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Trial registered on ANZCTR


Registration number
ACTRN12620000591954
Ethics application status
Approved
Date submitted
23/04/2020
Date registered
21/05/2020
Date last updated
21/05/2020
Date data sharing statement initially provided
21/05/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Individualised Theta Burst Transcranial Magnetic Stimulation (TBS) for Depression
Scientific title
A randomised trial on the effect of individualised versus non individualised theta burst transcranial magnetic stimulation on depression scores in patients with major depressive episodes.
Secondary ID [1] 300038 0
None
Universal Trial Number (UTN)
Trial acronym
IndTBS for Depression
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 315544 0
Condition category
Condition code
Mental Health 313828 313828 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a double blind randomised controlled trial investigating whether the outcome of Theta Burst Transcranial Magnetic Stimulation (TBS) can be optimised by using individualised treatment frequency, determined by EEG. The clinical and neurophysiological outcome of standard TBS and invidualised TBS will be compared.

Participants will be randomly allocated to one of two treatment conditions:
• Standard TBS (Participants receive the predetermined pulse frequency consistent with standard treatment protocol.)
TBS will be applied on left side and delivered as 3-pulse 50-Hz bursts applied at 5 Hz (i.e. 50 Hz burst of 3 pulses delivered every 200ms) with a 2-second train of TBS repeated every 10 seconds (i.e. 2 seconds of TBS followed by an 8 second rest). Total number of pulses is 600.
• Individualised TBS (Each participant undergoes treatment with TMS pulses applied at individualised frequency (in the range of 25-70 Hz) determined by EEG on left side.)
TBS will be applied with their own individualised frequency. Other parameters are the same as in the standard group.

Both groups will receive active treatment one session a day on weekdays for 20 treatment days. Participants will fortnightly take part in interviews for 4 weeks and another follow-up session at week 8. The interviewers will be blinded to the participant’s treatment group. The TBS treatment involves the application of magnetic stimulation to left DLPFC (Dorsolateral prefrontal cortex) by targeting on F3 location from the 10-20 EEG System at 120% of the RMT (resting motor threshold). 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. All treatments will be conducted by a fully 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. EEG (Electroencephalogram) and NIRS (Near-Infrared Spectroscopy) recordings will apply in the sessions for neurophysiological assessments. The duration of each treatment session will be about 15 mins including set up.
Intervention code [1] 316310 0
Treatment: Devices
Comparator / control treatment
The study aim is to investigate whether individualised TBS outperforms standard TBS. . Standard TBS is the comparator treatment. Individualised TBS will also be compared.

Standard TBS will be applied on left side (F3 location from the 10-20 EEG system) and delivered as 3-pulse 50-Hz bursts applied at 5 Hz (i.e. 50 Hz burst of 3 pulses delivered every 200ms) with a 2-second train of TBS repeated every 10 seconds (i.e. 2 seconds of TBS followed by an 8 second rest). Total number of pulses is 600.
Control group
Active

Outcomes
Primary outcome [1] 322223 0
Montgomery–Asberg Depression Rating Scale (MADRS)
Timepoint [1] 322223 0
Baseline, week 2, week 4 (primary timepoint) and week 8.

Response will be defined as a 50% reduction in the MADRS at week 4 from baseline.
Remission will be defined as a MADRS score < 7 at week 4.
Secondary outcome [1] 377797 0
Quick Inventory of Depressive Symptoms (QIDS-SR)
Timepoint [1] 377797 0
Baseline, week 2, week 4 and week 8.
Secondary outcome [2] 377798 0
Beck Anxiety Inventory (BAI)
Timepoint [2] 377798 0
Baseline, week 2, week 4 and week 8.
Secondary outcome [3] 377799 0
Clinical Global Impression - Improvement (CGI-I)
Timepoint [3] 377799 0
Baseline, week 2, week 4 and week 8
Secondary outcome [4] 377800 0
Change in Clinical Global Impression– Severity (CGI-S)
Timepoint [4] 377800 0
Baseline, week 2, week 4 and week 8
Secondary outcome [5] 377801 0
EEG (including TMS-EEG):
We will assess the plastic changes of the brain comparing between before and after TBS treatment by using TMS-EEG results (e.g. N45, P60, N100 and P200).
Timepoint [5] 377801 0
Baseline, week 2 and week 4
Secondary outcome [6] 382726 0
NIRS:
We will also measure how hemodynamic response changes before, during and after TBS treatment at the frontal brain by NIRS.
Timepoint [6] 382726 0
Baseline, week 2 and week 4

Eligibility
Key inclusion criteria
• Diagnosis of major depressive disorder as a single or recurrent episode, in accordance with the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V) with Mini-International Neuropsychiatric Interview-confirmed diagnosis.
• 18-80 years of age.
• Treatment resistant depression at Stage II of the Thase and Rush classification.
• Montgomery–Asberg Depression Rating Scale (MADRS) score of >19 (moderate–severe depression).
• No change 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
80 Years
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.
• Active suicidal intent
• Any psychotic disorder or current active psychotic symptoms
• Patients who have intracranial implants.

