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Trial registered on ANZCTR


Registration number
ACTRN12618001784202
Ethics application status
Approved
Date submitted
2/10/2018
Date registered
31/10/2018
Date last updated
27/03/2019
Date data sharing statement initially provided
31/10/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Adjuvant N Acetylcysteine for Post Traumatuic Stress Disorder
Scientific title
N-acetylcysteine as an Adjunctive Treatment in treatment-resistant Post-Traumatic Stress Disorder: a randomised controlled trial
Secondary ID [1] 296086 0
Austin Health Project Number: DT 16/188
Secondary ID [2] 296087 0
The Melbourne Clinic Project Number: 305
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
post traumatic stress disorder 309663 0
Condition category
Condition code
Mental Health 308464 308464 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A 12-week, double blind, randomised, placebo-controlled trial of N-acetylcysteine, given as an adjunct therapy to those who still have PTSD despite having received first-line treatment.This study will be conducted at the Psychological Trauma Recovery Service (PTRS) at the Heidelberg Repatriation Hospital, Melbourne, a specialist PTSD treatment centres that is a national centre of excellence at one of the few remaining repatriation hospitals, with corresponding service associations and service contracts with the military and veterans. The study will also be conducted at the Melbourne Clinic, a private psychiatric hospital that provides specialised PTSD services.
We aim to have 126 participants (63 per arm) complete the study. Participants will comprise individuals with PTSD at the Heidelberg Repatriation Hospital, the Melbourne Clinic and from the community. Individuals accepted into the trial will be randomly allocated in a double-blind fashion to receive either NAC or placebo, in addition to any established treatments for their PTSD, by the trial pharmacy at the Heidelberg Repatriation Hospital. Random block allocation of packs will be in a four-to-a-block design, randomly generated by a computer program. A fixed dose regime of 2.7g/day of NAC, administered orally as 900mg, three times daily, will be used. To facilitate the double-blinding process, the trial medications (both NAC and placebo) will be dispensed in identical numbers and tablet forms in sealed containers, and the placebo containers will be specially treated with microgram levels of NAC dust to produce its characteristic smell (as manufactured in our previous study). Placebos will be manufactured according to EMA guidelines. The trial medications will be supplied on a monthly basis, and participants instructed to return all containers to allow capsule counts by the trial monitor and the trial pharmacist. Participants will also be required to complete a daily pill diary to document treatment compliance.

Detailed clinical and demographic information will be collected on all participants at baseline. Participants will then be assessed at monthly clinical interviews throughout the 12-week trial, and at a post-discontinuation follow-up 16 weeks and 64 weeks post-randomisation, after completion of the trial (to assess retention of any treatment effects). Participants will be given the option to undertake blood analysis at baseline and at week 12 of the trial, to measure biomarkers associated with PTSD symptoms. Over the course of the trial, and for four weeks post-discontinuation, participants will complete a weekly questionnaire measure at home, assessing their PTSD symptoms. The baseline assessment will take about 90 minutes; the 4-weekly questionnaires take about 60 minutes to complete; the weekly self-report questionnaires take no more than 5 minutes. Information on potential adverse side effects will be collected systematically at 4, 8, 12 and 16 weeks post randomisation by the research clinicians, and will be managed according to medical assessment.
Intervention code [1] 312430 0
Treatment: Drugs
Comparator / control treatment
Participants randomly assigned to the placebo arm of the trial will be provided with placebo study medication by the trial pharmacist. The placebo medication will also be taken as fixed dose regime of 2.7g/day, which will be administered orally as 900mg, three times daily, for the duration of the 12 week trial. To facilitate the double-blinding process, the trial medications (both NAC and placebo) will be dispensed in identical numbers and tablet forms in sealed containers, and the placebo containers will be specially treated with microgram levels of NAC dust to produce its characteristic smell (as manufactured in our previous study). Both Placebo and NAC will be provided in effervescent tablet form using baking soda and citric acid. Placebos will be manufactured according to EMA guidelines. Placebo will also be supplied on a monthly basis, and participants instructed to return all containers to allow capsule counts by the trial monitor and the trial pharmacist. Participants in the placebo arm will also be required to complete a daily pill diary to document treatment compliance.

