Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000121662
Ethics application status
Submitted, not yet approved
Date submitted
11/10/2013
Date registered
31/01/2014
Date last updated
23/10/2020
Date data sharing statement initially provided
23/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial of targeted repetitive Transcranial Magnetic Stimulation (rTMS) in the treatment of auditory hallucinations in schizophrenia
Scientific title
A trial of targeted repetitive Transcranial Magnetic Stimulation (rTMS) in the treatment of auditory hallucinations in schizophrenia
Secondary ID [1] 283295 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Auditory hallucinations in schizophrenia/schizoaffective disorder 290179 0
Condition category
Condition code
Mental Health 290566 290566 0 0
Schizophrenia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Repetitive Transcranial Magnetic Stimulation (rTMS)

rTMS is a non-invasive technique for stimulating neural tissue. A rapid change in magnetic field induces a current in the neural tissue. If the current is of sufficient amplitude and duration it will excite nerve tissues.

In the current study we aim to determine whether neuro-navigationally targeted rTMS applied to the temporal cortex will reduce the intensity and frequency of auditory hallucinations to a greater degree than rTMS applied to the standard temporoparietal 10-20 EEG (TP3) site.

Participants will initially be randomised to receive rTMS treatment either based on an analysis of their MRI scan, or treatment localised using the traditional 10-20 EEG site method. Prior to the commencement of the treatment course, motor threshold (MT) will be measured with single pulse TMS applied to the motor cortex. The treatment course will consist of 20 treatment sessions conducted daily (Mon-Fri). During each session, one continuous train of 20 minutes duration will be applied at 120% of motor threshold.

Patients who do not achieve an adequate treatment response in this first phase will be crossed over to the alternate condition and offered a second treatment course. No washout period will be required before commencing in the second phase of treatment.

Patients who have experienced any reduction in symptom severity during either arm of the crossover trial will be offered participation in an open label phase.
Intervention code [1] 288071 0
Treatment: Devices
Comparator / control treatment
Active control - The comparator group will receive rTMS treatment localised using the standard approach for targeting the brain regions believed to be implicated in the pathophysiology of auditory hallucinations; namely, the 10-20 EEG site method of localising the left temporoparietal cortex.
Control group
Active

Outcomes
Primary outcome [1] 290651 0
A reduction in the severity of auditory hallucinations.

The PSYRATS hallucinations subscale - rating the intensity, frequency and characteristics of voices.

Response is defined as a reduction of at least 50% from baseline on this rating scale.
Timepoint [1] 290651 0
Baseline, Week 1, Week 4 (end of treatment course) and one month following the treatment course.
Secondary outcome [1] 304982 0
Positive and Negative Syndrome Scale (PANSS)
Timepoint [1] 304982 0
Baseline, Week 1, Week 4 (end of treatment course) and one month following the treatment course.
Secondary outcome [2] 305053 0
CogState Research - to assess a range of cognitive domains including attention, speed of processing, learning and memory (verbal and visual), executive function (including set shifting) and social cognition.
Timepoint [2] 305053 0
Baseline, Week 4 (end of treatment course) and one month following the treatment course.

Eligibility
Key inclusion criteria
Have a DSM-IV diagnosis of schizophrenia or schizoaffective disorder;

Are aged 18-75;

Experience auditory hallucinations that rate a minimum of 4 (moderate) on the PANSS auditory hallucinations item and are present at least on a daily basis;

Have failed to respond to a minimum of 2 adequate trials of antipsychotic medication;

Have demonstrated capacity to give informed consent.
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Have a history of epilepsy or baseline EEG abnormalities;

Have a significant or unstable neurological disorder or a cardiac pacemaker;

Have had a previous brain injury or neurosurgery, or have any metal clips, plates or other metal items in the head;

Are currently pregnant or lactating;

Are a professional driver;

Have a history of substance abuse or dependence in the last 6 months, as determined by the DSM-IV.

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)
Patients will be randomised to receive 20 days of rTMS treatment to a neuronavigationally localised site, or the standard TP3 EEG site in left temporoparietal cortex.
Allocation will be concealed via central randomisation by computer.

