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Trial registered on ANZCTR


Registration number
ACTRN12617001443381
Ethics application status
Approved
Date submitted
25/09/2017
Date registered
11/10/2017
Date last updated
14/08/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Accelerated Theta Burst Transcranial Magnetic Stimulation (TBS) for Depression
Scientific title
Effectiveness of accelerated theta burst transcranial magnetic stimulation for the treatment of depression
Secondary ID [1] 292489 0
None
Universal Trial Number (UTN)
U1111-1199-6602
Trial acronym
TBS for Depression
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 304115 0
Condition category
Condition code
Mental Health 303447 303447 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single blind randomised controlled trial investigating whether response to repetitive Transcranial Magnetic Stimulation (rTMS) can be substantially enhanced through the use of an accelerated Theta Burst Stimulation (TBS) treatment protocol. The relative efficacy of standard rTMS and two different strengths of TBS will be compared to explore this, and the most effective TBS treatment parameters.

Participants will be randomly allocated to one of three treatment conditions:
• standard rTMS
• low intensity TBS, or
• high intensity TBS.

All groups will receive 20 active treatments. All participants will take part in interviews at baseline, week 1, 2, 4 and 8-10 weeks. Participants responding to the treatment will be followed up for six months. The participant and the treater will be aware of the treatment condition. The person conducting weekly reviews will be blinded to the participant’s treatment group.

Treatment

Standard rTMS
Participants in standard rTMS will receive one treatment a day for 20 treatment days over 4 weeks. Each treatment session will involve the provision of 75 trains of 10 Hz rTMS to the left dorsolateral prefrontal cortex, in 4 second pulse trains, with 26 second inter-train intervals. Each treatment session will take approximately 37.5 minutes.

TBS treatment
Participants in the TBS groups will receive 11 sessions over 4 days in week 1 (2 sessions on day 1, and 3 sessions each on days 2, 3 and 4), and 9 sessions over 3 days in week 2 (3 sessions per day). Each treatment session will involve 3-pulse 50 Hz bursts applied bilaterally, to the right then left to the dorsolateral prefrontal cortices, at 5 Hz (ie 50 Hz burst of 3 pulses delivered every 200 msec). Right sided cTBS will involve a continuous 600 pulse sequence over 40 seconds. Left sided iTBS will involve a 2-seconds of TBS repeated every 10 seconds (i.e. 2 seconds of TBS followed by an 8 second rest), delivered over 180 seconds. Each TBS treatment session will take approximately 4 minutes. Where multiple sessions are provided in one day, there will be a minimum of 15 minutes break between the treatment sessions.

Both rTMS and TBS treatments involve the application of magnetic stimulation to the dorsolateral 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. The treatment intensity for each person for both rTMS and TBS is determined as a percentage of their resting motor threshold (RMT), which is measured by administering single pulse TMS to the motor cortex (area of the brain responsible for muscle control). Standard rTMS treatment will be applied at 120% of the RMT, low intensity TBS at 80% of the RMT, and high intensity TBS at 120% of the RMT. All treatments will be conducted by a qualified TMS nurse. Participants will be monitored at all times, and each treatment time, date and dosage will be logged on a participant's treatment sheet. Intervention adherence and fidelity will be monitored by the TMS accredited nursing staff providing the treatments, and study personnel, including Principal and Associated Investigators, who are trained in the provision and clinical supervision of rTMS/TBS therapy.
Intervention code [1] 298668 0
Treatment: Devices
Comparator / control treatment
The study aim is to investigate whether accelerated TBS is as efficacious as standard daily rTMS, and the most effective TBS treatment parameters. Standard unilateral left high frequency rTMS is the comparator treatment. Low and high intensity TBS will also be compared.
Control group
Active

Outcomes
Primary outcome [1] 302827 0
Quick Inventory of Depressive Symptomatology-Clinician version (QIDS-C)
Timepoint [1] 302827 0
Baseline, week 1, 2, 4 and 8-10. The primary timepoint is at week 2, two weeks after commencement of treatment. Responders (defined as a 50% reduction in total score) will be followed up for six months.
Secondary outcome [1] 337173 0
The rate of change in participants' depressive symptomatology, as measured by reduction in scores on the QIDS-C and SR analysed against the time period across which change occurred.
Timepoint [1] 337173 0
Baseline, week 1, 2, 4 and 8-10.
Secondary outcome [2] 337174 0
Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR)
Timepoint [2] 337174 0
Baseline, week 1, 2, 4 and 8-10. Responders (defined as 50% reduction on the QIDS-C from baseline) followed up for six months.
Secondary outcome [3] 337175 0
Scale for Suicidal Ideation
Timepoint [3] 337175 0
Baseline, week 1, 2, 4 and 8-10. Responders (defined as 50% reduction on the QIDS-C from baseline) followed up for six months.
Secondary outcome [4] 337176 0
EuroQol Rating Scale (EQ-5D)
Timepoint [4] 337176 0
Baseline, week 1, 2, 4 and 8-10. Responders (defined as 50% reduction on the QIDS-C from baseline) followed up for six months.