Detailed clinical and demographic information will be collected on all participants (including those allocated to the placebo arm) at baseline. All participants will also be assessed at monthly clinical interviews throughout the 12-week trial, and at a post-discontinuation follow-up 16 weeks and 64 weeks post-randomisation, after completion of the trial (to assess retention of any treatment effects). Participants will be given the option to undertake blood analysis at baseline and at week 12 of the trial, to measure biomarkers associated with PTSD symptoms. Over the course of the trial, and for four weeks post-discontinuation, participants will complete a weekly questionnaire measure at home, assessing their PTSD symptoms. The baseline assessment will take about 90 minutes; the 4-weekly questionnaires take about 60 minutes to complete; the weekly self-report questionnaire take no more than 5 minutes. Information on potential adverse side effects will be collected systematically at 4, 8, 12 and 16 weeks post randomisation by the research team.

Control group
Placebo

Outcomes
Primary outcome [1] 307450 0
The primary outcome measure of the study is post traumatic stress disorder symptom severity as rated by a research clinician using a diagnostic structured clinical interviewing tool (clincian administered PTSD Scale for DSM 5). This is a 30-item observer rated questionnaire, corresponding to the DSM-5 diagnosis for PTSD.
Timepoint [1] 307450 0
0, 4, 8 and 12 weeks post randomisation (primary timepoint) and 16 weeks and 64 weeks post randomisation (at 4 weeks and 52 weeks post trial disconinuation).
Secondary outcome [1] 351934 0
Depression symptom severity will be assesed using both The Hospital Anxiety and Depression Scale (a well validated 14 item self-report screening measure of anxiety and depression, designed to be used in medical settings) and the Hamilton Depression Rating Scale (a widely used, 17 item, observer rated scale of core depressive symptoms) (composite secodary outcome).
Timepoint [1] 351934 0
o, 4, 8 and 12 weeks post randomisation and at 16 weeks and 64 weeks post randomisation (at 4 weeks and 52 weeks post trial discontinuation).
Secondary outcome [2] 351935 0
Anxiety symptom severity will also be assesed using The Hospital Anxiety and Depression Scale (a well validated 14 item self-report screening measure of anxiety and depression, designed to be used in medical settings).
Timepoint [2] 351935 0
o, 4, 8 and 12 weeks post randomisation and at 16 weeks and 64 weeks post randomisation (at 4 weeks and 52 weeks post trial discontinuation).
Secondary outcome [3] 351936 0
Somatic symptoms will be assessed using the the Patient Health Questionnaire-15 (a 15 item self-report measure that requires individuals to rate the degree to which they have been bothered by various somatic symptoms over the past month).
Timepoint [3] 351936 0
o, 4, 8 and 12 weeks post randomisation and at 16 weeks and 64 weeks post randomisation (at 4 weeks and 52 weeks post trial discontinuation).
Secondary outcome [4] 351937 0
Subjective quality of life will be assessed using the World Health Organisation Quality of Life Scale, a widely used 26 item questionnaire measure.
Timepoint [4] 351937 0
o, 4, 8 and 12 weeks post randomisation and at 16 weeks and 64 weeks post randomisation (at 4 weeks and 52 weeks post trial discontinuation).
Secondary outcome [5] 351938 0
Alcohol misuse will be identified using the Alcohol Use Disorder Identification Test, which requires participants to answer ten-items relating to frequency of symptoms and behaviours associated with alcohol misuse.
Timepoint [5] 351938 0
o, 4, 8 and 12 weeks post randomisation and at 16 weeks and 64 weeks post randomisation (at 4 weeks and 52 weeks post trial discontinuation).
Secondary outcome [6] 351939 0
Self rated post traumatic stress disorder symptom severity will be assessed using the Post Traumatic Stress Disorder Checklist for DSM-5 (PCL-5), a widely used and validated 20 item self-report measure.
Timepoint [6] 351939 0
o,1,2,3,4,5,6,7, 8,9,10,11 and 12 weeks post randomisation and at 16 weeks and 64 weeks post randomisation (as part of follow up clinical interviews).
Secondary outcome [7] 352663 0
Biomarkers of post-traumatic stress disorder will be assessed using blood-based indicators of oxidative stress. These are IL-6 (interleukin-6), TNF-alpha (tumour necrosis factor alpha), TBARS (thiobarbituric acid reactive substances), MDA (malondialdehyde) and BDNF (brain-derived neurotrophic factor). 5 ml blood samples. that will be collected from participant to achieve this.
Timepoint [7] 352663 0
0 and 12 weeks post randomisation.
Secondary outcome [8] 352664 0
Though serious adverse events with NAC are extremely rare, patients will be advised to seek appropriate emergency medical help in such an instance. For less serious events, patients will be advised to contact their treating psychiatrist as usual. They are of course free to stop taking the trial medication/placebo at any time without risk. Adverse events will be queried by the trial clinian at clinical interviews, and participant respones recorded verbatim..There are some possible side effects associated with NAC. This information is based on more potent use of NAC at a much higher dose used intravenously for paracetamol overdose, so we don’t expect many side effects with the tablets at a lower dose. The most common side effects are tummy problems, like nausea, diarrhoea and vomiting which occur in between 1/10 – 1/100 people. Shortness of breath and joint pain are considered uncommon side effects (affecting 1/100 to 1/1000 people). Finally, irregular heart beat and chest pain are also possible, and considered rare, meaning 1/1000 to 1/10,000 people experience it.
Timepoint [8] 352664 0
4, 8, 12 and 16 weeks post randomisation
Secondary outcome [9] 353407 0
Substace craving will be assessed using the The Visual Analogue Scale, used in our pilot study. Participants will rate 5 items using anchors of 0 (“not at all) to 10 (“extreme” or “all the time”).
Timepoint [9] 353407 0
o, 4, 8 and 12 weeks post randomisation and at 16 weeks and 64 weeks post randomisation (at 4 weeks and 52 weeks post trial discontinuation).

