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Trial registered on ANZCTR


Registration number
ACTRN12615000187549
Ethics application status
Approved
Date submitted
12/02/2015
Date registered
26/02/2015
Date last updated
31/07/2019
Date data sharing statement initially provided
31/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The Efficacy of Sodium Benzoate as an Adjunctive Treatment in Early Psychosis
Scientific title
The Efficacy of Sodium Benzoate as an Adjunctive Treatment in Early Psychosis
Secondary ID [1] 286135 0
None
Universal Trial Number (UTN)
U1111-1167-0649
Trial acronym
CADENCE-BZ
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Early psychosis (including schizophrenia, schizophreniform psychosis, delusional disorder, bipolar disorder, psychosis not otherwise specified) 294141 0
Condition category
Condition code
Mental Health 294462 294462 0 0
Schizophrenia
Mental Health 294560 294560 0 0
Psychosis and personality disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study will include 100 individuals with first episode psychosis who will be randomised to receive either 1g/d (500mg twice daily) of sodium benzoate or placebo (1:1 ratio) for 12 weeks, in addition to their normal routine care.

Participants will be requested to return all unused study medication (i.e. unopened blister packs or capsules not taken) and empty blister packs 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, 6, 8, 10 and 12. Weekly phone contact will occur in between face to face visits to monitor medication compliance and discuss any concerns the participant may raise regarding the trial medication. A post-completion visit will be conducted at week 14.
Intervention code [1] 291133 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] 294265 0
Positive and Negative Syndrome Scale (PANSS) total score
Timepoint [1] 294265 0
12 week assessment
Secondary outcome [1] 312902 0
Positive and Negative Syndrome Scale (PANSS) subscales
Timepoint [1] 312902 0
12 week assessment
Secondary outcome [2] 313079 0
Global Assessment of Function (GAF)
Timepoint [2] 313079 0
12 week assessment
Secondary outcome [3] 313082 0
Clinical Global Impression (CGI)
Timepoint [3] 313082 0
12 week assessment
Secondary outcome [4] 313083 0
Hamilton Depression rating Scale-17items (HDRS)
Timepoint [4] 313083 0
12 week assessment
Secondary outcome [5] 316683 0
Physical Activity Questionnaire (PAQ)
Outcome measure is level of physical activity.
Timepoint [5] 316683 0
week 2
Secondary outcome [6] 316684 0
Patient Global Impression (PGI)- Improvement
Outcome measure is overall patient impression of level of improvement related to the treatment.
Timepoint [6] 316684 0
week 12

Eligibility
Key inclusion criteria
1. Aged between 15 and 45 years (inclusive).
2. Fulfil the DSM-IV criteria practice for broadly defined early psychosis, based on the Diagnostic Interview for Psychosis. This includes diagnoses such as schizophrenia, schizophreniform psychosis, delusional disorder, bipolar disorder, psychosis not otherwise specified.
3. Have had the onset of a psychotic disorder within the last two years
4. Have received antipsychotic medications for a period of at least one continuous month within the above two year period.
5. Have a Positive and Negative Syndrome Scale (PANSS) total score of at least 55.
6. Agree to participate, has capacity to consent and able to follow the study instructions and procedures.
7. If under 18 years of age, a parent or legal guardian consents to the young person’s participation.
Minimum age
15 Years
Maximum age
45 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)
One hundred (100) participants will be recruited through the mental health services in five Queensland Hospital and Health Services.

After verbal consent is provided, an assessment of inclusion/exclusion criteria will commence. Participants who meet all inclusion criteria and none of the exclusion criteria will be invited to participate in the study and the formal consent process will commence. For those who consent to participate, they will be enrolled in the study and randomized according to allocation concealment methods.

Randomization lists will be created by an independent statistician, using computerised methods and provided to the manufacturer. The compounding manufacturer will develop the investigational product according to the randomized list. The independent manufacturer will hold the closed randomisation list and be the only one who has the ability to unblind a participant. The Research Pharmacist will dispense the investigational product based on the randomisation list provided. All study personnel (including the research pharmacist) 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)
Randomisation will be carried out using a computer-generated randomization table, stratified by five sites. Each of the five sites will have separate randomization tables. Participants will receive either active treatment or placebo in a 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 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
Analysis will be based on the Intention-to-treat (ITT) sample of all subjects who were randomized regardless of how many weeks of treatment they received. Baseline demographic and clinical characteristics of each treatment arm will be summarised using descriptive statistics and then compared using Chi-square for categorical variables or independent t-test for continuous variables. If these variables show significant differences between both treatment arms, we will adjust for these predictors in our multivariable analysis to account for any imbalance that may have occurred by chance between the randomized groups (i.e. despite randomization of treatment arm, the order of subject recruitment may result in an imbalance in variables such as age, sex, baseline PANSS etc) (1, 2). It is recommended that these variables are adjusted in assessing the primary outcome (3).Changes in clinical assessment will be assessed using the mixed-effects model repeated measures (MMRM). The MMRM is a superior approach when compared to the ‘last value carried forward’ approach in controlling for type I error and minimize bias as it does not impute or exclude participants with missing data (4). We will include baseline measure, treatment group, week, and treatment-week interaction as fixed effects and intercept as random effects in the model. Sensitivity analysis will be repeated based on the per-protocol population by including participants:
(i) that stayed on the trial for 12 weeks
(ii) whose treatment compliance >= 80%
(iii) with absence of major protocol violation
All statistical test will be conducted using the SAS software and will be evaluated at the .05 level, using two sided test.