Eligibility
Key inclusion criteria
• Diagnosis of major depressive episode (MDE), in accordance with the Diagnostic
and Statistical Manual of Mental Disorders 5th edition (DSM-5), in the context
of unipolar major depressive disorder or bipolar affective disorder.
• 18+ years of age.
• Treatment resistant depression at Stage II of the Thase and Rush classification.
• Quick Inventory of Depressive Symptomatology (QIDS) score of >10 (moderate –
severe depression).
• No increase or initiation of new antidepressant (or other psychoactive) therapy
in the four weeks prior to screening.
• Demonstrated capacity to give informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Inability to provide informed consent
• Medically unstable
• Concomitant neurological disorder or a history of a seizure disorder
• Patients who are pregnant or breastfeeding
• Current Substance or Alcohol dependence

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 three 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)
Efficacy
Statistical methods / analysis
The primary analysis will take place after all participants, apart from those who may have withdrawn, have had their final assessments. This analysis will be based on the intention-to-treat principle (i.e. subjects will be analysed according to the treatment arm to which they were randomised and the notified stratum to which they belonged at randomisation). A ‘per protocol’ sensitivity analysis will be restricted to participants who did not have a major protocol deviation. Major protocol deviations will be identified prior to database lock.

The primary analysis will compare the proportion of patients who achieve response criteria 2 weeks after commencement of treatment (chi square test) on the QIDS (defined as a 50% reduction in total score).

Following this, a repeated measurements of all the outcome variables will be analysed by fitting linear mixed models using restricted maximum likelihood (REML).

With regard to the secondary hypothesis, to demonstrate non inferiority in the overall efficacy of the accelerated TBS and standard rTMS approaches, we will calculate and report the 90% confidence interval (CI) for the difference between the treatment arms in their mean QIDS levels at week 8. Additional exploratory secondary analyses will be conducted on the secondary measures including suicidality and quality of life using the same mixed model approach.

The projected sample size was based on hypothesised response rates after the initial two weeks of treatment:
- Results from previous studies indicate TBS will induce more rapid treatment
response than standard rTMS.
- At 2 weeks, there will therefore be a greater proportion of treatment responders
in the TBS group than the rTMS group.
- At 2 weeks, we predict a response rate of:
--~45% in the TBS group (expected response rate after a full course of rTMS treatment)
--~20% in the rTMS group (based on previous study response rates)
- Comparing these proportions with a power of 0.9 requires a sample size of 79
per group.
- Recruiting 90 patients per group allows for a 12% drop out rate (typical drop out
rates in our studies are <10%).

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] 8578 0
Epworth Rehabilitation Camberwell - Camberwell
Recruitment postcode(s) [1] 16685 0
3124 - Camberwell

Funding & Sponsors
Funding source category [1] 297057 0
Hospital
Name [1] 297057 0
Epworth HealthCare
Address [1] 297057 0
Epworth Camberwell
888 Toorak Road
Camberwell
VICTORIA 3124
Country [1] 297057 0
Australia
Primary sponsor type
Individual
Name
Professor Paul Fitzgerald
Address
Epworth Camberwell
888 Toorak Road
Camberwell
VICTORIA 3124
Country
Australia
Secondary sponsor category [1] 296066 0
None
Name [1] 296066 0
Address [1] 296066 0
Country [1] 296066 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298241 0
Epworth HealthCare Human Research Ethics Committee
Ethics committee address [1] 298241 0
Epworth HealthCare
89 Bridge Road
Richmond VIC 3121
Ethics committee country [1] 298241 0
Australia
Date submitted for ethics approval [1] 298241 0
19/07/2017
Approval date [1] 298241 0
07/09/2017
Ethics approval number [1] 298241 0
EH2017-255

Summary
Brief summary
Depression is a common, severe and often difficult to treat illness. Repetitive transcranial magnetic stimulation (TMS), a non-invasive brain stimulation technique, is an effective and well tolerated treatment for depression. TMS uses magnetic pulses to stimulate and change the activity in areas of the brain related to depression, using a specialised coil placed on the head while the patient is awake and alert. Although TMS is effective, it takes a long time to induce clinical response, often 4-6 weeks. This limits its applicability in clinical practice and is associated with considerable treatment costs. Response to rTMS can be accelerated with intensive treatment schedules involving a number of treatments a day, but these are also time consuming. Theta burst stimulation (TBS), a type of TMS, appears to produce similar effects to standard TMS when applied on a daily basis but with markedly less time demands (3 minutes compared to 40 minutes per session). TBS would appear to be an ideal intervention to use in an intensive / accelerated format where multiple daily sessions could be applied but still in a limited amount of time. However, the optimal TBS treatment parameters, such as treatment intensity, are still unknown and require investigation. This study is therefore a randomised controlled trial to compare an accelerated TBS intervention to standard once daily TMS to evaluate its relative effectiveness and rapidity of antidepressant effect. We will also compare the relative efficacy of two different strengths of TBS to investigate the most effective TBS treatment parameters. Participants will receive 20 sessions of lower intensity TBS, higher intensity TBS or standard TMS over a 2 - 4 week period. Participants will take part in interviews at baseline, week 1, 2, 4 and 8-10. Participants responding to the treatment will be followed up for six months
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76446 0
Prof Paul Fitzgerald
Address 76446 0
Epworth Camberwell
888 Toorak Road
Camberwell VIC 3124
Country 76446 0
Australia
Phone 76446 0
+61 3 9805 4287
Fax 76446 0
Email 76446 0
paul.fitzgerald@monash.edu
Contact person for public queries
Name 76447 0
Ms Rachel Hughes
Address 76447 0
Epworth Camberwell
888 Toorak Road
Camberwell VIC 3124
Country 76447 0
Australia
Phone 76447 0
+61 3 9805 4363
Fax 76447 0
Email 76447 0
mentalhealthresearch@epworth.org.au
Contact person for scientific queries
Name 76448 0
Prof Paul Fitzgerald
Address 76448 0
Epworth Camberwell
888 Toorak Road
Camberwell VIC 3124
Country 76448 0
Australia
Phone 76448 0
+61 3 9805 4287
Fax 76448 0
Email 76448 0
paul.fitzgerald@monash.edu

No data has been provided for results reporting
Summary results
Not applicable