Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12613000109707
Ethics application status
Not yet submitted
Date submitted
14/01/2013
Date registered
29/01/2013
Date last updated
29/01/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Standard upper limb therapy treatment with or without non-invasive brain stimulation to assist recovery after stroke
Scientific title
A pilot investigation of the effect of cathodal transcranial direct current stimulation (ctDCS) plus standard upper limb rehabilitation to augment motor recovery post acute stroke.
Secondary ID [1] 281764 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ischaemic stroke 288078 0
Condition category
Condition code
Stroke 288453 288453 0 0
Ischaemic
Physical Medicine / Rehabilitation 288454 288454 0 0
Physiotherapy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study aims to (1) Look at how easy it will be, over a 9 month period, to recruit 34 to 40 people presenting to Sir Charles Gairdner Hospital (SCGH) who have had a particular type of stroke and as a result are unable to use their hand/arm; (2) record techniques used by physiotherapists and occupational therapists to help these people to use their affected arm after stroke; (3) study the effects of a safe low current electrical stimulation (transcranial direct current stimulation - tDCS) to the healthy side of the brain to reduce its dampening down effect on activity in the stroke affected brain. Stimulation, via electrodes placed on the scalp, will be applied at the same time as the affected arm is being treated.

This study will recruit patients within 1 week after their stroke. They will be randomly split into two groups: group 1 will receive treatment to their affected arm plus tDCS to the healthy side of the brain and group 2 will receive treatment to their affected arm plus ‘pretend electrical stimulation’ (sham tDCS) to the brain. Both groups will receive 10 rehabilitation sessions over a period of 2 weeks (i.e. 5 days of treatment, 2 days rest, 5 days of treatment). All sessions will last for 30 minutes consisting of upper limb rehabilitation plus ctDCS or sham tDCS respectively.

Transcranial direct current stimulation (tDCS) is a commonly used non-invasive stimulation technique, which modulates cortical excitability by applying a weak direct current (1-2 mA) to the scalp overlying the area of the brain that it is intended to stimulate. 2 tDCS is usually applied via saline-soaked sponge electrodes applied to the skin.which are connected to a battery driven direct current stimulator. tDCS is a painless procedure which has been shown to have no major adverse effects, it uses relatively inexpensive equipment and is easy to apply in a clinical setting.
Three different tDCS electrode montages are used to enhance upper limb recovery after stroke: (1) anodal stimulation (atDCS) to increase excitability of intact parts of the damaged hemisphere (stroke side); (2) cathodal stimulation (ctDCS) to decrease excitability of the brain tissue on the contralesional hemisphere (healthy side), (3) bihemispheric tDCS which involves an anode electrode over the affected side (to increase excitability), with a cathode electrode on the unaffected side (to decrease excitability and therefore enhance the effect of the anodal electrode).
For the purposes of this study we will be investigating the effects of ctDCS over the unaffected hemisphere during standard upper limb rehabilitation. A total of 10 sessions over a period of 2 weeks, each session lasting for 30 minutes. Follow up assessments will last for 3 months after the 2-week intervention phase.
"Standard upper limb therapy" will be defined in phases I & II of this study. The principal investigator will conduct a retrospective notes audit of all MCA ischaemic strokes admitted at SCGH between January - September 2011. Documentation from therapists will be collated as key phrases. In phase II the principal investigator will conduct focus groups with relevant therapists in the area in order to define key terminology and obtain and document a consensus outlining what truly is standard upper limb rehabilitation. This standard package of care will then be followed in Phase III as upper limb rehabilitation.
Intervention code [1] 286306 0
Treatment: Devices
Intervention code [2] 286307 0
Rehabilitation
Comparator / control treatment
The control treatment consists of a "sham" group which would be described as sham ctDCS. All subjects will undergo the same rehabilitation protocol and only the treating therapist will know who is receiving stimulation and who is not. The sham group will have the electrodes placed on their head as per protocol and the machine will be turned on and the then off with in 30 seconds. The participant will not be able to tell wheather they are receiving treatment or sham stimulation; rehabilitation will continue as per usual. All control treatment sessions will be the same as the treatment or ctDCS group (i.e. total of 10 x 30 minute sessios over a period of 2 weeks each). Follow up assesments will take place at 3 months post treatment phase;therefore total study involvement will be about 4 months.
Control group
Placebo