Eligibility
Key inclusion criteria
To be considered for inclusion in this study, participants are required to be aged 18 or over; have the capacity to consent to the study and to follow its instructions and procedures; fulfil the DSM-5 diagnostic criteria for current PTSD (identified with the CAPS-5 monthly version); have completed a course of either trauma-focussed psychotherapy or an antidepressant; and if currently treated with an antidepressant the dose must have been stable for at least 2 weeks.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants are ineligible to enter the trial if they have a psychotic illness; known or suspected clinically unstable systemic medical disorder; epilepsy, asthma, recent gastrointestinal ulcers; currently use N-acetylcysteine, selenium or Vitamin E; a history of anaphylactic reaction to N-acetylcysteine . Female patients cannot be pregnant or lactating, and all participants must agree to using adequate contraception during the trial.

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 concealed. Allocation determined via pharmacy services at the central study site and all dispensed medication provided in identical, sealed containers.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be carried out by the pharmacy services at the Heidelberg Repatriation Hopsital. Randomisation will take place only once participants have provided written informed consent and undertaken the baseline assessment to confirm their eligibility for the trial. Participants will be randomised sequentially in a 1:1 ratio of active to placebo. Random block allocation of packs will be in a four-to-a-block design, randomly generated by a computer program.
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
placebo controlled trial whereby half of the participants receive active drug intervention (N-acetyl cysteine) and half of participants recieve placebo medication.
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
We are aiming for a final sample of 126 participants (63 per arm). For a two tailed analysis with alpha=0.05, beta=0.2, the study should be powered at 80% to detect a true difference in CAPS score between the N-acetylcysteine and placebo groups. In our pilot trial, effect sizes for PTSD symptoms as well as all secondary measures far exceeded this threshold. Using a conservative attrition rate of one-third (more conservative than our pilot data), we will need to recruit 190 to have 126 complete the trial and follow-up. The established outpatient body of the PTRS and the Melbourne Clinic programmes are many times larger than this, and participation rates for our previous trials have approached 50%, so recruitment is feasible.All analyses will be conducted by our trial statistician, and are based on all randomised participants with at least one post-baseline observation (modified intention to treat). The statistician will be blind to group allocations. Differences between study arms will be assessed using either chi-squared or Fisher’s exact test for categorical data and either student t–test or Mann-Whitney U test for continuous data. Non-parametric statistics will be used when assumptions for parametric methods are violated. Effect sizes will be calculated using Cohen’s guidelines. The primary efficacy analysis will assess the impact of the treatment on group differences for the primary outcome measure (CAPS) over the entire study period and use a likelihood based mixed-effects model, repeated measures approach (MMRM). The MMRM model includes the categorical effects of treatment, investigator, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. The MMRM includes all available data at each time point and is the preferred method of analyzing clinical trial data in psychiatry as compared to more traditional repeated measures analysis of variance (ANOVA) and analysis of covariance models (ANCOVA)

