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Trial registered on ANZCTR


Registration number
ACTRN12618001836224
Ethics application status
Approved
Date submitted
21/10/2018
Date registered
12/11/2018
Date last updated
12/11/2018
Date data sharing statement initially provided
12/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Enhancing balance and gait in patients with Multiple Sclerosis – combined use of balance training with non-invasive brain stimulation
Scientific title
Improving balance and walking in patients with Multiple sclerosis using balance training and brain stimulation
Secondary ID [1] 295911 0
None
Universal Trial Number (UTN)
U1111-1219-4952
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Sclerosis 309386 0
Condition category
Condition code
Neurological 308246 308246 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive 12 treatment sessions over 6 weeks (2 per week) at the Perron Institute. Each treatment will comprise brain stimulation (real or sham tDCS) for 20 minutes followed by ~ 1 hour of one on one supervised balance therapy provided by a neurophysiotherapist. tDCS will be administered by a trained physiotherapist or clinical psychologist.

Transcranial direct current stimulation (tDCS) is a non-invasive technique that changes the excitability of brain cells by applying a weak direct current (1-2mA) to the brain. The method of applying tDCS involves placing saline-soaked sponge electrodes onto the skin of the scalp. These electrodes are connected to a battery driven direct current stimulator. tDCS is painless, inexpensive, has no major adverse effects and is easy to apply clinically.

Each balance training session will be one hour in duration and will comprise the 2 balance treatments described below. A rest break (5-10 minutes) will be given between the 2 treatments to minimize fatigue.
Treatment 1 (25 minutes). Impairment based physiotherapy would specifically target problems identified on assessment. This would include poor posture, reduced range of passive and active joint movement, reduced lower limb and core strength, use of compensatory movements, overactivity on one side etc.
Treatment 2 (25 minutes). Task oriented functional therapy which would progress tasks in difficulty and repetition as performance improved. Tasks would include standing, stepping, turning, reaching, hopping, running and walking tasks, including steps and uneven surfaces.

tDCS has been shown to improve motor function in stroke but has not been trialled in MS. Another kind of brain stimulation (rTMS) has been shown to benefit hand dexterity and lower limb spasticity in MS (Koch et al. 2008: Centoze et al. 2007). This study will use anodal tDCS, which increases brain excitability, and 2mA tDCS will be applied for 20 minutes prior to balance therapy.
Intervention code [1] 312237 0
Treatment: Devices
Intervention code [2] 312854 0
Rehabilitation
Comparator / control treatment
This is a double blind placebo controlled trial. Half the participants will be randomized to receive sham tDCS, For sham stimulation current will ramp up to 2mA and then back to zero at the beginning and end of the 20-minute sham, but there will be no current flow between these periods. Participants in both groups (sham and real tDCS) will receive balance training.
Control group
Placebo

Outcomes
Primary outcome [1] 307216 0
Berg Balance Scale
Timepoint [1] 307216 0
single time point 1-2 weeks (primary time point) and 6 months after completion of treatments
Secondary outcome [1] 351142 0
Dynamic Gait Index,
Timepoint [1] 351142 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [2] 353131 0
Timed Up and Go Test,
Timepoint [2] 353131 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [3] 353132 0
10m walk test,
Timepoint [3] 353132 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [4] 353133 0
High level Mobility Assessment Tool (HiMAT),
Timepoint [4] 353133 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [5] 353134 0
Self reporting falls questionnaire
Based on:
Talbot, L. A., Musiol, R. J., et al. (2005). "Falls in young, middle-aged and older community dwelling adults: perceived cause, environmental factors and injury." BMC Public Health 5(1): 86.
Timepoint [5] 353134 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [6] 353135 0
Fatigue Severity Scale (FSS)
Timepoint [6] 353135 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [7] 353721 0
modified Barthel index,
Timepoint [7] 353721 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [8] 353722 0
Activities-specific Balance Confidence (ABC)
Timepoint [8] 353722 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [9] 353723 0
Dizziness handicap inventory (DHI)
Timepoint [9] 353723 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [10] 353724 0
Multiple Sclerosis Quality of Life-54 (MSQOL-54)
Timepoint [10] 353724 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [11] 353725 0
Cognitive assessment using the Montreal Cognitive Assessment Tool (MoCA)
Timepoint [11] 353725 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [12] 353726 0
Mood assessments using the Patient Health Questionnaire-9 (PHQ-9)
Timepoint [12] 353726 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [13] 353727 0
Mood assessments using the General Anxiety Disorder-7 (GAD-7)
Timepoint [13] 353727 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [14] 353728 0
Neurophysiological assessments using TMS (resting motor threshold)
Timepoint [14] 353728 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [15] 353729 0
Neurophysiological assessments using TMS (stimulus response curve)
Timepoint [15] 353729 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [16] 353730 0
Neurophysiological assessments using TMS (intra-cortical inhibition)
Timepoint [16] 353730 0
single time point 1-2 weeks and 6 months after completion of treatments
Secondary outcome [17] 353731 0
Neurophysiological assessments using TMS (intra-cortical facilitation)
Timepoint [17] 353731 0
single time point 1-2 weeks and 6 months after completion of treatments

