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Trial registered on ANZCTR


Registration number
ACTRN12618000413224
Ethics application status
Approved
Date submitted
24/01/2018
Date registered
21/03/2018
Date last updated
22/02/2019
Date data sharing statement initially provided
22/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
The efficacy and mechanisms of action of N-acetylcysteine as an adjunct treatment for first episode psychosis.
Scientific title
The efficacy and mechanisms of action of N-acetylcysteine as an adjunct treatment for first episode psychosis.
Secondary ID [1] 293096 0
None
Universal Trial Number (UTN)
U1111-1203-4178
Trial acronym
ENACT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
First episode psychosis 305033 0
Condition category
Condition code
Mental Health 304357 304357 0 0
Psychosis and personality disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
N-acetylcysteine 2000mg once daily (2 x oral capsules 1000mg each capsule) for 26 weeks. Medication adherence will be assessed using the Medication Adherence Rating Scale, and returned study medication will be counted and recorded.
Intervention code [1] 299335 0
Treatment: Drugs
Comparator / control treatment
The study is placebo-controlled. Placebo consists of 2000mg microcrystalline cellulose (2 x oral capsules 1000mg each capsule) for 26 weeks, with excipients matched to active treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 303656 0
Change from baseline in total score on the Positive and Negative Symptoms Scale (PANSS) total score for NAC versus placebo
Timepoint [1] 303656 0
4-, 8-, 12-, 26- (primary time point) and 52-weeks post commencement of intervention
Secondary outcome [1] 339800 0
Change from baseline for positive subscale of the PANSS, for NAC versus placebo
Timepoint [1] 339800 0
4-, 8-, 12-, 26- and 52-weeks post commencement of intervention
Secondary outcome [2] 339821 0
Change from baseline for Montgomery Åsberg Depression Rating Scale (MADRS) depressive symptom scores for NAC versus placebo
Timepoint [2] 339821 0
4-, 8-, 12-, 26- and 52-weeks post commencement of intervention
Secondary outcome [3] 339822 0
Change from baseline in functioning (Social and Occupational Functioning Assessment Scale, Sheehan Disability Scale), for NAC versus placebo
Timepoint [3] 339822 0
4-, 8-, 12-, 26- and 52-weeks post commencement of intervention
Secondary outcome [4] 339825 0
Change from baseline in quality of life (Assessment of Quality of Life, AQoL-8D), for NAC versus placebo
Timepoint [4] 339825 0
4-, 8-, 12-, 26- and 52-weeks post commencement of intervention
Secondary outcome [5] 339826 0
Change from baseline in neurocognitive functioning (CogState; Rey Auditory Verbal Learning Test (RAVLT); Symbol Digit Modality Test (SDMT); Digit Span) for NAC versus placebo
Timepoint [5] 339826 0
26- and 52-weeks post commencement of intervention
Secondary outcome [6] 339827 0
Change from baseline on blood-derived measures of inflammation for NAC versus placebo. A number of cytokines associated with acute and chronic inflammation will be assessed and may include for example interleukin-6, tumor necrosis factor – alpha, and C-reactive protein. However, as blood samples will be processed at the end of the trial it is possible that other/additional markers may be identified over the course of the trial as important in identifying inflammatory processes in first episode psychosis, and may also be included in the analysis.


Timepoint [6] 339827 0
26- and 52-weeks post commencement of intervention
Secondary outcome [7] 339831 0
Change from baseline on blood-derived measures of oxidative and nitrosative stress for NAC versus placebo. This can be considered a composite secondary outcome as the measures are very closely related and are interdependent. Antioxidant status will be assessed by examining the glutathione:oxidised glutathione ratio and total reactive antioxidant potential. Malondialdehyde will be used as a marker of oxidative and nitrosative stress. As with markers of inflammation, by the end of the trial period other markers may be demonstrated to be associated with antioxidant status and oxidative and nitrosative stress may also be included in the analysis.
Timepoint [7] 339831 0
26- and 52-weeks post commencement of intervention
Secondary outcome [8] 343131 0
Change from baseline in magnetic resonance spectroscopy (MRS; brain-derived measures of glutathione) for NAC versus placebo
Timepoint [8] 343131 0
26-weeks post commencement of intervention
Secondary outcome [9] 343133 0
Change from baseline in diffusion tensor imaging (DTI) derived measures of structural connectivity for NAC versus placebo
Timepoint [9] 343133 0
26-weeks post commencement of intervention
Secondary outcome [10] 343134 0
Change from baseline in MRI derived measures of functional (resting state) brain activity for NAC versus placebo
Timepoint [10] 343134 0
26-weeks post commencement of intervention
Secondary outcome [11] 344495 0
Change from baseline for negative subscale of the PANSS, for NAC versus placebo
Timepoint [11] 344495 0
4-, 8-, 12-, 26- and 52-weeks post commencement of intervention
Secondary outcome [12] 344496 0
Change from baseline for general subscale of the PANSS, for NAC versus placebo
Timepoint [12] 344496 0
4-, 8-, 12-, 26- and 52-weeks post commencement of intervention

Eligibility
Key inclusion criteria
i. Aged 15 to 25 years at time of study enrolment;
ii. Treatment stability: at least two weeks of stability in the use of primary medication
(e.g., anti-psychotic medications)
iii. Within their first three months of admission to the Early Psychosis Prevention and
Intervention Centre (EPPIC); and
iv. Capacity to consent to the study and comply with study procedures.
Minimum age
15 Years
Maximum age
25 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i. Previous episode of psychosis or previously been treated with an anti-psychotic
prior to entry to the program;
ii. Known or suspected clinically relevant systemic medical disorder;
iii. Females who are pregnant or lactating;
iv. Prior sensitivity or allergy to NAC;
v. Currently enrolled in another research study
vi. Inability to comply with either the requirements of informed consent or the treatment
protocol; and/or
vii. Non-fluency in English

