ANZCTR - Registration

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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]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Treatment refractory schizophrenia

Schizophrenia

Condition category

Condition code

Mental Health

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]

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]

Positive and Negative Syndrome Scale (PANSS) total score

Timepoint [1]

baseline (week 0), and weeks 2, 4, and 6
Primary timepoint 6 weeks

Secondary outcome [1]

Positive subscale of PANSS

Timepoint [1]

baseline (week 0), and weeks 2, 4, and 6

Secondary outcome [2]

Global Assessment of Function (GAF)

Timepoint [2]

baseline (week 0), and weeks 2, 4, and 6

Secondary outcome [3]

Clinical Global Impression (CGI)

Timepoint [3]

baseline (week 0), and weeks 2, 4, and 6

Secondary outcome [4]

Overall patient impression of treatment-related change as measured by Patient Global Impression (PGI)- Improvement

Timepoint [4]

baseline (week 0), and weeks 2, 4, and 6

Secondary outcome [5]

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]

baseline (week 0), and weeks 2, 4, and 6

Secondary outcome [6]

Negative subscale of PANSS

Timepoint [6]

baseline (week 0), and weeks 2, 4, and 6

Secondary outcome [7]

General psychopathology subscale of PANSS

Timepoint [7]

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]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [2]

The Prince Charles Hospital - Chermside

Recruitment hospital [3]

Caboolture Hospital - Caboolture

Recruitment hospital [4]

Ipswich Hospital - Ipswich

Recruitment postcode(s) [1]

4029 - Herston

Recruitment postcode(s) [2]

4032 - Chermside

Recruitment postcode(s) [3]

4510 - Caboolture

Recruitment postcode(s) [4]

4305 - Ipswich

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Royal Brisbane Hospital Foundation

Address [1]

Bowen Bridge Road,Herston, QLD 4006

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Brisbane & Women's Hospital Human Ethics Committee

Ethics committee address [1]

Level 14 Block 7
Royal Brisbane and Women's Hospital
Cnr Butterfield St and Bowen Bridge Rd
HERSTON QLD 4029

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

14/12/2020

Approval date [1]

04/01/2021

Ethics approval number [1]

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

Prof James Scott

Address

Metro North Mental Health Service
300 Herston Road
Herston QLD 4006

Country

Australia

Phone

+61 7 3845 3775

Fax

Email

[email protected]

Contact person for public queries

Name

James Scott

Address

Metro North Mental Health Service
300 Herston Road
Herston QLD 4006

Country

Australia

Phone

+61 7 3845 3775

Fax

Email

[email protected]

Contact person for scientific queries

Name

James Scott

Address

Metro North Mental Health Service
300 Herston Road
Herston QLD 4006

Country

Australia

Phone

+61 7 3845 3775

Fax

Email

[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.	Type	Citation	Link	Email	Other Details	Attachment
11012	Study protocol					381442-(Uploaded-15-03-2021-15-54-02)-Study-related document.docx
11013	Ethical 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

Source	Title	Year of Publication	DOI
Embase	Cadence discovery: study protocol for a dose-finding and mechanism of action clinical trial of sodium benzoate in people with treatment-refractory schizophrenia.	2021	https://dx.doi.org/10.1186/s13063-021-05890-6
Embase	Progress and Pitfalls in Developing Agents to Treat Neurocognitive Deficits Associated with Schizophrenia.	2022	https://dx.doi.org/10.1007/s40263-022-00935-z

N.B. These documents automatically identified may not have been verified by the study sponsor.