Outcomes
Primary outcome [1] 288620 0
Fugl Meyer Upper Extremity Scale (FMUE). which is a well established and recommended measure of upper limb impairment.
This outcome measure will assist in determining an improvement in upper limb function and any significant differences between groups.
Reliability and validity are established in subacute and chronic stroke cohorts.
Timepoint [1] 288620 0
Outcome measures will be taken at baseline, 1 day post intervention phase (two week period consisting of 10 treatment sessions), two weeks post intervention period and 3 months post intervention period.
Secondary outcome [1] 300604 0
Transcranial Magnetic Stimulation (TMS):
Evaluations will be taken at baseline, and day 1 and 3 months post intervention period. The purpose is to examine residual direct cortical spinal projections from the affected hemisphere.THis is achieved by applying TMS to the affected hemisphere and recording evoked MEP's of the first dorsal interosseous (FDI) muscle of the contralateral (affected hand) using surface electrodes. Paired pulsed paradigms will be used to explore cortical inhibition within and between hemispheres.
Timepoint [1] 300604 0
TMS evaluations will be undertaken before and after the tDCS intervention (1 day and 3 months).
Secondary outcome [2] 300605 0
National Institite of Health Stroke Scale (NIHSS) will be used to measure overall neurological deficit at entry of study
Timepoint [2] 300605 0
Study entry, screening and recruitment stages
Secondary outcome [3] 300606 0
Tardieu Scale, this scale is a widely used measure of spasticity.
Timepoint [3] 300606 0
Data will be recorded at baseline and at all 3 post intervention assessments (immediatley, 2 weeks and 3 months after the treatment phase). This will assist in monitoring and recording any changes in muscle tone that might impact on motor recovery.
Secondary outcome [4] 300607 0
Functional Independence Measure (FIM), is the most widely accepted functional assessment in rehabilitation settings. This is an 18-item scale that measures dependence.
Timepoint [4] 300607 0
The FIM scores will be recorded at entry to the study and at discharge from SCGH to rehabilitation and discharge from the rehabilitation setting (if this is near to the 3 month follow up).
Secondary outcome [5] 300608 0
Post Stroke Depression Scale, this tool is specifically devised to assess depression after stroke and has been shown to have a superior positive predictive value for major depression-like disorders, particularly in aphasic patients, and not influenced by cognitive dysfunction, a common consequence of stroke. Items assessing anxiety, depression and apathy will be assessed.
Timepoint [5] 300608 0
This scale will be administered at baseline, 1 day, 2 weeks, and 3 months post intervention phase.

Eligibility
Key inclusion criteria
All ischaemic strokes admitted to Sir Charles Gairdner Hospital under a consultant neurologist will be screened. A total of 37- 40 participants will be recruited for this study.

All subjects must meet the following inclusion criteria:
1. First ever ischaemic stroke (cortical or subcortical involving the territory of the middle cerebral artery (MCA) based on imaging findings.
2. Stroke onset less than 1 week prior to study enrolment.
3. Moderate to severe hemiparesis based on the Fugl Meyer Upper Extremity assessment (35-52 moderate and less than 35 severe upper limb deficit).
4. Detectable motor evoked potentials (MEPs) in the affected hand muscles via TMS assessment.
5. Stable blood pressure parameters within limits approved by treating neurologist.
6. Age between 18 to 80 years old.
7. MMSE greater than 24
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
1. Pre-existing upper limb impairment causing functional limitation
2. Hemiplegic shoulder pain
3. Metallic foreign body implant (pacemaker or artificial cochlea)
4. History of seizure or another unstable medical condition
5. Pregnancy
6. Severe language disturbance (Frenchay Aphasia Screening Test will be used to identify participants with communication difficulties; a more detailed evaluation will be performed by a speech pathologist to determine severity of language impairment).
7. English as a second language
8. Severe Neglect (score of < 44 out of 54 points on the Star Cancellation test)
9. History of depression, alcohol or drug abuse
10. Coexistent neurological or psychiatric disease
11. Current treatment with antidepressants, antipsychotics or benzodiazepines
12. Current treatment with Na+ or Ca 2+ Channel blockers or N-methyl-D-aspartate (NMDA) receptor antagonists.

