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Trial registered on ANZCTR


Registration number
ACTRN12615001273572
Ethics application status
Approved
Date submitted
18/11/2015
Date registered
23/11/2015
Date last updated
11/02/2021
Date data sharing statement initially provided
23/07/2019
Date results information initially provided
11/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
N-Acetyl Cysteine In Schizophrenia Resistant To Clozapine: A Double-Blind Randomised Placebo-Controlled Trial Targeting Negative Symptoms
Scientific title
N-Acetyl Cysteine In Schizophrenia Resistant To Clozapine: A Double-Blind Randomised Placebo-Controlled Trial Targeting Negative Symptoms
Secondary ID [1] 287845 0
Nil known
Universal Trial Number (UTN)
Trial acronym
ENHANCE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Schizophrenia resistant to clozapine 296731 0
Condition category
Condition code
Mental Health 296971 296971 0 0
Schizophrenia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In this study, the efficacy and tolerability 2g daily of oral N-acetyl cysteine (NAC) will be compared to placebo as an augmenting strategy in patients with SZ who have proven ‘resistant’ to clozapine. All participants will remain on clozapine for the duration of the trial (i.e. 52 weeks). Adherence will be monitored with pill checks at each visit and the supervision of all doses.
Intervention code [1] 293260 0
Treatment: Drugs
Comparator / control treatment
Placebo (lactose tablet).
Control group
Placebo

Outcomes
Primary outcome [1] 296612 0
Negative symptoms as assessed with the Positive and Negative Symptoms Scale (PANSS)
Timepoint [1] 296612 0
8, 24 and 52 weeks.
Secondary outcome [1] 318925 0
Cognition as assessed by the MATRICS.
Timepoint [1] 318925 0
8,24 and 52 weeks
Secondary outcome [2] 319054 0
Quality of life as assessed by the Manchester Short Assessment of Quality of Life (MANSA) and the Assessment of Quality of Life (AQoL)
Timepoint [2] 319054 0
8, 24 and 52 weeks
Secondary outcome [3] 319055 0
Peripheral and cortical glutathione concentrations as assessed through blood samples and magnetic resonance spectroscopy, respectively.
Timepoint [3] 319055 0
8, 24 and 52 weeks
Secondary outcome [4] 319056 0
Biomarkers pertinent to glutathione (including thiols (such as GSH, cysteine, cysteinyl-glycine, N-acetylcysteine) and corresponding disulphides (such as glutathione disulphide (GSSG) and cysteine), other markers of oxidative stress (lipid peroxidation – thiobarbaturic acid -TBARS, DNA damage - 8-oxoguanine and protein carbonylation) and antioxidant levels).
Timepoint [4] 319056 0
8, 24 and 52 weeks

Eligibility
Key inclusion criteria
To be included the participants will be required to meet DSM5 criteria for SZ and:
- Have been on clozapine at an adequate dose, ascertained by a serum level of >350mcg/L for at least 6 months with residual symptom
- Have a PANSS score of 60 or at least two negative symptom items of >4
- Have the capacity to consent to the study
- Aged between 18 and 65 years
- Be utilising effective contraception if female and of childbearing age
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Participants who are currently taking NAC
- Participants who are allergic to NAC or any component of the preparation
- Inability to comply with either the requirements of informed consent or the treatment protocol.
- People taking nitro-glycerine
- Diabetics on insulin replacement
- People taking Selenium or Vitamin E

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)
Allocation will be concealed from local investigators, who will assign a number to the participant that will be linked to a prescription from the associated pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed independently of the researchers by a statistician and will have a permuted block randomisation.
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
The proposed trial is a randomised controlled double blinded superiority trial of two parallel patient groups.
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Intention-to-treat analysis will be employed to prevent over-estimation of efficacy. Categorical variables will be analysed using chi-squared tests (or Fisher’s exact test for small samples). A mixed-effects model, repeated measures (MMRM) approach will be used to examine the longitudinal profile of all continuous variables at weeks 8, 24, and 52 post-baseline. For all MMRM analyses, baseline scores will be used as covariates and the models will include pre-specified fixed effects of treatment, site, and time, and treatment-by-time and treatment-by-site interactions.
The MMRM modelling for the primary outcome measure – PANSS Negative scores – will also include baseline PANSS Positive, Negative, and General Psychopathology scores, CDSS scores, and extrapyramidal side effects (AIMS, SAS) as covariates. The secondary outcomes consist of CDSS, LQoLP, and MCCB global score, while the process outcomes include GSH concentrations peripherally and cortically, respectively.
Secondary analyses using Analysis of Covariance will be conducted to compare change scores during treatment and follow-up phases for all primary, secondary, and process outcomes using treatment group as a main effect with the baseline score as a covariate. Correlational analyses will also be performed to examine for relationships between outcome variables (i.e. treatment response with cognition and GSH levels, peripherally and cortically).
Power was calculated to detect a medium effect size of d = 0.5. The calculations followed the method described by Diggle et al. and assumed one primary outcome measure (PANSS Negative scores), four assessment points (baseline, 8-weeks, 26-weeks, and 52-weeks follow-ups), a study-wide Type I error rate (alpha) of .05, a Type II error rate (beta) of .10 (power of .90), a correlation of post-treatment scores with baseline measurements (rho) of 0.70, and a two-tailed statistical test. To detect the effect size of d = 0.5, 45 participants in each of the control and intervention groups will be required. Allowing for up to 46% attrition (based on a 20% dropout over the first 8 weeks and a further 30% dropout over the ensuing 44 weeks), a total of 168 participants, or 84 in each group will be recruited. Similar attrition rates are reported in other treatment trials with treatment resistant SZ. To accommodate the required number of patients, at least 42 patients will need to be recruited from each of the four study sites. For the MRS component, groups of 15-20 are widely accepted as an appropriate size to permit appropriate neuroimaging analysis.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Other reasons/comments
Other reasons
Due to COVID-19 we were not able to continue recruitment safely and staff funding ran out in the meantime.
Date of first participant enrolment
Anticipated
1/06/2016
Actual
23/03/2017
Date of last participant enrolment
Anticipated
Actual
31/05/2019
Date of last data collection
Anticipated
Actual
10/02/2020
Sample size
Target
168
Accrual to date
Final
85
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 4630 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [2] 4631 0
Cumberland Hospital - Westmead
Recruitment hospital [3] 4632 0
Westmead Hospital - Westmead
Recruitment hospital [4] 4648 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [5] 4649 0
Logan Hospital - Meadowbrook
Recruitment hospital [6] 4650 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [7] 4651 0
Modbury Hospital - Modbury
Recruitment hospital [8] 4652 0
Redland Hospital - Cleveland

