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Trial registered on ANZCTR


Registration number
ACTRN12612000321842
Ethics application status
Approved
Date submitted
10/02/2012
Date registered
21/03/2012
Date last updated
22/04/2022
Date data sharing statement initially provided
22/04/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Investigating the effect of treatment dose on clinical response to Repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depression.
Scientific title
A Study of the Effect of Dose on Response to Repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depression.
Secondary ID [1] 279914 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Treatment Resistant Major Depression 285789 0
Condition category
Condition code
Mental Health 285966 285966 0 0
Depression

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

TMS will be administered with a Medtronic Magpro30 magnetic stimulator using a 70mm figure-of-eight coil. Prior to the commencement of treatment TMS, single pulse TMS will be used to measure the resting motor threshold (RMT) for the abductor pollicis brevis (APB) in the right hand using standard methods.


Patients will be randomised into one of four treatment conditions:

1. High dose Low Frequency rTMS applied to the right prefrontal cortex: Application of 2 continuous trains of 1 Hz rTMS of 30 minutes duration at 120% of the resting motor threshold (3600 pulses per session over 60 minutes).

2. High dose High Frequency rTMS applied to the left prefrontal cortex: Application of 125 trains of 10 Hz rTMS. 4.5 second trains will be applied at 120% of the resting motor threshold with a 15.5 second inter-train interval (5625 pulses per session over 41.6 minutes).

3. Standard dose Low Frequency rTMS applied to the right prefrontal cortex: Application of 1 continuous train of 1 Hz rTMS of 20 minutes duration at 120% of the resting motor threshold (1200 pulses per session over 20 minutes).

4. Standard dose High Frequency rTMS applied to the left prefrontal cortex: This will involve the application of 50 trains of 10 Hz rTMS. 4.5 second trains will be applied at 120% of the resting motor threshold with a 20.5 second inter-train interval (2250 pulses per session over 20.8 minutes).


Each treatment will be administered for up to four weeks, five days per week (total of 20 treatment sessions). Patients will receive an assessment at baseline, 1, 2, 3 and 4 weeks (briefer assessments at weeks 1 and 3), and the primary study analysis will be based on this data. Patients may terminate treatment if they have responded at 2, 3 or 4 weeks.

Patients who do not respond to one of the low dose treatment arms will be offered crossover treatment to the high dose condition using the opposite form of stimulation. Patients who do not respond to one of the high dose conditions will be offered the high dose form of stimulation applied to the opposite hemisphere.

A subset of participants will also take part in a sub-study looking at potential predictors of response to rTMS treatment, involving participation in some computer-based tasks and MRI imaging.
Intervention code [1] 284211 0
Treatment: Devices
Comparator / control treatment
Standard dose low frequency and high frequency repetitive Transcranial Magnetic Stimulation, as described above.


We will also recruit a group of up to 50 healthy controls, age and gender matched to the patient group, to participate in the brain imaging arm of the study. This will allow analyses of the behavioural assessment of reward and MRI data in relation to treatment response to be compared between patients and control participants. In turn, it will allow additional questions to be addressed in regards to the degree to which decision-making on these tasks varies from normal levels of function, and allow us to analyse the degree to which the relevant imaging variables differ from normal.
Control group
Dose comparison

Outcomes
Primary outcome [1] 286491 0
Primary Outcome 1: change in severity of depressive symptoms, defined as:

Hamilton Depression Rating Scale (HAMD; 17 item version) - Clinical response defined as a reduction of at least 50% from baseline, clinical remission defined as a score <= 7
Timepoint [1] 286491 0
Baseline, and after every 5 treatments (weeks 1, 2, 3, 4)
Secondary outcome [1] 296017 0
Predictors of antidepressant response to TMS.

Specifically, we will explore the potential predictors of antidepressant response to rTMS using brain imaging analyses, and the use of tasks related to risk and reward decision making, in a subset of participants:

1. We will conduct an assessment of decision making related to reward with several computer based experimental tasks (eg. the Ultimatum Game, Signal Detection Task).

2. We will use the MRI data to model the differences between patients and controls in subcortical activation patterns induced by the decision making task, and model the relationship between activation and response to treatment using response and other relevant clinical variables in regression analyses.
Timepoint [1] 296017 0
Analysis of a series of scans obtained in the one scanning session. Analysis will occur at the end of the study once all data has been collected.

