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Trial registered on ANZCTR


Registration number
ACTRN12616000443493
Ethics application status
Approved
Date submitted
29/03/2016
Date registered
6/04/2016
Date last updated
11/06/2019
Date data sharing statement initially provided
11/06/2019
Date results information initially provided
11/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Accelerated Theta Burst Stimulation (TBS) in the Treatment of Depression
Scientific title
Accelerated Theta Burst Transcranial Magnetic Stimulation in the Treatment of Depression
Secondary ID [1] 288515 0
none
Universal Trial Number (UTN)
U1111-1179-4083
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
depression 297587 0
Condition category
Condition code
Mental Health 297781 297781 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
It is a single blind randomised control trial where participants will receive either active daily repetitive Transcranial Magnetic Stimulation (rTMS) (20 treatments over 4 weeks) or active accelerated Theta Burst Stimulation (3 treatments per day on 7 treatment days over 4 weeks). The participant and the treater will be aware of the treatment condition however the person conducting weekly reviews will be blinded to the patient's treatment group. Participants will also be asked to submit a sample saliva for genetic analysis of potential predictors of response to TMS. Provision of the sample is voluntary and refusal to provide a sample will not affect the participant's inclusion in other study procedures.

Both the rTMS and TBS treatments involve the application of magnetic stimulation to the left side dorso-lateral-prefrontal cortex (DLPFC), During treatment patients will be reclined in a comfortable chair and will be alert and awake. The sensation associated with treatment is usually well tolerated with most people describing it as a tapping sensation.

rTMS the stimulation occurs at 10 Hz, with each pulse train lasting 4 seconds and there is intertrain interval of 15 seconds. There are 75 trains of stimulation and each treatment lasts approximately 24 minutes. TBS will be provided as 3-pulse 50 - Hz bursts applied at 5 Hz (ie 50 Hz burst of 3 pulses delivered every 200 msec). It will involve a 2 second train of TBS followed by an 8 second rest and will run for a total of 190 seconds. Thus each treatment takes a little over 3 minutes and there are 3 treatments on each treatment day with a minimum 15 minute break between treatments. The treatment intensity for both rTMS and TBS will be 120% of resting motor threshold which is measured by administering single pulse TMS to the muscle controlling area of the brain.

Adherence to the treatment schedule will be monitored by recording each treatment session on a participant's treatment sheet.
Intervention code [1] 293877 0
Treatment: Devices
Comparator / control treatment
The study aim is investigate whether accelerated TBS is as efficacious as standard daily rTMS. rTMS is the control treatment.
Control group
Active

Outcomes
Primary outcome [1] 297311 0
Montgomery Asperg Depression Rating Scale (MADRS)
Timepoint [1] 297311 0
Baseline and weekly for 4 weeks. The week 4 review is to be conducted immediately after treatment completion.
Secondary outcome [1] 320686 0
Quick Inventory of Depressive Symptoms (QIDS - SR)
Timepoint [1] 320686 0
Baseline and weekly for 4 weeks. The week 4 review is to be conducted immediately after treatment completion.
Secondary outcome [2] 320687 0
Clinical Global Impression - Improvement (CGI - I)

This is a 7 point scale completed by a reviewer blinded to the participant's treatment group and it assesses change in the participant's depression relative to a baseline.
Timepoint [2] 320687 0
Baseline and weekly for 4 weeks. The week 4 review is to be conducted immediately after treatment completion.
Secondary outcome [3] 320688 0
Change in Clinical Global Impression - Severity (CGI - S)

This is a 7 point scale completed by a reviewer blinded to the participant's treatment group and it rates severity of depression at time of assessment. .
Timepoint [3] 320688 0
Baseline and weekly for 4 weeks. The week 4 review is to be conducted immediately after treatment completion.
Secondary outcome [4] 322244 0
Columbia Suicide Severity Rating Scale (CSSR)
Timepoint [4] 322244 0
Baseline and weekly for 4 weeks. The week 4 review is to be conducted immediately after treatment completion.
Secondary outcome [5] 322245 0
Medical Outcomes Study Short Form - Quality of Life (SF - 12)
Timepoint [5] 322245 0
Baseline and weekly for 4 weeks. The week 4 review is to be conducted immediately after treatment completion.
Secondary outcome [6] 322246 0
Weschler Test of Adult Reading (WTAR). This and subsequent measures are cognitively based. Although the cognitive safety of rTMS has been repeatedly established a battery of cognitive tests have been included to explore whether there are any adverse cognitive effects of accelerated TBS.
Timepoint [6] 322246 0
Baseline and immediately after completion of treatment course.
Secondary outcome [7] 322247 0
Digit Span - WMS III
Timepoint [7] 322247 0
Baseline and immediately after completion of treatment course.
Secondary outcome [8] 322248 0
Trail Making Test A and B which assesses visual attention.
Timepoint [8] 322248 0
Baseline and immediately after completion of treatment course.
Secondary outcome [9] 322249 0
Brief Visuospatial Memory Test
Timepoint [9] 322249 0
Baseline and immediately after completion of treatment course.
Secondary outcome [10] 322250 0
Rey Auditory Verbal Learning Test
Timepoint [10] 322250 0
Baseline and immediately after completion of treatment course.
Secondary outcome [11] 322251 0
STROOP colour and word test (adult version) will be used to measure:
-selective attention capacity
-processing speed ability
Timepoint [11] 322251 0
Baseline and immediately after completion of treatment course.

