Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000417886
Ethics application status
Approved
Date submitted
15/02/2021
Date registered
15/04/2021
Date last updated
15/04/2024
Date data sharing statement initially provided
15/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of multi-day continuous theta-burst stimulation on symptoms of cervical dystonia
Scientific title
The effect of multi-day continuous theta-burst stimulation on symptoms of cervical dystonia in adults
Secondary ID [1] 303691 0
NIL known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cervical dystonia 320743 0
Condition category
Condition code
Neurological 318581 318581 0 0
Other neurological disorders
Musculoskeletal 318895 318895 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will undergo 2 weeks (10 sessions) of continuous theta-burst stimulation (cTBS) to the somatosensory cortex (S1). Participants will be randomised before beginning the trial to receive either the intervention (cTBS) or a sham/placebo in the first block of sessions, and then the opposite form of stimulation in the second block of sessions (i.e., 20 sessions in total, separated into two blocks). The order of stimulation will be counterbalanced amongst participants. A washout period of approximately 2 weeks will separate the two blocks of sessions.
A Magventure Magpro R30 machine will be used to apply cTBS to the S1 bilaterally, which takes approximately 40 seconds each side. The cTBS intervention will consist of three pulses delivered at 50Hz every 200 milliseconds, for a total of 600 pulses.
The first, sixth, and last sessions in the intervention block are expected to take approximately 3 hours, due to the extra outcome measures collected (such as interhemispheric inhibition and single pulse TMS). The rest of the sessions are expected to take less than 30 minutes.
The intervention will take place at Deakin University's Cognitive Neuroscience Unit (Burwood). The intervention will be delivered by a student researcher and the principal investigator, who has over 5 years experience in TMS application.
Intervention code [1] 319740 0
Treatment: Devices
Comparator / control treatment
Participants will undergo 2 weeks (10 sessions) of sham cTBS to the S1. A Magventure Magpro R30 machine with a sham coil attached will be used to apply the sham cTBS to the S1 bilaterally, taking approximately 40 seconds per side. The first, sixth, and last sessions in the sham/placebo block are expected to take approximately 3 hours, due to the extra outcome measures collected (such as interhemispheric inhibition and single pulse TMS). The rest of the sessions are expected to take less than 30 minutes.
The intervention will take place at Deakin University's Cognitive Neuroscience Unit (Burwood). The intervention will be delivered by a student researcher and the principal investigator, who has over 5 years experience in TMS application.
Control group
Placebo

Outcomes
Primary outcome [1] 326540 0
Changes to average Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score - clinical rating scale used to measure cervical dystonia symptoms.
Timepoint [1] 326540 0
The TWSTRS will be measured both before and after the intervention in each session.
Primary outcome [2] 326541 0
A composite measure which will assess changes to the range of motion, angle, tilt and position of a participants head and neck in space, as measured through a custom-made neck kinematics device.
Timepoint [2] 326541 0
The range of motion of a participants head and neck will be measured both before and after the intervention in each session.
Secondary outcome [1] 392832 0
Finger-to-nose dysmetria test, which will be assessed whilst the participant is wearing the neck kinematics device, to measure proprioception.
Timepoint [1] 392832 0
The dysmetria test will be conducted before and after the intervention in each session.
Secondary outcome [2] 408725 0
Changes to fMRI data, to determine if there are objective functional or structural changes in a participants brain, after the application of cTBS. The fMRI will be acquired whilst the participant is at rest (no task).
Timepoint [2] 408725 0
The participant will undergo a scan before and after one block of the intervention..
Secondary outcome [3] 408726 0
Changes to DWI data (white matter microstructure within the brain), to determine if there are objective structural changes within a participants brain, after the application of cTBS.
Timepoint [3] 408726 0
A scan will take place before and after one block of the intervention.

Eligibility
Key inclusion criteria
To be included in the study participants must be cervical dystonia patients aged 18 to 85, diagnosed by a physician with cervical dystonia 12 or more months ago. Participants must have had a subjective response to botulinum toxin treatment at some point, with their last botulinum toxin injection 2 or more months ago.
Minimum age
18 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Severe head tremor, trauma to head or neck < 12 months prior to onset of dystonia, acquired dystonia (i.e., dystonia as a result of a traumatic brain injury, drug-induced, or as a result of another neurological condition), or pronounced head or neck tremor when lying down with neck supported.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The projected sample size was guided by similar previous research which examined the effect of multi-day TBS to the cerebellum of cervical dystonia patients (Bradnam et al., 2016; Koch et al., 2014). For a significant difference between pre and post-intervention TWSTRS scores, moderate effect sizes of d=0.31 (Koch et al., 2014) and d=0.42 (Bradnam et al., 2016) were reported. Working under the assumption that lesion network mapping increases efficacy for selection of treatment targets, a large effect size (d=0.8) was estimated for this study. Assuming 80% power (alpha level of 0.05), G*power indicated a sample size of 20 participants will be required.

