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Trial registered on ANZCTR


Registration number
ACTRN12619001118190
Ethics application status
Approved
Date submitted
30/07/2019
Date registered
12/08/2019
Date last updated
12/08/2019
Date data sharing statement initially provided
12/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A clinical research study investigating repetitive transcranial magnetic stimulation (rTMS) in treating persistent post-concussion symptoms in children compared to placebo/dummy treatment
Scientific title
A single centre, double-blind, randomized controlled trial investigating repetitive transcranial magnetic stimulation (rTMS) to treat persistent post-concussion symptoms in children
Secondary ID [1] 297942 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Persistent post-concussion syndrome 312336 0
Condition category
Condition code
Neurological 310898 310898 0 0
Other neurological disorders
Injuries and Accidents 312314 312314 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive neuromodulation that uses a series of brief magnetic pulses to increase or decrease cortical excitability in specific brain regions. These trains of pulses are non-invasive, painless magnetic stimulations which modulates neuronal activity to induce neuroplasticity in the brain. In general, where rTMS is used as a treatment, it is intended to “normalise” overactivity or underactivity within a brain region.

All TMS interventions in this study will take place at the Child Health Research Centre (CHRC) KidStim neuromodulation Laboratory in Brisbane, Australia. TMS will be delivered by research investigators and personnel trained and experienced in giving TMS. Children aged 11-18 years experiencing post concussion symptoms for 2 or more months will be asked to participate.

Participants will be invited to have a structural and functional MRI at Herston Imaging Research Facility and high-density EEG at CHRC pre- and post-treatment. This will allow review of any changes before and after treatment. It will also enable real-time and accurate positioning of an rTMS coil over the treatment stimulation site through the upload of the individual's MRI in the TMS neuronavigation system.

At the beginning of each TMS session, a “motor threshold” procedure is performed. The lowest intensity of the machine that can reliably produce this twitch is the motor threshold, and this is used to set the TMS intensity. Briefly, surface EMG electrodes are placed of the right first dorsal interosseous muscle (FDI) to record motor evoked potentials (MEP). Single pulse TMS is then applied over the left primary motor cortex to determine the ideal location (hotspot) for maximal evoked potentials. The RMT is then defined as the stimulator intensity required to elicit MEP > 0.5mV in 5 of 10 consecutive trials.

Interventional rTMS will consist of 40 suprathreshold (120% RMT) pulses over 4 seconds (10 Hz) with an inter-train interval of 26 seconds over the dorsolateral prefrontal cortex (DLPFC). Treatment sessions will last 37.5 minutes (75 trains/3000 pulses). Treatments will occur on each weekday for two weeks (10 treatment days total), where up to 54 participants will be randomised to receive either active rTMS or sham rTMS (placebo with no magnetic field). A further optional 10 treatment sessions over 2 weeks will be offered, where all participants will receive active rTMS only.

During participation, participants will be asked to complete a number of questionnaires and assessments measuring symptoms, quality of life, mood, strength and difficulties and neurocognitive abilities.
Intervention code [1] 314169 0
Treatment: Devices
Intervention code [2] 314170 0
Rehabilitation
Comparator / control treatment
Active rTMS will be compared to sham rTMS (placebo with no magnetic field) for 10 treatment sessions over 2 weeks
Control group
Placebo