Eligibility
Key inclusion criteria
- DSM-IV diagnosis of Major Depressive Disorder (MINI)
- HAMD score of > 20 (moderate - severe depression)
- no increase or initiation of new antidepressant therapy in 4 weeks prior to screening
- have treatment resistant depression (stage II of Thase and Rush classification)
- have had no increase or initiation of new antidepressant therapy in the four weeks prior to screening
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- unstable medical condition, neurological disorder, history of seizure disorder, pregnant or lactating
- metal in the head, except in mouth, which may interfer with the magnetic field
- 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)
The treatment group is determined by a computer program that generates random numbers. The researcher with access to this program and who is not involved in patient selection securely provides the treatment group to a member of the treatment team by email or in a sealed envelope. The staff member in receipt of the treatment group is not involved in assessing a patient's eligibility at the baseline assessment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation to one of two treatment conditions will occur via the generation of a single computer number sequence (no stratification).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
For the primary analysis we will compare the rate of change of depressive symptoms across the four weeks of treatment with a mixed model approach where a time by group interaction will indicate a significantly different response. Depression scores will be compared using the PROC Mixed procedure in SAS (SAS Version 9.1 SAS Institute Inc., Cary, NC, USA). The covariance structure will be treated as unstructured using the MADRS as there are likely to be differing drop out rates across time. The PROC MIXED procedure does not delete missing values listwise, but rather handles missing values by treating them as being missing at random. The PROC MIXED procedure uses a restricted maximum likelihood algorithm that enables specific modeling of the within-patient covariance structure. Using the lowest Akaike’s Information criteria as a guide to goodness of fit enables the most appropriate covariance structure to then be evaluated for each situation.
In addition, we will compare the percentage of patients meeting response (50% MADRS reduction) and remission (HAMD score <8) criteria at three and six weeks with chi squared analyses. Finally, we will compare change in baseline to end point cognitive performance between the groups with independent t-tests.

This sample size calculation was based on the acute treatment period (four week assessment), and was conducted assuming a standard deviation of 7.5 for change in MADRS scores (the standard deviation for MADRS scores varied between 4.8 and 9.9 at various study points in our largest rTMS trial to date). A difference of at least four points between the groups on the mean change in MADRS score would be clinically significant demonstrating a more rapid reduction in depression in the TBS group. With an alpha of 0.05, the study will have >95% power to detect this difference allowing for a withdrawal rate of 8.3% (this is a conservative estimate based on the ongoing and previous trials) and a total analysable sample of 110 (55 per group).

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 5263 0
The Alfred - Prahran
Recruitment postcode(s) [1] 12726 0
3181 - Prahran

Funding & Sponsors
Funding source category [1] 292863 0
University
Name [1] 292863 0
Monash University Central Clinical School
Address [1] 292863 0
Level 6, The Alfred Centre (Alfred Hospital)
99 Commercial Road
Melbourne Vic 3004
Country [1] 292863 0
Australia
Primary sponsor type
Individual
Name
Professor Paul Fitzgerald
Address
Monash Alfred Psychiatry Research Centre
Level 4 - 607 St Kilda Road
Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 291609 0
None
Name [1] 291609 0
na
Address [1] 291609 0
na
Country [1] 291609 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294364 0
Alfred Hospital's Human Research Ethics Committee
Ethics committee address [1] 294364 0
The Alfred Hospital
55 Commercial Rd, Prahran VIC 3181
Ethics committee country [1] 294364 0
Australia
Date submitted for ethics approval [1] 294364 0
17/12/2015
Approval date [1] 294364 0
13/01/2016
Ethics approval number [1] 294364 0
577/15

Summary
Brief summary
The purpose of this project is to investigate whether the use of a rapid form of transcranial magnetic stimulation (TMS), called Theta Burst Stimulation (TBS), is a successful treatment for patients with treatment resistant depression compared to the standard form of TMS that has been used to date.
TMS involves the application of magnetic stimulation to your head and, given repeatedly over time this stimulation has been shown to change the activity levels in the brain. Previous experience has shown that people with depression may have an imbalance in the excitability, or ‘activity levels’, of cells in the brain. TMS appears to work by changing how excitable the cells of the brain are, which may help reduce or alleviate depressive symptoms. We are conducting this study to see if we can speed up the response to TMS using a rapid form of TMS called Theta Burst Stimulation (TBS). Theta burst stimulation (TBS) is a type of TMS where the magnetic pulses are applied in very short bursts (three pulses at a time) at a high frequency (30-50 pulses a second).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63438 0
Prof Paul Fitzgerald
Address 63438 0
Monash Alfred Psychiatry Research Centre
Level 4 - 607 St Kilda Road
Melbourne VIC 3004
Country 63438 0
Australia
Phone 63438 0
+613 9076 6564
Fax 63438 0
+613 9076 6588
Email 63438 0
paul.fitzgerald@monash.edu
Contact person for public queries
Name 63439 0
Mr David Elliot
Address 63439 0
Monash Alfred Psychiatry Research Centre
Level 4 - 607 St Kilda Road
Melbourne VIC 3004
Country 63439 0
Australia
Phone 63439 0
+613 9076 6595
Fax 63439 0
+613 9076 6588
Email 63439 0
tms-enquiry@monash.edu
Contact person for scientific queries
Name 63440 0
Prof Paul Fitzgerald
Address 63440 0
Monash Alfred Psychiatry Research Centre
Level 4 - 607 St Kilda Road
Melbourne VIC 3004
Country 63440 0
Australia
Phone 63440 0
+613 9076 6564
Fax 63440 0
+613 9076 6588
Email 63440 0
paul.fitzgerald@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This was not a requirement at the time of study commencement and consent to release this information was not obtained.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary