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Trial registered on ANZCTR


Registration number
ACTRN12621001186842
Ethics application status
Approved
Date submitted
9/08/2021
Date registered
3/09/2021
Date last updated
3/09/2021
Date data sharing statement initially provided
3/09/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Transcranial Magnetic Stimulation (TMS) as a Treatment/Intervention for Depression in Adolescents and Young adults
Scientific title
Acceptability and Tolerability of Transcranial Magnetic Stimulation for Depression in Adolescents and Young Adults.
Secondary ID [1] 304864 0
Orygen Protocol Number : Orygen 58852
Universal Trial Number (UTN)
U1111-1268-2889
Trial acronym
TDAY
Linked study record
NA

Health condition
Health condition(s) or problem(s) studied:
Depression 322971 0
Condition category
Condition code
Mental Health 320545 320545 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Repetitive Transcranial Stimulation (rTMS) is a technique known to modulate brain cortical activity and has demonstrated efficacy in the treatment of treatment resistant depression. Participants in this rTMS based study will be randomised to one of two active treatment groups with one of the groups (1) receiving "standard" treatment while the other group (2) will receive intermittent Theta Burst Stimulation (iTBS) treatment (the intervention). Participants in the iTBS groups will receive treatment at the left side dorsolateral prefrontal cortex, a site approximately 7 cm above the left eyebrow. The treatment schedule for the iTBS group is outlined below:

Group 2 (iTBS) – Participants will receive 2 iTBS treatments per day, on three weekdays (Mondays, Wednesdays, Fridays) for the first two weeks and on two weekdays per week (Tuesdays and Thursdays) for the last two weeks. They will receive the same total number of treatments (20) as Group 1. Each treatment lasts for just over 3 minutes and is comprised of 20 trains of stimulation. Each train contains a 50 Hz burst of 3 pulses delivered every 200msec (i.e. 5 Hz) for 2 seconds followed by an 8 second intertrain interval. There will be a minimum of 30 minutes between treatments on each treatment day. The total duration of each session will be approximately 45 minutes.

Treatments will be administered by a Division 1 nurse with specialist rTMS training and experience.

Treatment attendance will be recorded in a paper copy treatment record form.

Intervention code [1] 321254 0
Treatment: Devices
Comparator / control treatment
The control treatment is given to Group 1 as described above in Description of intervention(s)/Exposure section.
Participants in Group 1 will receive treatment at the left side dorsolateral prefrontal cortex, a site approximately 7 cm above the left eyebrow.

The treatment schedule for the control group is outlined below:

Group 1 (Standard)– Participants will receive 1 treatment per day on 5 weekdays (Monday to Friday) over the 4 weeks. Each treatment will last 30 minutes and is comprised of 75 trains of stimulation each with a 4 second pulse duration at 10 Hz and a 20 second inter-train interval. These parameters are typical of what is considered a “standard” rTMS treatment course for depression.

The total duration of each session will be approximately 45 minutes.

Treatments will be administered by a Division 1 nurse with specialist rTMS training and experience.

Treatment attendance will be recorded in a paper copy treatment record form.
Control group
Active

Outcomes
Primary outcome [1] 328415 0
To determine the acceptability of two TMS protocols in the treatment of depression in adolescents and young adults. Acceptability will be determined by assessing the number of planned treatments received by the participants as recorded in the patient's paper copy treatment record. For the purposes of measuring acceptability receiving 80% of the prescribed dose, which is 16 treatments for both treatment groups, will be considered the minimum therapeutic dose.
Timepoint [1] 328415 0
Acceptability will be determined by assessing the number of planned treatments received by the participants. For the purposes of measuring acceptability receiving 80% of the prescribed dose, which is 16 treatments for both treatment groups, will be considered the minimum therapeutic dose. This will be measured at the end of Week 4.
Primary outcome [2] 328691 0
To determine the safety/tolerability of two TMS protocols in the treatment of depression in adolescents and young adults. To explore safety/tolerability participants will be continually monitored throughout treatment days and any adverse events will be entered into a floating AE form. Before receiving a treatment participants will be asked about any residual side effects experienced after their last treatment and they will be asked about any side effects they are experiencing during a treatment.
Timepoint [2] 328691 0
To explore safety/tolerability participants will be continually monitored throughout treatment days and any adverse events will be entered into a floating AE form.
Secondary outcome [1] 398942 0
To explore the efficacy of the intensive iTBS compared to the standard rTMS in the treatment of depression in adolescents and young adults as assessed by changes in 16 item Quick Inventory of Depressive Symptomatology (Clinician Rated) (QIDS-C).
Timepoint [1] 398942 0
• Trajectory of 16 item Quick Inventory of Depressive Symptomatology (Clinician Rated) (QIDS-C) measured at baseline, weeks 2, 4 and 8.