Outcomes
Primary outcome [1] 319722 0
Post Concussive Symptom Inventory (PCSI)
Timepoint [1] 319722 0
Baseline visit (pre-treatment); treatment day 10 (post-treatment); outcome visit (1-3 days post 10th treatment) and follow-up visit (1 month post final treatment). In the optional open label arm, PSCI will be done after the final dose.
Primary outcome [2] 319723 0
Pediatric Quality of Life Inventory (PedsQL)
Timepoint [2] 319723 0
Baseline visit (pre-treatment); outcome visit (1-3 days post 10th treatment) and follow-up visit (1 month post final treatment). In the optional open label arm, PedsQL will be done after the final dose.
Primary outcome [3] 319724 0
rTMS Tolerability Score
Timepoint [3] 319724 0
Baseline visit (pre-treatment); on treatment day 5, on treatment day 10.
In the optional open label arm, the tolerability score will be taken on treatment day 11, day 15 and day 20.
Secondary outcome [1] 369298 0
Patient Health Questionnaire (PHQ-9)
Timepoint [1] 369298 0
Baseline visit (pre-treatment); outcome visit (1-3 days post 10th treatment) and follow-up visit (1 month post final treatment). In the optional open label arm, PHQ-9 will be done after the final dose.
Secondary outcome [2] 369299 0
Screen for Child and Adolescent Anxiety Disorders (SCARED)
Timepoint [2] 369299 0
Baseline visit (pre-treatment); outcome visit (1-3 days post 10th treatment) and follow-up visit (1 month post final treatment). In the optional open label arm, SCARED will be done after the final dose.
Secondary outcome [3] 369300 0
Strength and Difficulties Questionnaire (SDQ)
Timepoint [3] 369300 0
Baseline visit (pre-treatment); outcome visit (1-3 days post 10th treatment) and follow-up visit (1 month post final treatment). In the optional open label arm, SDQ will be done after the final dose.
Secondary outcome [4] 369301 0
Headache Impact Test (HIT-6)
Timepoint [4] 369301 0
Baseline visit (pre-treatment); outcome visit (1-3 days post 10th treatment) and follow-up visit (1 month post final treatment). In the optional open label arm, HIT-6 will be done after the final dose.
Secondary outcome [5] 369302 0
CNS Vital Signs Computerized Cognitive Test
Timepoint [5] 369302 0
Baseline visit (pre-treatment); outcome visit (1-3 days post 10th treatment).
Secondary outcome [6] 373280 0
Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL MDFS)
Timepoint [6] 373280 0
Baseline visit (pre-treatment); outcome visit (1-3 days post 10th treatment) and follow-up visit (1 month post final treatment). In the optional open label arm, the fatigue scale will be done after the final dose.
Secondary outcome [7] 373281 0
Structural MRI - to provide anatomical landmarks for accurate TMS coil positioning
Timepoint [7] 373281 0
MRI is an optional procedure. If opted in, participants will have an MRI at the baseline visit and the outcome visit (1-2 days post 10th treatment)
Secondary outcome [8] 373473 0
Resting-state Functional MRI (rs-fMRI) to assess signal change and re-organisation of functional brain networks
Timepoint [8] 373473 0
MRI is an optional procedure. If opted in, participants will have an MRI at the baseline visit and the outcome visit (1-2 days post 10th treatment)
Secondary outcome [9] 373474 0
Diffusion MRI - to measure and characterise injury at baseline and assess changes post-TMS
Timepoint [9] 373474 0
MRI is an optional procedure. If opted in, participants will have an MRI at the baseline visit and the outcome visit (1-2 days post 10th treatment)
Secondary outcome [10] 373475 0
T2 Flair - additional brain injury characterisation for information on overall recovery trajectory
Timepoint [10] 373475 0
MRI is an optional procedure. If opted in, participants will have an MRI with T2 Flair at the baseline visit
Secondary outcome [11] 373476 0
Magnetic Resonance Spectroscopy (MRS) - insight into neurophysiological and metabolites related to structural damage/changes, neurotransmission and neuronal health
Timepoint [11] 373476 0
MRI is an optional procedure. If opted in, participants will have an MRI at the baseline visit and the outcome visit (1-2 days post 10th treatment)
Secondary outcome [12] 373477 0
Arterial spin labelling (ASL) - provide an additional marker of cerebral blood flow pre and post-stimulation.
Timepoint [12] 373477 0
MRI is an optional procedure. If opted in, participants will have an MRI at the baseline visit and the outcome visit (1-2 days post 10th treatment)
Secondary outcome [13] 373479 0
HD-EEG - Exploratory outcome to examine evidence of brain connectivity change (as detected by HD-EEG) following stimulation, and how this connectivity change is correlated with neuropsychological outcomes and recovery
Timepoint [13] 373479 0
Participants will have 128-channel EEG (HD-EEG) at baseline and outcome visit (1-3 days post 10th treatment). In the optional open-label arm, an EEG will be performed on the last dosing day after treatment

Eligibility
Key inclusion criteria
1. Male or female, 11-18 years of age inclusive (at time of initial pre-screening), currently experiencing post concussive symptoms.
2. Documentation of persistent post concussive symptoms as evidenced by two or more clinical symptoms: headache, difficulty concentrating or remembering, sleep problems, dizziness, fatigue or nausea/vomiting – not explained by another disorder.
3. Post concussive symptoms for more than/equal to 2 months.
4. No history of rTMS treatments.
Minimum age
11 Years
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Epilepsy or other seizure disorders.
2. Chronic treatment with psychotropic medication or any other medications deemed unsuitable for TMS application as deemed by the Investigator.
3. Neurological disorders, including moderate to severe learning difficulties.
4. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
5. Females of child-bearing potential only: Pregnant as confirmed by urine pregnancy test at baseline visit; and unwillingness to use contraception from pre-screening to follow-up visit (if sexually active); currently breastfeeding.
6. No recreational drug use.