A two-way ANOVA will be conducted, and will explore the relationship between the primary outcome measure (TWSTRS), time, and treatment. The factors will be time and treatment, with two levels to each variable – baseline and post-intervention for time, and sham or cTBS for treatment.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
3/05/2021
Actual
29/03/2022
Date of last participant enrolment
Anticipated
27/09/2024
Actual
Date of last data collection
Anticipated
13/12/2024
Actual
Sample size
Target
20
Accrual to date
7
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 37359 0
3125 - Burwood

Funding & Sponsors
Funding source category [1] 307858 0
University
Name [1] 307858 0
Deakin University
Country [1] 307858 0
Australia
Funding source category [2] 316304 0
Charities/Societies/Foundations
Name [2] 316304 0
Dystonia Coalition
Country [2] 316304 0
United States of America
Primary sponsor type
University
Name
Deakin University - Australian Government Research Training Program Scholarship
Address
221 Burwood Highway
Burwood
VIC 3125
Country
Australia
Secondary sponsor category [1] 308580 0
None
Name [1] 308580 0
Address [1] 308580 0
Country [1] 308580 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307862 0
Deakin University Human Research Ethics Committee
Ethics committee address [1] 307862 0
221 Burwood Highway
Burwood
VIC 3125
Ethics committee country [1] 307862 0
Australia
Date submitted for ethics approval [1] 307862 0
14/04/2021
Approval date [1] 307862 0
02/03/2022
Ethics approval number [1] 307862 0

Summary
Brief summary
Dystonia is a neurological disorder causing involuntary muscle contractions, and is thought to be caused by abnormal firing of specific brain networks. There are a number of types of dystonia, each defined by the body region/s that are affected. For example, and relevant to the present application, cervical dystonia (CD) affects the muscles of the neck. The current ‘gold standard’ treatments for CD are the injection of botulinum toxin type A (botox) into the affected muscles, or deep brain stimulation via brain surgery in more severe cases. However, injections only treat patients’ symptoms, rather than the underlying substrate of the disorder, and include side effects such as muscle wasting, while surgery is invasive and can be risky. As such, new treatments for CD are needed.
Repetitive transcranial magnetic stimulation (rTMS) has shown some promise in patients with CD, however, overall results have not yet been compelling enough to carry rTMS forward as an approved treatment method. rTMS in CD has been hindered by the fact that the particular brain region that should be stimulated is still unknown. This is because previous neuroimaging findings have identified many different brain regions as abnormal in CD. This research will build upon findings by Corp et al. (2019), who demonstrated that the somatosensory cortex is abnormal in CD patients. Thus, this will be the first study to investigate whether a form of rTMS (called continuous theta-burst stimulation, or cTBS) to this brain region can effectively relieve CD symptoms.
Aim 1 of the project is to investigate whether cTBS is an effective treatment for CD symptoms. It is hypothesised that there will be a significant overall reduction in CD symptoms post-intervention, as measured by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). CD symptoms will also be measured through kinematic testing using a custom-made device to measure head and neck angle, tilt, and position.
Aim 2 of this study is to investigate neurophysiological changes within the somatosensory cortex, due to the application of cTBS. It is hypothesised that there will be significant changes in the excitability of the somatosensory cortex (as measured by IHI) after the application of real cTBS in comparison to sham stimulation. Further, it is hypothesised that there will be a correlation between these changes in excitability, and reductions in CD symptom scores (as measured by the TWSTRS).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108738 0
Dr Daniel Corp
Address 108738 0
Deakin University
Cognitive Neuroscience Unit (CNU)
Building BC, Level 5
221 Burwood Highway
Burwood
VIC 3125
Country 108738 0
Australia
Phone 108738 0
+61 3 924 43019
Fax 108738 0
Email 108738 0
daniel.corp@deakin.edu.au
Contact person for public queries
Name 108739 0
Miss Jordan Morrison-Ham
Address 108739 0
Deakin University
Cognitive Neuroscience Unit (CNU)
Building BC, Level 5
221 Burwood Highway
Burwood
VIC 3125
Country 108739 0
Australia
Phone 108739 0
+61 3 924 43019
Fax 108739 0
Email 108739 0
jmorriso@deakin.edu.au
Contact person for scientific queries
Name 108740 0
Miss Jordan Morrison-Ham
Address 108740 0
Deakin University
Cognitive Neuroscience Unit (CNU)
Building BC, Level 5
221 Burwood Highway
Burwood
VIC 3125
Country 108740 0
Australia
Phone 108740 0
+61 3 924 43019
Fax 108740 0
Email 108740 0
jmorriso@deakin.edu.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?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11009Informed consent form  jmorriso@deakin.edu.au



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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