Secondary outcome [2] 398943 0
To explore the effect of the TMS treatment on changes in symptoms of suicidal ideation as measured by the QIDS-C, sub item 12
Timepoint [2] 398943 0
QIDS-C subitem 12 Suicidal Ideation is measured at baseline, weeks 2,4 and 8.

Secondary outcome [3] 398945 0
Pattern of remission (QIDS-C of 5 or less) in depression for the two groups
Timepoint [3] 398945 0
Pattern of remission (defined as QIDS-C of 5 or less) measured at baseline, weeks 2,4 and 8.
Secondary outcome [4] 399974 0
To explore the effect of the TMS treatment on changes in symptoms of anxiety as measured by the self rated GAD7 scale.
Timepoint [4] 399974 0
Pattern of self rated GAD7 is measured at baseline, weeks 2,4 and 8.
Secondary outcome [5] 400556 0
To explore the efficacy of the intensive iTBS compared to the standard rTMS in the treatment of depression in adolescents and young adults as assessed by changes in Hamilton Depression Rating Scale 6 – Self Report, .
Timepoint [5] 400556 0
Trajectory of Hamilton Depression Rating Scale 6 – Self Report measured at baseline, weeks 1-4, and week 8.

Eligibility
Key inclusion criteria
A participant will be considered eligible for inclusion in this study only if ALL of the following criteria apply:
• Aged 15 – 25years old
• Capacity to consent
• Current major depressive episode as determined by psychiatrist/ psychiatry trainee (persons with BPAD in a depressive phase can be included)
• A QIDS-C of > 10 (moderate to severe depression)
• Treatment resistance defined as a failure to respond to first-line treatment with structured psychotherapy or antidepressant medication
• If taking psychotropic medication regime, on a stable dose in the four weeks prior to screening
Minimum age
15 Years
Maximum age
25 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants who meet ANY of the following criteria will not be eligible for participation in this study.
• History of seizure disorder or any condition leading to an increased risk of seizure
• Significant neurological disorder or brain trauma
• Presence of internal metal objects in the head, either implanted or result of shrapnel injury, that would be considered unsafe for MRI (dental work is not an exclusion)
• Any implanted medical devices with electronic components (e.g.: pacemaker, neural stimulator)
• Current severe or uncontrolled substance use as assessed by study psychiatrist interview at screening
• Any unstable or poorly managed significant medical condition
• Females who are pregnant or currently breastfeeding, or who are not using effective contraception.
• Participation in any other clinical intervention trial from baseline to the Week 8 follow-up
• Comorbid psychotic/delusional disorders or any psychiatric disorder that would prevent patient from attending treatment schedule
• Severe behavioural disturbances such that they would be unable to comply with the requirements of informed consent or comply with the study protocol

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 allocation sequence will be concealed using the online Research Project Management System (RPMS) that has been developed at Orygen.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation sequence will be developed by a statistician independent of the trial. Random permutated blocks will be used.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary outcomes are acceptability and safety/tolerability. The former will be assessed by the proportion of participants receiving 80% of the prescribed dose (i.e. 16 treatment sessions). The latter will be measured by the proportion of participants belonging to various frequency categories for side effects (such as 0, 1-5, >5) and the proportion of drop-outs. Comparison between the two trial treatments will be performed using Fisher’s exact test.

