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Trial registered on ANZCTR


Registration number
ACTRN12622000775718
Ethics application status
Approved
Date submitted
28/04/2022
Date registered
31/05/2022
Date last updated
7/04/2024
Date data sharing statement initially provided
31/05/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The use of MRI guided focused ultrasound for the management of focal hand dystonia
Scientific title
Evaluation of the efficacy and safety of MRI guided focused ultrasound (MRgFUS) for focal hand dystonia
Secondary ID [1] 307020 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
focal hand dystonia 326149 0
Condition category
Condition code
Neurological 323467 323467 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial aims to assess the efficacy and safety of MRgFUS in the treatment of focal hand dystonia. We aim to enrol 10 patients with focal hand dystonia, according to specific inclusion and exclusion criteria, and assess the benefit of MRgFUS in the treatment of this condition.

All patients will undergo regular physical examination by a consultant neurologist and fellow with specialisation in movement disorders. Administration of standardised questionnaires, including the Arm Dystonia Disability Scale (ADDS), Michigan Health Outcome Questionnaire (MHOQ), Tubiana Musicians Dystonia Scale/Writer's Cramp Rating Scale (TMDS/WCRS), Short-Form 36 (SF-36) and pain numerical rating scale (NRS) will be administered at all visits except for the day of the procedure. Pre-procedure cognitive impairment will be screened using the mini-mental state examination (MMSE) and, similarly, pre- and post procedure depressive illness will be screened using the Beck Depression Inventory (BDI). If the participants meet all relevant inclusion, and no exclusion, criteria, a CT brain scan will be performed to measure the skull density ratio (SDR) using a low radiation dose CT scanner (at baseline only, not a treatment outcome). Further pre-procedural baseline screening will include assessment of neural pathways with MRI DTI tractography and resting state fMRI. Kinematic measures will be obtained using AMADEO upper extremity system and neurophysiological testing, using paired associative stimulation (PAS), will be used to measure cortical plasticity. The neurophysiological assessments are non-invasive (no recording needles are inserted) and the duration of neurophysiological testing is 60-90 minutes per study visit, with the patient seated comfortably in a neurophysiology laboratory with opportunities for rest breaks when needed. Participants will reviewed at baseline by an expert examiner in the field appropriate to their presenting complaint, that is, an expert musicologist for musician’s dystonia and a calligraphist for writer’s cramp.

The MRgFUS intervention will be performed according to the standard protocol for MRgFUS at SVHNS and is delivered in a single session. The intervention is delivered by the senior consultant neurosurgeon involved in the study concept and protocol development. on the day of treatment, participants will undergo a head shave and the administration of local anaesthetic blocks prior to application of a stereotactic head frame. An elastic diaphragm is then placed over the scalp and affixed to the ultrasound transducer prior to being filled with cooled, degassed water. Participants are then placed into the 3-Tesla MRI scanner (SIGNA Architect, General Electric) and 3D T1 weighted imaging performed for localisation of the ventro-oral anterior and ventro-oral posterior nuclei. Lesions are created using an Exblate Neuro (InSightec) 650Hz, 1024-element, phased array ultrasound transducer. Initial operative planning is performed with a series of low power sonications producing temperatures of 40-45 °C to confirm accurate focusing in three orthogonal planes with magnetic resonance thermography. MR thermometry is utilised to measure the maximum temperature at target’s central voxel, centring on the target. Following confirmation of accurate targeting, therapeutic sonications are performed by gradually increasing the ultrasound energy and monitoring both the maximal and average temperatures at the target for each sonication. Clinical examinations are performed between each sonication to assess for focal hand dystonia and for the presence of side effects. This protocol is in keeping with the current TGA approved protocol for the use of MRgFUS in tremor treatment. The safety of this protocol is supported by the established safety profile of thalamic MRgFUS ablation for tremor syndromes and the existing body of literature for MRgFUS VOA/VOP thalamic ablation in focal hand dystonia as well as MRgFUS pallido-thalamic ablation for tremor syndromes.

Treatment efficacy will be determined based administration of the ADDS, either the TMDS or WCRS based on the underlying syndrome, in addition to the SF-36 questionnaires at 1 month, 3 months, 6 months and 12 months post treatment. The pain NRS, MMSE and BDI will be administered at all follow up appointments. Kinematic hand function will be measured at 1, 3, 6 and 12 months using the specialised equipment that allows measurement of independent finger force and velocity in motor paradigms to assess manual dexterity required for high-level manual tasks. These assessments will allow defects of timing, force control (coordination), finger independence, and sequencing to be formally quantified to fully assess motor costs of treatment. Additionally, expert opinion by a musicologist, or calligraphist, will be sought at the baseline, 3, 6 and 12 month follow up appointments. Imaging outcomes will be collected at 3 and 12 months as in alignment with previous studies of MRgFUS in tremor. Repeat neurophysiological testing will be performed at 1, 3 and 12 months post treatment to assess for changes in cortical inhibition and neuroplasticity.

Safety will be determined based on the incidence of predetermined adverse events experienced on the day of treatment, day 1 post procedure, 1 week post procedure (via phone call) and at each follow up appointment.
Intervention code [1] 323467 0
Treatment: Other
Comparator / control treatment
There is no control treatment group employed in this study. However, 10 age-matched control participants will be recruited and undergo both MRI and neurophysiological testing (to ascertain measures of cortical plasticity) to compare and assess for differences in participants with focal hand dystonia both at baseline and post MRgFUS thalamotomy.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331207 0
Change in Arm Dystonia Disability Scale (ADDS)
Timepoint [1] 331207 0
Baseline, and 1, 3, 6, and 12 months post the procedure
Primary outcome [2] 331252 0
Change in Burke-Fahn-Marsden Scale of Dystonia
Timepoint [2] 331252 0
Baseline, and 1, 3, 6 and 12 months post the procedure
Primary outcome [3] 331253 0
Tubiana Musicians Dystonia Scale (TMDS) for musicians dystonia

OR

Writers Cramp Rating Scale (WCRS)
Timepoint [3] 331253 0
Baseline, and 1, 3, 6, and 12 months post the procedure
Secondary outcome [1] 409316 0
Safety using study specific questionnaire/sheet
Timepoint [1] 409316 0
Occurrence of any adverse events at the following timepoints:
Intraprocedural (day 0), day 1, 1 week, and 1, 3, 6, 12 months post procedure
Secondary outcome [2] 409317 0
Kinematic measures:
Finger/hand strength and velocity using the AMADEO upper extremity rehabilitation and analysis system
Timepoint [2] 409317 0
Baseline, and 1, 3, 6, 12 months post procedure
Secondary outcome [3] 409318 0
Upper limb function using the Purdue 9-hole peg-test
Timepoint [3] 409318 0
Baseline, and 1, 3, 6, and 12 months post the procedure
Secondary outcome [4] 409319 0
Upper limb function using the Michigan Hand Outcome Questionnaire (MHOQ)
Timepoint [4] 409319 0
Baseline, and 1, 3, 6, and 12 months post the procedure
Secondary outcome [5] 409320 0
Changes in cortical plasticity using paired associative stimuli latency and spatial specificity
Timepoint [5] 409320 0
Baseline, and 1, 3, and 12 months post the procedure
Secondary outcome [6] 409321 0
Changes in neural pathways using MRI diffusion tract imaging
Timepoint [6] 409321 0
Baseline, and 1, 3, and 12 months post the procedure
Secondary outcome [7] 409322 0
Screening for depression and low mood using the Beck Depression Inventory (BDI)
Timepoint [7] 409322 0
Baseline, and 1, 3, 6, and 12 months post the procedure
Secondary outcome [8] 409323 0
Quality of life using the Short-Form 36
Timepoint [8] 409323 0
Baseline, and 1, 3, 6, and 12 months post the procedure
Secondary outcome [9] 409324 0
Hand pain/discomfort using the Pain numerical rating scale (NRS)
Timepoint [9] 409324 0
Baseline, and 1, 3, 6, and 12 months post the procedure