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)
Phase I & II consist of a retrospective notes audit Phase II: documentation of upper limb motor recovery and the establishment of consensus in regards to define current practice and to develop a description of ‘standard approaches’ to rehabilitation of the upper limb post MCA stroke. This will be used to inform the therapy provided to participants in the subsequent pilot investigation (phase III).

Phase III: A randomized double blind sham-controlled pilot study
1. Screening: (SCGH- Ward G51 Stroke Unit, day 1-10 post stroke)
Physiotherapist A –Jimena Garcia-Vega; Physiotherapist B – Gillian Bowater

1.1 Physiotherapist A to liaise with nursing shift coordinator and ward senior physiotherapists who hold the ‘stroke-call’ pager which alerts them to the most recent stroke admissions.
1.2 Determine subjects’ eligibility of study entry by inclusion/exclusion criteria.
1.3 Screening of medical notes for complete medical history and current medications (please refer to exclusion criteria).
1.4 Obtain consent from treating consultant neurologist to approach possible participants and to complete TMS readings under the supervision of Professor Gary Thickbroom (non-invasive brain stimulation expert).
1.5 Obtain NIHSS and FIM scores from medical notes.
1.6 Complete screening log.

2. Recruitment (Greater than 10 days post stroke onset)
2.1 Approach possible participants to inform about the study, issue “Participant’s Information Sheet” (PIS) and answer any questions. A senior family members or next of kin must be present during this discussion.
2.2 Obtain participant’s written consent
2.3 Place sticker on medical notes to alert other clinicians of the patients’ recruitment into study. Sticker will include patient’s name, consultant’s name and consent, principal investigators contact details (physiotherapists A & B).
2.4 A magnet will also be placed next to the patients name on the ward board.
2.5 Complete relevant paper work in compliance with SCGH Ethics
2.6 All medical staff and treating Physiotherapists and Occupational Therapists involved in participant’s care will be informed of their recruitment.
3. Allocation concelment
Physiotherapist A to inform Physiotherapist B once participants have been successfully recruited in the studyParticipants will be randomised either in Group 1: treatment group (ctDCS and standard physiotherapy) or Group 2: control group (Sham tDCS and standard physiotherapy). Physiotherapist A will be blinded to group allocation. Physiotherapist B will be administering the treatment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sealed opaque envelopes will be used for randomisation. Physiotherapist B will ensure that both groups have the same number of participants and will stratify randomisation to effect equivalence of severity of upper limb impairment (based on FMUE scores) in both groups.

Stratification:
The first four subjects will undergo randomisation and then block stratification will be used in order to achieve similar distributions of impairment between groups. Two strata of upper limb impairment severity based on Fugl Meyer scores (35-52 moderate impairment and less than 35 severe impairment.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Study Designed: Randomised, double blind, sham controlled pilot study
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Data to be analysed:
Primary outcome measures: differences in motor impairment scores in the short (immediate) and long term (3 months) after the intervention period. MEP amplitude (single and paired pulse paradigms) will also be compared to determine if there was an effect on interhemispheric inhibition between hemispheres and whether there were significant differences in the amplitude prior to and following treatment between the treatment group and sham stimulation.

Secondary outcome measures: to determine and document changes in functional independence, mood, spasticity and general neurological impairment.

Analysis populations:
Both groups will be included in each component of the analysis. The trial will yield an "Intention to treat" population (all those who have completed part of the 10 treatment sessions) and a "Per protocol" population (all those who have completed without a protocol violation).

Withdrawals (protocol violations, broken blinding, withdrawal in the participant's interest, etc)
Participants who withdraw for any reason will be considered “intention to treat” cases. This study will aim to analyze all available data. The last observation on treatment will be carried forward and substitute for the closest observation (post 1, post 2 or post 3 outcome measures).
In case of a medical emergency where the treatment requires knowledge of the intervention type (cathodal stimulation or sham stimulation) the principal investigators may break the randomization code for that participant. This event will be treated as a serious adverse event.