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 receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
We aim to randomise 48 participants to each treatment arm in this trial (total n=96). With an allowance for approximately 10% drop out, we anticipate that 44 participants in each arm will have assessments at both baseline and week 8. With respect to the primary hypothesis, we foresee initial decline in MADRS will be more than 6 units greater in the Ind TBS arm compared to the standard TBS arm with a group SD of 10: this will provide power of 0.8 with an alpha of 0.05.
Data will be collated, cleaned and validated using programmed edit checks, and stored in a secure database that will be locked prior to the unblinding of the Trial Statistician and the Chief Investigators at the time of the analysis of the primary endpoint. This primary analysis will take place after all subjects, apart from those who may have withdrawn, have had their week 8 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 repeated measurements of the primary outcome variable will be analysed by fitting linear mixed models using restricted maximum likelihood (REML) – this will allow all available data to be used without the need for imputation of missing values, the selection of the most suitable variance-covariance model for the repeated measures, using Akaike’s Information Criterion, and the investigation of commonality of any nonlinear trends over time via smoothing splines. The F-test will be used to test for a treatment by time interaction and comparisons between treatment groups at each time point will be based on t-tests that utilize the predicted means and standard errors of difference that are recovered from the fitted mixed model. Diagnostic plots of residuals will be assessed and if deemed necessary, variance-stabilizing transformations will be applied to the outcome variables and inferences will be based on the analyses conducted on the transformed scale. In a series of exploratory analyses, mixed models with covariates for gender, age and time since diagnosis, and their interactions with treatment group and time, will be fitted in order to identify possible moderating effects. The complete list of candidate covariates, and details of the analyses, including the generalized linear mixed model analyses for the response and remission endpoints, will be specified in a Statistical Analysis Plan that will be reviewed and approved by the Study Management Committee prior to database lock.


Recruitment
Recruitment status
Not yet 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] 15443 0
Epworth Rehabilitation Camberwell - Camberwell
Recruitment postcode(s) [1] 28770 0
3124 - Camberwell

Funding & Sponsors
Funding source category [1] 305540 0
Hospital
Name [1] 305540 0
Epworth Camberwell
Address [1] 305540 0
888 Toorak Road
Camberwell
VICTORIA 3124
Country [1] 305540 0
Australia
Funding source category [2] 305671 0
University
Name [2] 305671 0
Monash University
Address [2] 305671 0
Wellington Rd, Clayton VIC 3800
Country [2] 305671 0
Australia
Funding source category [3] 305672 0
Government body
Name [3] 305672 0
NHMRC Investigator grant
Address [3] 305672 0
414 La Trobe St,
Melbourne VIC 3000
Country [3] 305672 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Wellington Rd, Clayton VIC 3800
Country
Australia
Secondary sponsor category [1] 304759 0
None
Name [1] 304759 0
Address [1] 304759 0
Country [1] 304759 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304925 0
Monash Health
Ethics committee address [1] 304925 0
246 Clayton Road, CLAYTON VIC 3168
Ethics committee country [1] 304925 0
Australia
Date submitted for ethics approval [1] 304925 0
10/01/2020
Approval date [1] 304925 0
16/04/2020
Ethics approval number [1] 304925 0
RES-20-0000-035E

Summary
Brief summary
This study is a randomised controlled trial investigating whether response to TBS can be substantially enhanced through the application of TBS at an individualised frequency. We hypothesised that treatment with an individualised TBS (Ind TBS) protocol will result in greater improvement in depressive symptoms, compared with standard TBS. So we will compare an individualised TBS intervention to standard TBS to evaluate its relative effectiveness in regards to antidepressant effects. Participants will take part in assessments of depression severity before, during and after four weeks of TBS and at another follow-up review at week 8. They will receive a course of 20 treatments of either Ind TBS or standard TBS. All assessments and treatments will take place at Epworth Camberwell.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98654 0
Prof Paul Fitzgerald
Address 98654 0
Epworth Camberwell
888 Toorak Road
Camberwell VIC 3124
Country 98654 0
Australia
Phone 98654 0
+61 398054287
Fax 98654 0
Email 98654 0
paul.fitzgerald@monash.edu
Contact person for public queries
Name 98655 0
Dr Pakin Kaewpijit
Address 98655 0
Epworth Camberwell
888 Toorak Road
Camberwell VIC 3124
Country 98655 0
Australia
Phone 98655 0
+61 398814450
Fax 98655 0
Email 98655 0
pakin.kaewpijit@monash.edu
Contact person for scientific queries
Name 98656 0
Dr Pakin Kaewpijit
Address 98656 0
Epworth Camberwell
888 Toorak Road
Camberwell VIC 3124
Country 98656 0
Australia
Phone 98656 0
+61 398814450
Fax 98656 0
Email 98656 0
pakin.kaewpijit@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
What supporting documents are/will be available?
No other documents available
Summary results
No Results