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)
Participants will be screened for eligibility and receive their first treatment as per their schedule. The randomisation number will be allocated sequentially and stratified based on time since injury. It will not be know at the time of eligibility which treatment the participant will receive
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A stratified randomization approach will used to allow for the influence of time since injury on change of PCSI-Y over time. Three stratifications will be used: 2-4 months post injury, 4-6 months post injury, and more than 6 months post-injury. The randomization list will be generated using available online software by non-study personnel, and only the randomisation number will be entered into the Redcap research data management system
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
54 subjects will be enrolled over 2 years. A study sample of 21 per group should detect a PCSI change of 10 (clinically significant,4) with 80% power and 5% type 1 error (G-power). As the treatment is intensive, we have allowed for a 25% attrition rate i.e., 6 per group.

All eligible patients who are enrolled into the study and receive at least one treatment of rTMS, will be included in the intention to treat analysis and safety analyses. Subjects who withdraw during study participation will be offered a voluntary follow-up visit and but have no further data collected. Data collected up to the point of withdrawal will be included in the datasets and analysis. Participants will be allowed to miss up to 2 study treatment days (2 rTMS treatments) without violating protocol (to be included in a per protocol analysis).

Treatment response will be assessed at 1 month post treatment.
Overall changes in PCSI and PedQL scores will be evaluated using analysis of variance controlling for effects of pre-treatment PCSI score (ANCOVA).
Adverse events will be tabulated by treatment group and will include the number of patients for whom the event occurred, the rate of occurrence, and the severity and relationship to study treatment. Secondary endpoints are change in SCARED, PHQ-9 and SDQ scores.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/09/2019
Actual
Date of last participant enrolment
Anticipated
23/11/2021
Actual
Date of last data collection
Anticipated
20/01/2022
Actual
Sample size
Target
54
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 13609 0
Queensland Children's Hospital - South Brisbane
Recruitment postcode(s) [1] 26271 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 302456 0
Government body
Name [1] 302456 0
Motor Accident Insurance Commission
Country [1] 302456 0
Australia
Primary sponsor type
Individual
Name
Associate Professor Karen Barlow
Address
University of Queensland Child Health Research Centre
Centre for Children's Health Research
62 Graham St
South Brisbane
QLD 4101 Australia
Country
Australia
Secondary sponsor category [1] 302371 0
None
Name [1] 302371 0
Address [1] 302371 0
Country [1] 302371 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303125 0
The Children’s Health Queensland Human Research Ethics Committee
Ethics committee address [1] 303125 0
Ethics committee country [1] 303125 0
Australia
Date submitted for ethics approval [1] 303125 0
23/07/2018
Approval date [1] 303125 0
17/09/2018
Ethics approval number [1] 303125 0
HREC/QRCH/43508
Ethics committee name [2] 303136 0
The University of Queensland Human Research Ethics Committee
Ethics committee address [2] 303136 0
Ethics committee country [2] 303136 0
Australia
Date submitted for ethics approval [2] 303136 0
25/09/2018
Approval date [2] 303136 0
08/10/2018
Ethics approval number [2] 303136 0
2018002015/HREC/QRCH/43508

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92558 0
A/Prof Karen Barlow
Address 92558 0
The University of Queensland Child Health Research Centre
Centre for Children's Health Research
62 Graham Street
South Brisbane
QLD 4101
Country 92558 0
Australia
Phone 92558 0
+61 730694786
Fax 92558 0
Email 92558 0
k.barlow@uq.edu.au
Contact person for public queries
Name 92559 0
Karen Barlow
Address 92559 0
The University of Queensland Child Health Research Centre
Centre for Children's Health Research
62 Graham Street
South Brisbane
QLD 4101
Country 92559 0
Australia
Phone 92559 0
+61 730694786
Fax 92559 0
Email 92559 0
k.barlow@uq.edu.au
Contact person for scientific queries
Name 92560 0
Karen Barlow
Address 92560 0
The University of Queensland Child Health Research Centre
Centre for Children's Health Research
62 Graham Street
South Brisbane
QLD 4101
Country 92560 0
Australia
Phone 92560 0
+61 730694786
Fax 92560 0
Email 92560 0
k.barlow@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified participant data only. Demographic and injury characteristics, outcome measures, tms parameters, dose, trial data report, data dictionary
When will data be available (start and end dates)?
Upon publication of the the major outcome paper of the trial with no end date determined
Available to whom?
Researchers with a reasonable research question will be considered.
Available for what types of analyses?
Any reasonable research question.
How or where can data be obtained?
The data will be shared through mendeley data using a link from the principal investigator.
Principal Investigator (Associate Professor Karen Barlow) can be contacted via email at:
k.barlow@uq.edu.au or uq_ABiC@uq.edu.au


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
No additional documents have been identified.