Eligibility
Key inclusion criteria
1. Adults (>18 years old) with definite diagnosis of Multiple Sclerosis (Relapsing Remitting, Secondary Progressive or Primary Progressive)
2. Mild to moderate balance impairment
a. Symptoms of gait or balance impairment (including falls)
b. Medical and physiotherapy assessment suggestive of balance impairment
3. EDSS < 6
a. Able to walk at least 20m, +/ aid (need to be able to complete 10 Meter Walk Test and Dynamic Gait Index)
b. Able to stand independently for at least 10 minutes (to complete the Sensory Organization Test on the Balance Master)
c. Can step up and down 1 step with a maximum of 1 person assist
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Recent relapse (last 1 month)
2. Significant medical comorbidities that would reduce exercise tolerance and rehabilitation potential such as heart failure, unstable angina etc.
3. Significant psychiatric comorbidities, such as depression, anxiety
4. History of seizures, epilepsy or unexplained loss of consciousness
5. Cognitive impairment
6. Moderate to severe back or lower limb pain
7. Lower limb injury including orthopaedic injuries/complaints precluding participation
8. Presence of magnetically or electrically sensitive implants such as cardiac pacemakers, stimulators and pumps, cochlear implants etc.
9. To minimise potential risks, all participants will be thoroughly screened for tDCS/TMS risk factors twice: prior to enrolment and immediately prior to the experimental session

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)
Neurologist assessing eligibility for trial will be blinded to subsequent allocation of real or sham tDCS.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomization using computer sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Statistical analysis: The primary outcome (Berg Balance score) at 1-2 weeks and 6 months will be compared between the two groups using t-tests. ANOVA and t-tests will also be performed to compare primary and secondary outcomes before and after intervention, as well as scores between the 2 groups. Corrections will be made for multiple comparisons. Subgroup analysis will be performed to examine the consistency of the effects among participants with different patterns (e.g. lower limb spasticity and sensory deficits, gait ataxia, visual impairment) and range (EDSS 1-3 vs EDSS 4-5) of disability.
Sample size: We aim to enrol ~80 patients for the study (with an expected maximum drop out of ~15%). The anticipated mean Berg Balance Scale score in the control group at 6 months after randomisation will be about 50 (with standard deviation of 5, Cattaneo et al. 2007). The smallest additional treatment effect of adding brain stimulation to physical therapy which would be clinically important is 4 points on the Berg Balance Scale. Thus assuming a SD of 5 points on the Berg Balance Scale. we would detect a difference of 4 points between groups with a probability of 90% at a two-sided significance level of 0.05 if we enrol 68 patients in the present study. Patients will be randomized to anodal/sham tDCS treatment using online software (http://www.randomization.com).