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 hospital [1] 11909 0
Austin Health - Heidelberg Repatriation Hospital - Heidelberg West
Recruitment hospital [2] 11910 0
The Melbourne Clinic - Richmond
Recruitment postcode(s) [1] 24045 0
3081 - Heidelberg West
Recruitment postcode(s) [2] 24046 0
3121 - Richmond

Funding & Sponsors
Funding source category [1] 300676 0
Charities/Societies/Foundations
Name [1] 300676 0
Defence Health Foundation
Address [1] 300676 0

PO Box 7518
Melbourne VIC 3004
Country [1] 300676 0
Australia
Funding source category [2] 300760 0
Charities/Societies/Foundations
Name [2] 300760 0
Sir Edward Dunlop Medical Research Foundation
Address [2] 300760 0

PO Box 5444
Heidelberg West, VIC 3081
Australia
Country [2] 300760 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Rd
Heidelberg VIC 3084
Country
Australia
Secondary sponsor category [1] 300203 0
Hospital
Name [1] 300203 0
The Melbourne Clinic
Address [1] 300203 0
130 Church St
Richmond VIC 3121
Country [1] 300203 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301458 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 301458 0
Austin Health
Level 8, Harold Stokes Building
Austin Health
PO Box 5555
Heidelberg
Victoria
Australia 3084
Ethics committee country [1] 301458 0
Australia
Date submitted for ethics approval [1] 301458 0
05/05/2016
Approval date [1] 301458 0
10/08/2016
Ethics approval number [1] 301458 0
DT 16/188
Ethics committee name [2] 301539 0
The Melbourne Clinic Human Research Ethics Committtee
Ethics committee address [2] 301539 0
130 Church Street
Richmond VIC 3121
Ethics committee country [2] 301539 0
Australia
Date submitted for ethics approval [2] 301539 0
01/06/2018
Approval date [2] 301539 0
20/06/2018
Ethics approval number [2] 301539 0
305

Summary
Brief summary
Post Traumatic Stress Disorder (PTSD) is hard to treat effectively, as most patients who take the standard treatments still have PTSD symptoms afterwards. We have found that a drug called n-acetylcysteine (NAC), which supports the body’s anti-oxidants, can help to treat PTSD, as well as the depression and addictions that many people with PTSD also have. We would like to prove this by doing a trial comparing NAC with placebo, in patients with PTSD who have already had the standard treatments, to see if NAC helps cure them.
We will ask 192 individuals with PTSD at the Heidelberg Repatriation Hospital, the Melbourne Clinic and from the community to join the study, individuals who have already had the best treatments for PTSD but who haven’t been cured. We will randomly divide them into two groups – one group which is given the NAC for 12 weeks, and one group which is given a placebo pill – though neither the researchers, nor the patients, will know which is which until the trial ends. They will keep taking their other treatments as usual. Every four weeks we will measure their PTSD symptoms, as well as their mood, their drug and alcohol use, somatic symptoms and their quality of life, until four weeks after the trial is over, when we will open the list that tells us who was taking the NAC, and who was taking the placebo, and compare the two groups. We expect that those who took the NAC will have fewer PTSD symptoms, better mood, less drug and alcohol use, fewer somatic symptoms and a better quality of life, and, most importantly, that more patients who took the NAC will no longer have PTSD.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87074 0
Prof Richard Kanaan
Address 87074 0
Level 10
Lance Townsend Building
Austin Hospital
Studley Road
Heidelberg VIC 3070
Country 87074 0
Australia
Phone 87074 0
+61 3 9496 3351
Fax 87074 0
+61 3 9459 0821
Email 87074 0
Richard.Kanaan@austin.org.au
Contact person for public queries
Name 87075 0
Ms Anita Dharan
Address 87075 0
Psychological Trauma Recovery Service
Heidelberg Repatriation Hospital
300 Waterdale Road
Heidelberg West VIC 3084
Country 87075 0
Australia
Phone 87075 0
+61 3 9496 2624
Fax 87075 0
Email 87075 0
Anita.DHARAN2@austin.org.au
Contact person for scientific queries
Name 87076 0
Prof Richard Kanaan
Address 87076 0
Level 10
Lance Townsend Building
Austin Hospital
Studley Road
Heidelberg VIC 3070
Country 87076 0
Australia
Phone 87076 0
+61 3 9496 3351
Fax 87076 0
+61 3 9459 0821
Email 87076 0
Richard.Kanaan@austin.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
What supporting documents are/will be available?
No other documents available
Summary results
No Results