1. Steyerberg EW, Bossuyt PM, Lee KL. Clinical trials in acute myocardial infarction: should we adjust for baseline characteristics? American heart journal. 2000;139(5):745-51.
2. Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, et al. CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340.
3. Rothman KJ. Epidemiologic methods in clinical trials. Cancer. 1977;39(4 Suppl):1771-5.
4. Siddiqui O, Hung HM, O'Neill R. MMRM vs. LOCF: a comprehensive comparison based on simulation study and 25 NDA datasets. Journal of biopharmaceutical statistics. 2009;19(2):227-46.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
17/08/2015
Actual
19/08/2015
Date of last participant enrolment
Anticipated
29/06/2018
Actual
10/07/2018
Date of last data collection
Anticipated
9/10/2018
Actual
9/10/2018
Sample size
Target
100
Accrual to date
Final
100
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 3431 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 3432 0
Ipswich Hospital - Ipswich
Recruitment hospital [3] 3433 0
The Prince Charles Hospital - Chermside
Recruitment hospital [4] 3434 0
Gold Coast Hospital - Southport
Recruitment hospital [5] 3435 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [6] 3436 0
Logan Hospital - Meadowbrook
Recruitment hospital [7] 3437 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [8] 8324 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [9] 8325 0
Caboolture Hospital - Caboolture
Recruitment postcode(s) [1] 9197 0
4305 - Ipswich
Recruitment postcode(s) [2] 9198 0
4006 - Herston
Recruitment postcode(s) [3] 9199 0
4032 - Chermside
Recruitment postcode(s) [4] 9200 0
4215 - Southport
Recruitment postcode(s) [5] 9201 0
4122 - Upper Mount Gravatt
Recruitment postcode(s) [6] 9202 0
4131 - Meadowbrook
Recruitment postcode(s) [7] 9203 0
4101 - South Brisbane
Recruitment postcode(s) [8] 16388 0
4575 - Birtinya
Recruitment postcode(s) [9] 16389 0
4510 - Caboolture

Funding & Sponsors
Funding source category [1] 290723 0
Government body
Name [1] 290723 0
National Health and Medical Research Council (NHMRC)
Country [1] 290723 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
St Lucia, QLD 4072
Country
Australia
Secondary sponsor category [1] 289410 0
None
Name [1] 289410 0
Address [1] 289410 0
Country [1] 289410 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292360 0
Metro South Hospital and Health Service Human Research Ethics Committee (EC00167)
Ethics committee address [1] 292360 0
Ethics committee country [1] 292360 0
Australia
Date submitted for ethics approval [1] 292360 0
05/11/2014
Approval date [1] 292360 0
12/02/2015
Ethics approval number [1] 292360 0
HREC/14/QPAH/598

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 54774 0
Prof John McGrath
Address 54774 0
Queensland Brain Institute
University of Queensland
St Lucia, QLD, 4072 Australia
Country 54774 0
Australia
Phone 54774 0
+61 7 3346 6372
Fax 54774 0
Email 54774 0
j.mcgrath@uq.edu.au
Contact person for public queries
Name 54775 0
John McGrath
Address 54775 0
Queensland Brain Institute
University of Queensland
St Lucia, QLD, 4072 Australia
Country 54775 0
Australia
Phone 54775 0
+61 7 3346 6372
Fax 54775 0
Email 54775 0
j.mcgrath@uq.edu.au
Contact person for scientific queries
Name 54776 0
John McGrath
Address 54776 0
Queensland Brain Institute
University of Queensland
St Lucia, QLD, 4072 Australia
Country 54776 0
Australia
Phone 54776 0
+61 7 3346 6372
Fax 54776 0
Email 54776 0
j.mcgrath@uq.edu.au

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
3569Study protocol    367929-(Uploaded-29-07-2019-12-20-17)-Study-related document.pdf
3570Statistical analysis plan    367929-(Uploaded-29-07-2019-12-20-17)-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
EmbaseThe efficacy of sodium benzoate as an adjunctive treatment in early psychosis - CADENCE-BZ: Study protocol for a randomized controlled trial.2017https://dx.doi.org/10.1186/s13063-017-1908-5
EmbaseProtocol update and statistical analysis plan for CADENCE-BZ: A randomized clinical trial to assess the efficacy of sodium benzoate as an adjunctive treatment in early psychosis.2019https://dx.doi.org/10.1186/s13063-019-3232-8
Dimensions AIEffect of Sodium Benzoate vs Placebo Among Individuals With Early Psychosis2020https://doi.org/10.1001/jamanetworkopen.2020.24335
N.B. These documents automatically identified may not have been verified by the study sponsor.