Funding & Sponsors
Funding source category [1] 292388 0
Government body
Name [1] 292388 0
NHMRC
Country [1] 292388 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
The University of Melbourne, Parkville, VIC 3010
Country
Australia
Secondary sponsor category [1] 291075 0
None
Name [1] 291075 0
Address [1] 291075 0
Country [1] 291075 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293861 0
St Vincent's Hospital Melbourne Human Research Ethics Committee D
Ethics committee address [1] 293861 0
41 Victoria Parade, Fitzroy VIC 3065
Ethics committee country [1] 293861 0
Australia
Date submitted for ethics approval [1] 293861 0
15/12/2015
Approval date [1] 293861 0
30/03/2016
Ethics approval number [1] 293861 0

Summary
Brief summary
A proportion of individuals with schizophrenia (SZ) do not respond adequately to clozapine, with anything from 40-60% of individuals having residual symptoms at the completion of an adequate trial of clozapine. Agents that could work synergistically with clozapine to improve efficacy whilst not increasing the side effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ, such as N-acetyl cysteine (NAC). Our group has extensive experience with NAC with pilot data support from a rigorous RCT exploring the efficacy of NAC in clozapine-resistant SZ. This project grant seeks funding to expand this work by conducting a multi-site randomised placebo-controlled trial of NAC in the treatment of clozapine-resistant schizophrenia, with 8, 24 and 52 week endpoints.
We will target negative symptoms as our primary outcome measure, with quality of life and cognition as secondary outcomes. We will examine both peripheral and cortical glutathione concentrations. Additionally, we will measure a number of other biomarkers pertinent to the glutathione hypothesis. Such analyses will further our understanding the role of oxidative stress in SZ.
The trial is a randomised controlled double-blinded superiority trial of two parallel patient groups. The study will be conducted across four Australian sites, namely Melbourne (St Vincent’s Mental Health Service), Sydney (Cumberland Hospital), Adelaide (Northern Adelaide Local Health Network), and Brisbane (Metro South Addiction and Mental Health Service). Forty-two patients will be recruited from each of the sites, with a total target of 168 patients aged 18 - 65 years meeting DSM-5 criteria for schizophrenia. Block randomisation will be used.
This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a ‘go to’ adjunct in patients only partly responsive to
clozapine.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61462 0
Prof David Castle
Address 61462 0
Department of Mental Health, St Vincent's Hospital, Level 2, 46 Nicholson St, Fitzroy 3065 VIC
Country 61462 0
Australia
Phone 61462 0
+61 3 9231 4751
Fax 61462 0
Email 61462 0
david.castle@svha.org.au
Contact person for public queries
Name 61463 0
Prof David Castle
Address 61463 0
Department of Mental Health, St Vincent's Hospital, Level 2, 46 Nicholson St, Fitzroy 3065 VIC
Country 61463 0
Australia
Phone 61463 0
+61 3 9231 4751
Fax 61463 0
Email 61463 0
david.castle@svha.org.au
Contact person for scientific queries
Name 61464 0
Prof David Castle
Address 61464 0
Department of Mental Health, St Vincent's Hospital, Level 2, 46 Nicholson St, Fitzroy 3065 VIC
Country 61464 0
Australia
Phone 61464 0
+61 3 9231 4751
Fax 61464 0
Email 61464 0
david.castle@svha.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
group data will be available


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseN-acetylcysteine (NAC) in schizophrenia resistant to clozapine: A double blind randomised placebo controlled trial targeting negative symptoms.2016https://dx.doi.org/10.1186/s12888-016-1030-3
EmbaseCould N-acetylcysteine improve the safety of clozapine?.2021https://dx.doi.org/10.1002/hup.2769
N.B. These documents automatically identified may not have been verified by the study sponsor.