 6
Primary timepoint 6 weeks
Secondary outcome [1] 391883 0
Positive subscale of PANSS
Timepoint [1] 391883 0
baseline (week 0), and weeks 2, 4, and 6
Secondary outcome [2] 391884 0

Global Assessment of Function (GAF)
Timepoint [2] 391884 0
baseline (week 0), and weeks 2, 4, and 6
Secondary outcome [3] 391886 0
Clinical Global Impression (CGI)
Timepoint [3] 391886 0
baseline (week 0), and weeks 2, 4, and 6
Secondary outcome [4] 391887 0

Overall patient impression of treatment-related change as measured by Patient Global Impression (PGI)- Improvement
Timepoint [4] 391887 0
baseline (week 0), and weeks 2, 4, and 6
Secondary outcome [5] 391888 0
Safety and tolerablity of the three doses (1000mg daily, 2000mg daily or 4000mg daily) of sodium benzoate under investigation measured by participant self-report of adverse events,
Timepoint [5] 391888 0
baseline (week 0), and weeks 2, 4, and 6
Secondary outcome [6] 392860 0
Negative subscale of PANSS
Timepoint [6] 392860 0
baseline (week 0), and weeks 2, 4, and 6
Secondary outcome [7] 392861 0
General psychopathology subscale of PANSS
Timepoint [7] 392861 0
baseline (week 0), and weeks 2, 4, and 6

Eligibility
Key inclusion criteria
1.Aged between 18 and 64 years (inclusive).
2.Fulfil the DSM-IV criteria practice for schizophrenia, based on the Diagnostic Interview for Psychosis.
3.Have had the diagnosis of schizophrenia for at least 12 months duration
4.Have a Positive and Negative Syndrome Scale (PANSS) total score greater than or equal to 70
5.Have received antipsychotic medications for a period of at least one continuous month prior to assessment for the study and remained symptomatic despite taking antipsychotic therapy
6.Agree to participate, has capacity to consent and able to follow the study instructions and procedures.
Minimum age
18 Years
Maximum age
64 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.Known allergies to sodium benzoate (E211) or any part of the formulation of the
investigational product.
2.Suspected allergies or known adverse reactions to food preservatives in general.
3.Comorbid physical illnesses that would impair the participants’ ability to complete the trial.
4.People who are unable to understand or communicate in English.
5.For female participant, those currently pregnant, or planning to become pregnant or lactating during the study period.
6.Inability to follow the study instructions and procedures.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
For those who consent to participate, they will be enrolled in the study and randomized according to allocation concealment methods.

An independent Biostatistician will generate the randomisation list which will be provided to the designated Research Pharmacist only. The designated Research Pharmacist will hold the closed randomisation list and dispence trial medication according to the randomisation list.

The designated Research Pharmacist will dispense the investigational product based on the randomisation list provided. All study personnel will be blinded to a participants’ drug group allocation (placebo versus active).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Participants will be randomised to one of the treatment groups, using a computer-generated randomization table. Participants will receive either active treatment or placebo in a 1:1:1:1 ratio.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
The primary analysis will be a mixed effect repeated measures analysis comparing total PANSS scores across 4 time points (baseline, 2, 4, and 6 weeks) across 4 dose groups (placebo, 1000mg, 2000mg, and 4000mg). Based on our previous study total PANSS score had a standard deviation of around 15 for all subjects, and closer to 10 for cases with baseline PANSS scores > 75. The autoregressive (AR(1)) correlation between weeks was estimated at 0.815. Assuming a decrease in PANSS scores similar to our previous study, of 7 point in the first 2 weeks and an additional 3 points per 2-week period thereafter, this study has at least 80% power to detect an effect size of 0.55 between treatments. Power calculations were performed in PASS (v 2020 Power Analysis and Sample Size Software (2020). NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass) using the repeated measures platform.