Eligibility
Key inclusion criteria
Patients with depression:
1. Have a DSM-IV diagnosis of a major depressive episode

2. Have failed to respond to adequate antidepressant medical therapy. This will be defined by at least two courses of antidepressant medication (from two medication classes) at therapeutic doses for a minimum of six weeks. Adequate daily dose will be considered to be a minimum of: 150mg of Imipramine or equivalent for tricyclic antidepressants, 20mg of Fluoxetine or equivalent for serotonin re-uptake inhibitors, 600mg of Moclobemide, 600mg of Nefazadone, 150mg of Venlafaxine, 60mg of Phenelzine or equivalent for monoamine oxidase inhibitors

3. Have a Hamilton Depression Rating Scale of > 16 (moderate – severe depression)

4. Have had no increase in, or initiation of new antidepressant therapy in the 4 weeks prior to screening.

Healthy controls for the scanning sub study:
1. No personal history of psychiatric illness as determined via clinical interview.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Have an unstable medical condition, neurological disorder or any history of a seizure disorder, or are currently pregnant or lactating

For depression participants only:
2. In the opinion of the investigator, are at sufficient risk of suicide to require immediate ECT

3. Have a current DSM-IV diagnosis of substance abuse or dependence disorder, a diagnosis of a personality disorder or another Axis 1 disorder.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
17/08/2011
Actual
1/02/2012
Date of last participant enrolment
Anticipated
Actual
30/09/2015
Date of last data collection
Anticipated
Actual
30/10/2015
Sample size
Target
300
Accrual to date
Final
300
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 22229 0
The Victoria Clinic - Prahran
Recruitment postcode(s) [1] 37393 0
3181 - Prahran

Funding & Sponsors
Funding source category [1] 284683 0
Self funded/Unfunded
Name [1] 284683 0
Country [1] 284683 0
Australia
Primary sponsor type
Individual
Name
Professor Paul Fitzgerald
Address
Monash Alfred Psychiatry Research Centre
Level One Old Baker Bld
Alfred Hospital
Commerical Rd
Prahran
VIC 3181
Country
Australia
Secondary sponsor category [1] 283585 0
None
Name [1] 283585 0
Address [1] 283585 0
Country [1] 283585 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286682 0
Melbourne Clinic Human Research Ethics Committeee
Ethics committee address [1] 286682 0
Ethics committee country [1] 286682 0
Australia
Date submitted for ethics approval [1] 286682 0
Approval date [1] 286682 0
10/08/2011
Ethics approval number [1] 286682 0
194

Summary
Brief summary
Major depressive disorder is a severe illness of high prevalence. A significant percentage of patients fail to respond to standard treatments and continue to experience marked disability and high morbidity. Repetitive transcranial magnetic stimulation (rTMS), which is a non-invasive means of stimulating nerve cells in superficial areas of the brain, is a promising therapy for those with treatment-resistant depression. Previous research conducted by our group clearly indicates that rTMS has antidepressant activity and that the response to rTMS is clinically meaningful in some patients. Whilst several forms of rTMS are clearly effective, no one type of rTMS has demonstrated markedly greater responses that other approaches. In recent years interest has developed into whether the dose of rTMS, in particular the number of pulses applied, is related to response to treatment (the percentage of patients that respond to treatment, the ‘response rate’). However, as there is a considerable time cost to higher dose protocols, their usefulness requires systematic evaluation.

Therefore, the primary goal of this study is to examine whether response to rTMS is greater or more rapid when treatment is applied at a higher dose. To do this we will compare standard and high dose strategies for both low frequency rTMS applied to the right prefrontal cortex, and high frequency rTMS applied to the left prefrontal cortex. A secondary goal of the study is to explore potential predictors of antidepressant response to rTMS using brain imaging analysis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33741 0
Prof Paul Fitzgerald
Address 33741 0
ECIMH
888 Toorak rd, Victoria, 3184
Country 33741 0
Australia
Phone 33741 0
+61 3 9805 4287
Fax 33741 0
Email 33741 0
[email protected]
Contact person for public queries
Name 16988 0
Professor Paul Fitzgerald
Address 16988 0
MAPrc
Level One Old Baker Bld
Alfred Hospital
Commerical Rd
Prahran
VIC 3181
Country 16988 0
Australia
Phone 16988 0
+61 3 9076 6564
Fax 16988 0
Email 16988 0
[email protected]
Contact person for scientific queries
Name 7916 0
Professor Paul Fitzgerald
Address 7916 0
MAPrc
Level One Old Baker Bld
Alfred Hospital
Commerical Rd
Prahran
VIC 3181
Country 7916 0
Australia
Phone 7916 0
+61 3 9076 6564
Fax 7916 0
Email 7916 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
ethics not obtained for this data use


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
EmbaseA pragmatic randomized controlled trial exploring the relationship between pulse number and response to repetitive transcranial magnetic stimulation treatment in depression.2020https://dx.doi.org/10.1016/j.brs.2019.09.001
N.B. These documents automatically identified may not have been verified by the study sponsor.