ANZCTR - Registration

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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]

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

Condition category

Condition code

Mental Health

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]

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]

Change from baseline in total score on the Positive and Negative Symptoms Scale (PANSS) total score for NAC versus placebo

Timepoint [1]

4-, 8-, 12-, 26- (primary time point) and 52-weeks post commencement of intervention

Secondary outcome [1]

Change from baseline for positive subscale of the PANSS, for NAC versus placebo

Timepoint [1]

4-, 8-, 12-, 26- and 52-weeks post commencement of intervention

Secondary outcome [2]

Change from baseline for Montgomery Åsberg Depression Rating Scale (MADRS) depressive symptom scores for NAC versus placebo

Timepoint [2]

4-, 8-, 12-, 26- and 52-weeks post commencement of intervention

Secondary outcome [3]

Change from baseline in functioning (Social and Occupational Functioning Assessment Scale, Sheehan Disability Scale), for NAC versus placebo

Timepoint [3]

4-, 8-, 12-, 26- and 52-weeks post commencement of intervention

Secondary outcome [4]

Change from baseline in quality of life (Assessment of Quality of Life, AQoL-8D), for NAC versus placebo

Timepoint [4]

4-, 8-, 12-, 26- and 52-weeks post commencement of intervention

Secondary outcome [5]

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]

26- and 52-weeks post commencement of intervention

Secondary outcome [6]

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]

26- and 52-weeks post commencement of intervention

Secondary outcome [7]

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]

26- and 52-weeks post commencement of intervention

Secondary outcome [8]

Change from baseline in magnetic resonance spectroscopy (MRS; brain-derived measures of glutathione) for NAC versus placebo

Timepoint [8]

26-weeks post commencement of intervention

Secondary outcome [9]

Change from baseline in diffusion tensor imaging (DTI) derived measures of structural connectivity for NAC versus placebo

Timepoint [9]

26-weeks post commencement of intervention

Secondary outcome [10]

Change from baseline in MRI derived measures of functional (resting state) brain activity for NAC versus placebo

Timepoint [10]

26-weeks post commencement of intervention

Secondary outcome [11]

Change from baseline for negative subscale of the PANSS, for NAC versus placebo

Timepoint [11]

4-, 8-, 12-, 26- and 52-weeks post commencement of intervention

Secondary outcome [12]

Change from baseline for general subscale of the PANSS, for NAC versus placebo

Timepoint [12]

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

Sex

Both males and females

Can healthy volunteers participate?

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

2/04/2018

Actual

13/12/2018

Date of last participant enrolment

Anticipated

30/09/2021

Actual

Date of last data collection

Anticipated

30/09/2022

Actual

Sample size

Target

162

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment postcode(s) [1]

3052 - Parkville

Recruitment postcode(s) [2]

3020 - Sunshine

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

GHD Building Level 1, 16 Marcus Clarke St, Canberra ACT 2601

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health Human Research Ethics Committee

Ethics committee address [1]

Level 2
South West
300 Grattan Street
Parkville Victoria 3052

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

27/09/2017

Approval date [1]

06/12/2017

Ethics approval number [1]

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

Prof Sue Cotton

Address

Orygen, The National Centre of Excellence in Youth Mental Health 35 Poplar Rd Parkville VIC 3025

Country

Australia

Phone

+61 3 9342 2859

Fax

[email protected]

Contact person for public queries

Name

Sue Cotton

Address

Orygen, The National Centre of Excellence in Youth Mental Health 35 Poplar Rd Parkville VIC 3025

Country

Australia

Phone

+61 3 9342 2859

Fax

[email protected]

Contact person for scientific queries

Name

Sue Cotton

Address

Orygen, The National Centre of Excellence in Youth Mental Health 35 Poplar Rd Parkville VIC 3025

Country

Australia

Phone

+61 3 9342 2859

Fax

[email protected]

Data sharing statement

Will the study consider sharing individual participant data?

Yes

Will there be any conditions when requesting access to individual participant data?

Persons/groups eligible to request access:
• Data will potentially be available to researchers from not-for-profit organisations, commercial organisations or other based in any location. All data requests will be considered by the data custodian and the primary sponsor on a case-by-case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted. For further information, see Orygen's data management policy.

Conditions for requesting access:
• -

What individual participant data might be shared?

• All of the individual participant data collected during the trial, after de-identification.

What types of analyses could be done with individual participant data?

• To any type of analyses; assessed on a case-by-case basis.

When can requests for individual participant data be made (start and end dates)?

From:
Data will be available after the main results have been published for an indefinite time.

To:
-

Where can requests to access individual participant data be made, or data be obtained directly?

• Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health). Search for the ACTRN number in the catalogue to find datasets associated with this trial.

Are there extra considerations when requesting access to individual participant data?

What supporting documents are/will be available?

Current supporting documents:

Updated to:

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
23564	Study protocol		https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3786-5

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	ENACT: A protocol for a randomised placebo-controlled trial investigating the efficacy and mechanisms of action of adjunctive N-acetylcysteine for first-episode psychosis.	2019	https://dx.doi.org/10.1186/s13063-019-3786-5

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

Trial Review

Documents added manually

Documents added automatically