All data will be analysed using SAS 9.4. We will compare demographic and clinical differences between the groups at baseline (Fisher exact test for nominal variables and Mann-Whitney test or independent sample t test for continuous variables). Efficacy will be
assessed according to standard Intention to Treat (ITT) analytic procedures (i.e. for those who do not complete the 6 week study period, we will carry forward their last observation on the study outcomes). Mean changes in clinical assessment will be assessed using mixed-model repeated-measure (MMRM) methods with treatment, week, and treatment-week interaction as fixed effects and intercept as the only random effect; baseline value will be the covariant. The MMRM analyses will be performed using the SAS PROC Mixed procedure. P values will be based on 2-tailed tests with significance levels of 0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
29/11/2021
Actual
21/12/2021
Date of last participant enrolment
Anticipated
30/04/2025
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
52
Accrual to date
36
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 18728 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 18729 0
The Prince Charles Hospital - Chermside
Recruitment hospital [3] 18730 0
Caboolture Hospital - Caboolture
Recruitment hospital [4] 18731 0
Ipswich Hospital - Ipswich
Recruitment postcode(s) [1] 33172 0
4029 - Herston
Recruitment postcode(s) [2] 33173 0
4032 - Chermside
Recruitment postcode(s) [3] 33174 0
4510 - Caboolture
Recruitment postcode(s) [4] 33175 0
4305 - Ipswich

Funding & Sponsors
Funding source category [1] 307888 0
Charities/Societies/Foundations
Name [1] 307888 0
Royal Brisbane Hospital Foundation
Country [1] 307888 0
Australia
Primary sponsor type
Hospital
Name
QIMR Berghofer Medical Institute of Research
Address
300 Herston Rd, Herston QLD 4006
Country
Australia
Secondary sponsor category [1] 308597 0
None
Name [1] 308597 0
Address [1] 308597 0
Country [1] 308597 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307887 0
Royal Brisbane & Women's Hospital Human Ethics Committee
Ethics committee address [1] 307887 0
Level 14 Block 7
Royal Brisbane and Women's Hospital
Cnr Butterfield St and Bowen Bridge Rd
HERSTON QLD 4029
Ethics committee country [1] 307887 0
Australia
Date submitted for ethics approval [1] 307887 0
14/12/2020
Approval date [1] 307887 0
04/01/2021
Ethics approval number [1] 307887 0
HREC/2020/QRBW/66768

Summary
Brief summary
The study will be a randomised, placebo-controlled double-blind parallel-group trial; over a 6 week period. The primary objective in this study is to determine the dose of sodium benzoate which maximises the clinical benefits in patients with treatment refractory schizophrenia. Specifically, it is hypothesised those participants allocated to the active arms (1000mg daily or 2000mg daily or 4000mg daily) of Sodium Benzoate treatment will have significant reductions in PANSS total score at week 6 compared to individuals taking placebo.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108826 0
Prof James Scott
Address 108826 0
Metro North Mental Health Service
300 Herston Road
Herston QLD 4006
Country 108826 0
Australia
Phone 108826 0
+61 7 3845 3775
Fax 108826 0
Email 108826 0
[email protected]
Contact person for public queries
Name 108827 0
Prof James Scott
Address 108827 0
Metro North Mental Health Service
300 Herston Road
Herston QLD 4006
Country 108827 0
Australia
Phone 108827 0
+61 7 3845 3775
Fax 108827 0
Email 108827 0
[email protected]
Contact person for scientific queries
Name 108828 0
Prof James Scott
Address 108828 0
Metro North Mental Health Service
300 Herston Road
Herston QLD 4006
Country 108828 0
Australia
Phone 108828 0
+61 7 3845 3775
Fax 108828 0
Email 108828 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There will be no IPD sharing for this project. Group data analysis will be conducted and this data will be used for all publications.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11012Study protocol    381442-(Uploaded-15-03-2021-15-54-02)-Study-related document.docx
11013Ethical approval    381442-(Uploaded-15-03-2021-15-54-28)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseCadence discovery: study protocol for a dose-finding and mechanism of action clinical trial of sodium benzoate in people with treatment-refractory schizophrenia.2021https://dx.doi.org/10.1186/s13063-021-05890-6
EmbaseProgress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia.2022https://dx.doi.org/10.1007/s40263-022-00935-z
N.B. These documents automatically identified may not have been verified by the study sponsor.