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)
The allocation schedule will be held within the web-based Research Project Management System (RPMS) which has been developed at Orygen and will only be accessible to the unblinded statistician, unblinded study monitor and database manager. Treatment allocation will be made available to the trial pharmacist after eligibility to the trial has been confirmed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation sequence will be based on a permutated block randomisation scheme with stratification for site. The randomisation sequence will be computer-generated by a statistician who is independent of the day-to-day conduct of the trial.
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 3 / Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Previously, moderate effects (Cohen’s d= 0.57) have been observed in those who received NAC on global symptom outcomes over a 24 week period (Berk et al., 2008). A conservative estimate of effect of 0.45 (Cohen’s d) for between group differences on the PANSS total score. With power (1-ß) set at 0.80, alpha (a) set at .05, and a one-tailed test a sample size of 124 (62 per group) was estimated. Allowing for attrition rate of 30%, a total sample size of 162 (81 per group) is needed.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 18027 0
3020 - Sunshine
Recruitment postcode(s) [2] 18026 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 297721 0
Government body
Name [1] 297721 0
National Health and Medical Research Council
Address [1] 297721 0
GHD Building Level 1, 16 Marcus Clarke St, Canberra ACT 2601
Country [1] 297721 0
Australia
Primary sponsor type
Other
Name
Orygen, The National Centre of Excellence in Youth Mental Health
Address
35 Poplar Rd
Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 296982 0
None
Name [1] 296982 0
Address [1] 296982 0
Country [1] 296982 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298787 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 298787 0
Level 2
South West
300 Grattan Street
Parkville Victoria 3052
Ethics committee country [1] 298787 0
Australia
Date submitted for ethics approval [1] 298787 0
27/09/2017
Approval date [1] 298787 0
06/12/2017
Ethics approval number [1] 298787 0

Summary
Brief summary
First episode psychosis (FEP) may lead to devastating, chronic illness. For many individuals with FEP, a progressive worsening of symptoms, decline in cognition, and associated reduction in quality of life is often observed. There is evidence to suggest that this illness progression can be diminished, and perhaps even averted, if appropriate treatments are given at the early stages of illness. N-acetyl cysteine (NAC) is a supplement form of an amino acid antioxidant found naturally in foods such as meat, fish and green leafy vegetables. NAC is currently used for treating some respiratory conditions and paracetamol overdose. NAC boosts the body’s antioxidant defences. There is evidence that the antioxidant defences are impaired in people who suffer from psychotic disorders. Antipsychotic medication is currently the best treatment for FEP; however, sometimes these medications are not effective at treating all of the symptoms of psychosis such as negative and cognitive symptoms. Several studies have shown a significant benefit for NAC in schizophrenia and bipolar disorder when it has been used in addition to antipsychotics; however, its benefits have not yet been determined for individuals with FEP. In this project we will test if NAC administered to young people who have experienced FEP can help to reduce some of the symptoms they experience. We will also investigate whether NAC can help to prevent this early psychotic experience from developing into a chronic disorder. Young people between the ages of 15 - 25 years admitted to the Early Psychosis Prevention and Intervention Centre for treatment of first episode of psychosis (N=162) will be randomised to 2000 mg daily NAC or placebo for 26 weeks, with a further 26-week non-treatment follow-up period, as an addition to treatment as usual (TAU). The primary outcome is reduction in global symptom severity. A range of symptomatic, functioning, quality of life, neuropsychological, neuroimaging and blood biomarkers of inflammation, oxidative and nitrostative stress measures will be included as secondary outcomes. Through this study, we will not only determine the clinical efficacy of NAC as an adjunct treatment for FEP, but potentially unlock some of the neurobiological mechanisms underpinning psychotic disorders.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 78230 0
Prof Sue Cotton
Address 78230 0
Orygen, The National Centre of Excellence in Youth Mental Health
35 Poplar Rd
Parkville VIC 3025
Country 78230 0
Australia
Phone 78230 0
+61 3 9342 2859
Fax 78230 0
Email 78230 0
sue.cotton@orygen.org.au
Contact person for public queries
Name 78231 0
Prof Sue Cotton
Address 78231 0
Orygen, The National Centre of Excellence in Youth Mental Health
35 Poplar Rd
Parkville VIC 3025
Country 78231 0
Australia
Phone 78231 0
+61 3 9342 2859
Fax 78231 0
Email 78231 0
sue.cotton@orygen.org.au
Contact person for scientific queries
Name 78232 0
Prof Sue Cotton
Address 78232 0
Orygen, The National Centre of Excellence in Youth Mental Health
35 Poplar Rd
Parkville VIC 3025
Country 78232 0
Australia
Phone 78232 0
+61 3 9342 2859
Fax 78232 0
Email 78232 0
sue.cotton@orygen.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification.
When will data be available (start and end dates)?
Immediately following publication and for a further 3 years.
Available to whom?
Investigators whose proposed use of the data has been approved by an independent review committee.
Available for what types of analyses?
To achieve aims outlined in the approved protocol
How or where can data be obtained?
Proposals can be submitted up to three years following article publication. Initial contact should be directed to an Executive Officer at Orygen, The National Centre of Excellence in Youth Mental Health, located in Parkville, Victoria. Phone +61 (0) 3 9966 9574 or via https://www.orygen.org.au/Contact/Contact-Us#ContactForm. Note: To gain access to the data requesters must sign a data access agreement.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Summary results
No Results