After four weeks of treatment, patients who have achieved an inadequate treatment response in phase one will be offered a second treatment course. For patients in the TP3 group, this will be at the optimal neuronavigationally selected site. For the patients in the neuro-navigational group, this will be at the optimally selectable site in the contralateral hemisphere.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will occur via the generation of a single computer number sequence.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
We will aim to recruit a total of 100 patients. There is no pilot data to base a power analysis on but this sample will give 98% power to detect a 4 point difference in change scores on the PSYRATS with a standard deviation of 10.0.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Date of first participant enrolment
Anticipated
1/08/2018
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 288079 0
Self funded/Unfunded
Name [1] 288079 0
Country [1] 288079 0
Primary sponsor type
Individual
Name
Professor Paul Fitzgerald
Address
Monash Alfred Psychiatry Research Centre (MAPrc)
Level 4
607 St Kilda Rd
Melbourne
VIC 3004
Country
Australia
Secondary sponsor category [1] 286803 0
None
Name [1] 286803 0
Address [1] 286803 0
Country [1] 286803 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 290005 0
Alfred Hospital Human Research Ethics Committee
Ethics committee address [1] 290005 0
Ethics and Research Governance Office
Ground Floor, Linay Pavilion
The Alfred
Melbourne VIC 3004
Ethics committee country [1] 290005 0
Australia
Date submitted for ethics approval [1] 290005 0
02/10/2013
Approval date [1] 290005 0
Ethics approval number [1] 290005 0
405/13

Summary
Brief summary
Auditory hallucinations (AH) are one of the most common and distressing symptoms of schizophrenia, occurring in more than 70% of patients. Whilst the primary form of treatment for AH is antipsychotic medications, a significant proportion (30-40%) of patients fail to respond significantly to pharmacological therapy. Novel treatment options are therefore needed.

A substantial body of evidence suggests that auditory hallucinations may be improved with repetitive Transcranial Magnetic Stimulation (rTMS), although in these studies, and in our clinical experience, only a small proportion of patients respond to this treatment. The majority of studies which have demonstrated modest response rates to rTMS for AH have used a relatively standard approach for targeting the brain regions believed to be implicated in AH; namely, the 10–20 EEG system for localising the left temporoparietal cortex. It is therefore reasonable to propose that by more accurately targeting brain regions implicated in AH for each individual patient, a greater reduction in the intensity and frequency of AH may be observed.

We propose to investigate this using neuro-navigational methods combined with resting state functional connectivity MRI-based scanning to more precisely pinpoint the site of stimulation in individual patients. We will recruit participants with a diagnosis with schizophrenia or schizoaffective disorder who experience auditory hallucinations, and they will undergo a resting state MRI scan prior to treatment. They will then receive rTMS treatment either based on an analysis of their MRI scan, or treatment localised using the standard 10-20 EEG method.

This study has the potential to substantially contribute to the development of rTMS as a new therapeutic tool for treatment-resistant auditory hallucinations.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 43254 0
Prof Paul Fitzgerald
Address 43254 0
MAPrc,
Level 4, 607 St Kilda Road
Melbourne VIC 3004
Country 43254 0
Australia
Phone 43254 0
+61 3 9076 6552
Fax 43254 0
Email 43254 0
[email protected]
Contact person for public queries
Name 43255 0
Dr Kaye Hoy
Address 43255 0
MAPrc,
Level 4, 607 St Kilda Road
Melbourne VIC 3004
Country 43255 0
Australia
Phone 43255 0
+61 3 9076 5034
Fax 43255 0
Email 43255 0
[email protected]
Contact person for scientific queries
Name 43256 0
Prof Paul Fitzgerald
Address 43256 0
MAPrc,
Level 4, 607 St Kilda Road
Melbourne VIC 3004
Country 43256 0
Australia
Phone 43256 0
+61 3 9076 6552
Fax 43256 0
Email 43256 0
[email protected]

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


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
No additional documents have been identified.