Recruitment
Recruitment status
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)
WA
Recruitment hospital [1] 12223 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 12224 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 24402 0
6009 - Nedlands
Recruitment postcode(s) [2] 24403 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 300507 0
Other
Name [1] 300507 0
Perron Institute for Neurological and Translational Science
Address [1] 300507 0
QEII Medical Centre RR Block
Verdun Street, Nedlands
WA 6009
Country [1] 300507 0
Australia
Primary sponsor type
Individual
Name
Clinical Professor Soumya Ghosh
Address
Perron Institute for Neurological and Translational Science
QEII Medical Centre RR Block
Verdun Street, Nedlands
WA 6009
Country
Australia
Secondary sponsor category [1] 299983 0
None
Name [1] 299983 0
Address [1] 299983 0
Country [1] 299983 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301300 0
Sir Charles Gairdner Osborne Park Health Care Group Human Research Ethics Commitee
Ethics committee address [1] 301300 0
Sir Charles Gairdner Hospital
Department of Research
Hospital Avenue
Nedlands WA 6009
Ethics committee country [1] 301300 0
Australia
Date submitted for ethics approval [1] 301300 0
11/03/2014
Approval date [1] 301300 0
05/05/2014
Ethics approval number [1] 301300 0
2014-026

Summary
Brief summary
Multiple sclerosis (MS) is the most frequent neurological disease in young and middle-aged adults in Australia and has a lifelong impact. Abnormalities in gait and balance are common in patients with MS. A number of different mechanisms are known to contribute to recovery from neural injury and relapses in MS. Functional imaging studies suggest that cortical plasticity and reorganization can promote recovery from brain injury in MS (Reddy et al. 2000; Pantano et al. 2002; Rocca et al. 2010, 2002). Balance training is an important rehabilitation intervention for MS patients, and most studies show a small, but significant, effect of physiotherapy on balance in people with multiple sclerosis who have a mild to moderate level of disability (Lord et al. 1998; Cattaneo et al. 2007a; Paltaama et al. 2012). Non-invasive brain stimulation (NIBS) is being increasingly trialled for enhancing brain plasticity after neural injury and shows promising results in patients with stroke, dystonia and Parkinson's disease (Edwardson et al. 2012; Ridding and Rothwell, 2007). Brain stimulation can be used to excite the brain and promote relearning.

This study aims to recruit MS patients who have mild to moderate difficulty with balance and walking. We will evaluate if brain stimulation (transcranial direct current stimulation – tDCS) added to a structured balance training program will provide added benefit in mobility. This will be in addition to their regular outpatient therapy program prescribed by their physicians.

This study will recruit patients with MS who have mild to moderate impairment of balance and walking. They will be randomly split into two groups: Both groups will complete a structured balance training program (1 hour sessions, 2 days a week for 6 weeks). Group 1 will also receive brain stimulation (tDCS) prior to each balance therapy session, while Group 2 will receive a sham-tDCS session. A physiotherapist who is not involved in the treatment will test each patient's balance and walking, as well as administering some questionnaires and a cognitive test. These assessments will be done before the treatment commences, immediately after the 6 week program and 6 months, 12 months and 24 months after the initial assessment date.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 86550 0
Prof Soumya Ghosh
Address 86550 0
Perron Institute for Neurological and Translational Science
QEII Medical Centre RR Block
Verdun Street, Nedlands WA 6009
Country 86550 0
Australia
Phone 86550 0
+61 8 6457 0200
Fax 86550 0
+61 8 6457 0281
Email 86550 0
Soumya.Ghosh@health.wa.gov.au
Contact person for public queries
Name 86551 0
Mr Jesse Dixon
Address 86551 0
Perron Institute for Neurological and Translational Science
QEII Medical Centre RR Block
Verdun Street, Nedlands WA 6009
Country 86551 0
Australia
Phone 86551 0
+61 8 64570207
Fax 86551 0
+61 8 6457 0281
Email 86551 0
Jesse.Dixon@health.wa.gov.au
Contact person for scientific queries
Name 86552 0
Prof Soumya Ghosh
Address 86552 0
Perron Institute for Neurological and Translational Science
QEII Medical Centre RR Block
Verdun Street, Nedlands WA 6009
Country 86552 0
Australia
Phone 86552 0
+61 8 64570200
Fax 86552 0
+61 8 6457 0281
Email 86552 0
Soumya.Ghosh@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No funding available
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable