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Trial registered on ANZCTR


Registration number
ACTRN12617000298314
Ethics application status
Approved
Date submitted
22/02/2017
Date registered
27/02/2017
Date last updated
26/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Melting freezing of gait with non-invasive cerebellar stimulation
Scientific title
Cerebellar Transcranial Magnetic Stimulation as a novel treatment for Freezing of Gait in Parkinson's disease
Secondary ID [1] 291243 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Freezing of Gait in Parkinson's disease 302173 0
Condition category
Condition code
Neurological 301782 301782 0 0
Parkinson's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Summary:
Freezing of Gait (FOG) is a devastating symptom of Parkinson's disease (PD), causing regular falls and nursing home placement. Unfortunately, clinical management of FOG is very challenging with no current treatment completely alleviating FOG. As such, this study sets out to reduce FOG by using a safe stimulation technique called intermitted Theta Burst Stimulation (iTBS) of the cerebellum, which is a structure known to be involved with Parkinsonian gait disorders. iTBS is a form of Transcranial Magnetic Stimulation (TMS). This potential treatment has the advantage of non-invasively accessing a promising target for one of the most debilitating symptoms of PD, without the surgical risks associated with invasive brain stimulation techniques like deep brain stimulation.

Study design:
This is a single-blind sham controlled cross-over study.

Aims:
The aim of this study is to test the effects of intermitted Theta Burst Stimulation (iTBS) of the lateral cerebellum (Active 1), of the cerebellar vermis (Active 2) and of a control sham stimulation condition (Sham) of the neck muscles on Freezing of Gait in Parkinson's disease to be assessed on three separate mornings with a minimum washout period of 48 hours between visits. Subjects will be tested on standardised Timed-up-and-Go (Gait performance) and will be assessed on section 3 of the Unified Parkinson's Disease Rating Scale (UPDRS) before and after stimulation. Each subject's Active Motor Threshold (AMT) will be obtained, as further described below. The active stimulation parameters will be set to 80% of the subject's AMT as per TMS safety guidelines (Rossi et al. 2009). Participants will be blinded to treatment allocation and the order of stimulation will be randomized across participants.

Materials:
iTBS will be applied using a Magpro bi-phasic figure-of-eight coil connected to a MagPro R30 (MagVenture) stimulator with theta-burst option.

Stimulation protocol:
Subjects will first have their active motor thresholds determined by the first visible twitching of the FDI muscle which is actively contracted, related to single pulse TMS to the primary motor cortex controlling their dominant hand as per TMS safety guidelines (Rossi et al. 2009). The active motor threshold is the minimum amount of power necessary to make the subject's thumb twitch, and varies from individual to individual. The cerebellar stimulations will be set at 80% of active motor threshold, as per safety guidelines (Rossi et al. 2009). The two active stimulations will be set to 3 pulses at 50Hz, repeated at 5Hz (e.g. an inter-burst interval of 200 milliseconds) during a train of 2 seconds, repeated 20 times every 10 seconds administering a total of 600 pulses, as per previous investigation and safety guidelines (Koch et al. 2008; Rossi et al. 2009). In addition, during one of the three visits patients will undergo a brief (190 seconds) and low intensity (20% of active motor threshold) sham stimulation of the neck muscles to act as a control condition (Bologna et al. 2015).

Procedures:

iTBS stimulation
The coil will be positioned tangentially to the scalp, with the handle pointing upwards as per previous investigations showing that this orientation is able to modulate contralateral M1 excitability (Koch et al. 2008). The targets for active stimulation are the ipsilateral cerebellum (1cm below and 3cm lateral to inion), corresponding to the most affected side; and the cerebellar vermis (1 cm below inion) (Bologna et al. 2015; Hardwick et al. 2014). A sham stimulation of the neck muscles will also be applied (Bologna et al. 2015; Koch et al. 2008). This sham stimulation will induce the same auditory stimuli and a mild subjective sensation of neck muscle contraction similar to that obtained with real stimulation but does not stimulate the cerebellum and does not produce neurophysiological changes of the cerebellar connectivity, thus acting as a control condition (Bologna et al. 2015). Each stimulation protocol only takes little over three minutes and will be applied during a separate visit several days apart to account for wash-out effects. The study coordinator, who completed extensive training on applicability and safety of Transcranial Magnetic Stimulation will apply the stimulation. A licensed medical officer will always be present during each visit to ensure participant safety. The Chief Medical Officer, a Neurologist and Movement Disorder Specialist, will also be available for medical supervision during each study visit.

Behavioural measures:
During each visit (3 visits in total) the subjects will be assesses on standardised Timed-up-and-Go tasks and the motor section of the UPDRS immediately before and after iTBS stimulation. During the Timed-up-and-Go tasks subjects will be asked to stand up from a chair, walk 5 meters towards a square taped box on the floor, turn around and walk back towards the starting position. A total of eight trials will be performed where subjects are asked to make the following turns:
-2x 180 degrees, once left and once right;
-2x 540 degrees turns, once left and once right;
-2x shuffling around the outside of the taped box, once left and once right;
-2x 180 degrees turn while performing a cognitive dual task, once left and once right.
A researcher will always walk alongside the participants to reduce the risk for falls.

The motor section of the Unified Parkinson's Disease Rating Scale will be used to assess motor symptom severity associated with Parkinson's disease, such as bradykinesia, rigidity and tremor.