As a pilot study, the sample size is not likely to be large enough to determine statistically significant differences on efficacy measures. We have determined a sample size that is large enough to obtain preliminary data on acceptability and tolerability.

The secondary outcomes of symptom trajectories will be analysed using linear mixed-effects modelling. Between-treatment comparison of suicidal ideation and remission at particular time points and the corresponding patterns over time will be performed using Fisher’s exact test.

For the exploratory aims, the relationship between demographic/clinical characteristics and outcome measures at end of treatment (week 4) and follow-up (week 8) will be analysed using analysis of variance or Fisher’s exact test as appropriate.

The intention-to-treat approach will be adopted in the analysis. If necessary, multiple imputation will be used to handle missing data.

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

Funding & Sponsors
Funding source category [1] 309238 0
Other
Name [1] 309238 0
Orygen
Address [1] 309238 0
35 Poplar Road
Parkville VIC 3052
Country [1] 309238 0
Australia
Primary sponsor type
Other
Name
Orygen
Address
35 Poplar Road, Parkville VIC Australia 3052
Country
Australia
Secondary sponsor category [1] 310251 0
None
Name [1] 310251 0
Address [1] 310251 0
Country [1] 310251 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309086 0
Melbourne Health Human Research Ethics Comittee
Ethics committee address [1] 309086 0
Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville, VIC 3050
Australia
Ethics committee country [1] 309086 0
Australia
Date submitted for ethics approval [1] 309086 0
26/08/2020
Approval date [1] 309086 0
24/11/2020
Ethics approval number [1] 309086 0
HREC/58852/MH-2020

Summary
Brief summary
TDAY is a pilot open-label randomised control study comparing two different forms of repetitive Transcranial Magnetic Stimulation (rTMS) as a treatment for Major Depressive Disorder (MDD) in adolescents and young adults. Participants with MDD will be randomised to one of two rTMS treatment groups. In both groups a magnetic coil will be applied to L) side of the scalp, in which the coil generates an electrical impulse to the stimulate the underlying brain tissue, No anaesthetic is required. Group 1 will receive what is considered a standard 10Hz treatment protocol while Group 2 will receive a more novel, intensive intermittent thetaburst (iTBS) treatment protocol. Treatments will be administered Monday - Friday for 4 weeks. All participants will be engaged with their treating doctor for the duration of the trial, and will continue their current treatment regimen (i.e., either maintain a stable dose of antidepressant medication, or continue without antidepressant treatment). The primary outcome measures of safety and tolerability will be assessed continually across the study by monitoring adverse events and dropout rates. The secondary outcome measure (change in depression score) will be assessed at the end of week 2 and week 4, with a further assessment at week 8 to ascertain if any improvements have been maintained, and if some participants have a delayed response to treatment.

The study hypothesis is that the acceptability and safety/tolerability of the more novel intensive iTBS treatment protocol (Group 2) will similar or greater than that of the standard rTMS treatment protocol (Group 1).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112922 0
Dr Aswin Ratheesh
Address 112922 0
Orygen
35 Poplar Road (Locked Bag 10)
Parkville, Victoria 3052
Australia
Country 112922 0
Australia
Phone 112922 0
+61 3 9966 9207
Fax 112922 0
Email 112922 0
aswin.ratheesh@orygen.org.au
Contact person for public queries
Name 112923 0
Dr David Elliot
Address 112923 0
Orygen
35 Poplar Road (Locked Bag 10)
Parkville, Victoria 3052
Australia
Country 112923 0
Australia
Phone 112923 0
+61 3 9966 9258
Fax 112923 0
Email 112923 0
David.elliot@orygen.org.au
Contact person for scientific queries
Name 112924 0
Dr Aswin Ratheesh
Address 112924 0
Orygen
35 Poplar Road (Locked Bag 10)
Parkville, Victoria 3052
Australia
Country 112924 0
Australia
Phone 112924 0
+61 399669100
Fax 112924 0
Email 112924 0
aswin.ratheesh@orygen.org.au

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