Eligibility
Key inclusion criteria
Patients will be included based on a formal diagnosis of focal hand dystonia (of either musician’s dystonia or writer’s subtype) as made by a consultant neurologist with specialisation in movement disorders. All patients must be at least 18 years of age and be willing to provide written consent to participate in the study. Patients must have tried and failed first line therapies for focal hand dystonia including hand therapy, oral medications and/or botulinum toxin injections.
All patients must be ambulant at the time of the procedure.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded if any of the following criteria are fulfilled
• History of ischaemic stroke or transient ischaemic event
• History of stereotactic cerebral surgery
• Diagnosis of unstable cardiac disease
• Diagnosis of psychiatric disease
• Cognitive impairment as indicated by a mini-mental state examination score of < 24
• Coagulopathy or on anticoagulation that cannot be withheld for the intervention
• Skull density ratio of <0.3
• Absolute contraindication to MRI (eg: non-MR compatible pacemaker/defibrillator or other non-MR compatible device in situ).
• Relative contraindication to MRI (such as severe claustrophobia) will be assessed on a case-by-case basis
• Unwilling to provide written consent

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A preliminary sample-size calculation indicates that we will require 8 patients to detect a 50% improvement in focal hand dystonia (based on standardised rating scales and a predicted similar outcome to a recent pilot study) at p < 0.05 with 0.9 power and a standard deviation of 0.30. Ideally, we aim to recruit at least 10 patients to the trial and possibly more pending patients fulfilling inclusion criteria. The data will be analysed using ANOVA with main effect of time at 1, 3, 6 and 12 month follow up intervals. Post hoc t-tests will be used where effects of time are identified by ANOVA. Non-parametric variables will be compared pre and post using Wilcoxon signed-rank test.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/08/2022
Actual
9/01/2023
Date of last participant enrolment
Anticipated
Actual
21/03/2024
Date of last data collection
Anticipated
Actual
21/03/2024
Sample size
Target
10
Accrual to date
Final
11
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 22285 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 37447 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 311331 0
Charities/Societies/Foundations
Name [1] 311331 0
Dr Tisch Research Trust Fund/Curran Foundation/Philanthropic Donation
Country [1] 311331 0
Australia
Funding source category [2] 312948 0
Charities/Societies/Foundations
Name [2] 312948 0
Dystonia Network of Australia
Country [2] 312948 0
Australia
Funding source category [3] 312949 0
Charities/Societies/Foundations
Name [3] 312949 0
Brain Foundation
Country [3] 312949 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Health Network Sydney
Address
St Vincents Health Network
390 Victoria Road, Darlinghurst
NSW 2010
Country
Australia
Secondary sponsor category [1] 312707 0
None
Name [1] 312707 0
Address [1] 312707 0
Country [1] 312707 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310830 0
St Vincent's Hospital Research Ethics Committee
Ethics committee address [1] 310830 0
Ethics committee country [1] 310830 0
Australia
Date submitted for ethics approval [1] 310830 0
24/05/2022
Approval date [1] 310830 0
22/06/2022
Ethics approval number [1] 310830 0
2022/ETH00778

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

Contacts
Principal investigator
Name 119014 0
Dr Joel Maamary
Address 119014 0
Level 4, Xavier Building, Department of Neurology
390 Victoria Road, Darlinghurst NSW 2010
Country 119014 0
Australia
Phone 119014 0
+61 2 8382 2640
Fax 119014 0
Email 119014 0
[email protected]
Contact person for public queries
Name 119015 0
Joel Maamary
Address 119015 0
Level 4, Xavier Building, Department of Neurology
390 Victoria Road, Darlinghurst NSW 2010
Country 119015 0
Australia
Phone 119015 0
+61 2 8382 2640
Fax 119015 0
Email 119015 0
[email protected]
Contact person for scientific queries
Name 119016 0
Joel Maamary
Address 119016 0
Level 4, Xavier Building, Department of Neurology
390 Victoria Road, Darlinghurst NSW 2010
Country 119016 0
Australia
Phone 119016 0
+61 2 8382 2640
Fax 119016 0
Email 119016 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual patient data will not be available, due to the small sample size and optimising risk to privacy. Aggregate data will be made available on request.


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.