Location:
This study will be conducted at the Brain and Mind Centre, The University of Sydney.
Intervention code [1] 297246 0
Treatment: Devices
Comparator / control treatment
This study has a single-blind randomized cross-over design. Three stimulation protocols: Active stimulation of the lateral cerebellum (Active 1), active stimulation of the cerebellar vermis (Active 2) and Sham stimulation of the Neck muscles (Sham) will be compared within subjects.

The effects of the two active stimulations will be compared to each other to assess the most optimal stimulation site and to the sham condition to account for placebo effects.

Control group
Placebo

Outcomes
Primary outcome [1] 301183 0
Percentage of time spent experiencing Freezing of Gait during the Timed-up-and-Go gait tasks, assessed by video recordings of the subject's feet.
Timepoint [1] 301183 0
Immediately before and after iTBS stimulation during each of the three study visits.
Secondary outcome [1] 331969 0
Motor severity as determined through the Motor Section of the Unified Parkinson's Disease Rating Scale.
Timepoint [1] 331969 0
Immediately before and after iTBS stimulation during each of the three study visits.

Eligibility
Key inclusion criteria
* Age over 18 (Majority of participants will be aged between 50-90 years)
* Diagnosis of idiopathic Parkinson's Disease by a Neurologist
* Subjective complaints of Freezing of Gait symptoms, as obtained from a previously filled out Freezing of Gait-Questionnaire
* Able to walk for at least 30 meters unassisted
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Significant other neurological, psychiatric or cognitive disorder (including epilepsy, mania, psychosis, dementia, high suicidal risk, alcohol and substance use disorders, intellectual disability) as determined by a Neurologist
* History of seizures or epilepsy as determined by a Neurologist
* Subjects taking neuroleptic agents and other medications that can lower
their seizure threshold as determined by a Neurologist
* Intracranial or spinal cord metallic or magnetic implants, such as deep
brain stimulators, aneurysm clips and non-invasive Vagus Nerve
Stimulators (VNS)
* Pacemakers and other implantable medical devices (e.g. Cochlear
implants)
* Pregnancy (although most subjects will be over 40 years of age)

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)
Central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary analysis compares both active interventions to sham stimulation; secondary analyses compare freezing between stimulating the lateral cerebellum or vermis. Based on no expected improvements after sham stimulation and pilot data from eleven patients indicating a 40% improvement in freezing of the upper hand duration after iTBS of the lateral cerebellum, both analyses will have >80% power to allow an improvement of 20% in the more variable FOG episodes to be considered significant with an alpha of 0.05.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Safety concerns
Other reasons/comments
Other reasons
Previous work has indicated that a similar stimulation protocol did not improve freezing of gait in Parkinson's disease, see Janssen et al. (2017).
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)
NSW
Recruitment hospital [1] 7539 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment postcode(s) [1] 15363 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 295697 0
Charities/Societies/Foundations
Name [1] 295697 0
Parkinson's NSW
Address [1] 295697 0
Macquarie Hospital Building 17
51 Wicks Road
North Ryde NSW 2113
Country [1] 295697 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
100 Mallett Street
Camperdown, NSW, 2050
Country
Australia
Secondary sponsor category [1] 294537 0
None
Name [1] 294537 0
Address [1] 294537 0
Country [1] 294537 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297003 0
University of Sydney Human Research Ethics Committee
Ethics committee address [1] 297003 0
Human Ethics Office
Margaret Telfer Building (K07)
University of Sydney
NSW 2006
Ethics committee country [1] 297003 0
Australia
Date submitted for ethics approval [1] 297003 0
01/08/2016
Approval date [1] 297003 0
07/11/2016
Ethics approval number [1] 297003 0
2016/737

Summary
Brief summary
Freezing of Gait (FOG) is a devastating symptom of Parkinson’s disease (PD), causing regular falls and nursing home placement. Unfortunately, clinical management of FOG is very challenging with no current treatment completely alleviating FOG. As such, this study sets out to reduce FOG by using a safe and non-invasive magnetic stimulation technique called intermitted Theta Burst Stimulation (iTBS) of the cerebellum, which is a structure known to be involved with Parkinsonian gait disorders. This potential treatment has the advantage of non-invasively accessing a promising target for one of the most debilitating symptoms of PD, without the surgical risks associated with invasive brain stimulation techniques like deep brain stimulation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72682 0
Prof Simon Lewis
Address 72682 0
Parkinson's Disease Research Clinic
Brain and Mind Centre
Level 2, 100 Mallett Street
Camperdown, NSW, 2050
Country 72682 0
Australia
Phone 72682 0
+61293510702
Fax 72682 0
Email 72682 0
simonl@med.usyd.edu.au
Contact person for public queries
Name 72683 0
Mr Moran Gilat
Address 72683 0
Parkinson's Disease Research Clinic
Brain and Mind Centre
Level 2, 100 Mallett Street
Camperdown, NSW, 2050
Country 72683 0
Australia
Phone 72683 0
+61293510889
Fax 72683 0
Email 72683 0
moran.gilat@sydney.edu.au
Contact person for scientific queries
Name 72684 0
Prof Simon Lewis
Address 72684 0
Parkinson's Disease Research Clinic
Brain and Mind Centre
Level 2, 100 Mallett Street
Camperdown, NSW, 2050
Country 72684 0
Australia
Phone 72684 0
+61293510702
Fax 72684 0
Email 72684 0
simonl@med.usyd.edu.au

No data has been provided for results reporting
Summary results
Not applicable