Statistical Analysis:
Summary statistics such as means and standard deviations will be calculated for all variables. Comparisons between the two treatment groups will be made using standard analyses such as repeated measures (before treatment, immediately after and at 3 months post treatment). Demographic variables such as age, severity of upper limb impairment, hand dominance and stroke location (affected hemisphere and cortical/sub-cortical) will be considered as confounders when conducting any statistical analysis.

Interim analyses: not applicable

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
4/02/2013
Actual
Date of last participant enrolment
Anticipated
31/12/2013
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
37
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 406 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 6173 0
6009 - Broadway Nedlands

Funding & Sponsors
Funding source category [1] 286550 0
Hospital
Name [1] 286550 0
Sir Charles Gairdner Group Research Advisory Committee grant
Country [1] 286550 0
Australia
Funding source category [2] 286551 0
Hospital
Name [2] 286551 0
Sir Charles Gairdner Hospital- Physiotherapy Department
Country [2] 286551 0
Australia
Primary sponsor type
Hospital
Name
Sir Charles Gairdner Hospital
Address
Hospital Avenue
Nedlands, WA
6009
Country
Australia
Secondary sponsor category [1] 285338 0
University
Name [1] 285338 0
University of Western Australia
Address [1] 285338 0
35 Hackett Drive
Crawley, WA
6009
Country [1] 285338 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 288622 0
Sir Charles Gairdner Human Research Ethics Committee
Ethics committee address [1] 288622 0
Department of Health WA
Sir Charles Gairdner Hospital
QE II Medical Centre
Hospital Avenue
Nedlands, WA
6009
Ethics committee country [1] 288622 0
Australia
Date submitted for ethics approval [1] 288622 0
21/12/2012
Approval date [1] 288622 0
Ethics approval number [1] 288622 0
2012-127

Summary
Brief summary
A stroke occurs when the blood flow to the brain is suddenly stopped which causes brain cells in the area to die (infarct) because they are no longer receiving the oxygen and nutrients that they need to function. A stroke can have a devastating effect on the person because the brain controls the way we move, think, speak, and perform different tasks. It is very important to treat people after a stroke as soon as possible so that they are able to recover movement in the affected body parts and look after themselves without having to be dependent on others. Normally movement of the arm and leg is controlled by the opposite side of the brain. After stroke, the unaffected side of the brain may exert a dampening effect on the stroke affected side, preventing it from being active and controlling the opposite side of the body.

This study aims to (1) Look at how easy it will be, over a 9 month period, to recruit 40 people presenting to SCGH who have had a particular type of stroke and as a result are unable to use their hand/arm; (2) record techniques used by physiotherapists and occupational therapists to help these people to use their affected arm after stroke; (3) study the effects of a safe low current electrical stimulation (transcranial direct current stimulation - tDCS) to the healthy side of the brain to reduce its dampening down effect on activity in the stroke affected brain. Stimulation, via electrodes placed on the scalp, will be applied at the same time as the affected arm is being treated.

This study will recruit patients within 1 week after their stroke. They will be randomly split into two groups: group 1 will receive treatment to their arm plus tDCS to the healthy side of the brain and group 2 will receive treatment to their arm plus ‘pretend electrical stimulation’ (sham tDCS) to the brain.
Trial website
Trial related presentations / publications
Public notes
This trial is currently under final Ethics review.

The primary outcome on this study is the difference between the active (cathodal tDCS) and sham treatment groups on the Fugl Meyer Upper extremity scores post treatment. In previous studies12 the detectable clinical difference within each subject group was normally distributed with a standard deviation of 10 points on the FMUE scale. If the true difference we wish to detect between groups is 10 points, we will need 17 experimental subjects and 17 control subjects to be able to reject the null hypothesis that the population mean differences of the experimental and control groups are equal with probability (power) of 0.8. The Type I error probability associated with this test of this null hypothesis is 0.05. Based on an approximate 10% drop out rate, we propose to recruit 20 patients per treatment group.

Contacts
Principal investigator
Name 37010 0
Ms Jimena Garcia-Vega
Address 37010 0
Sir Charles Gairdner Hospital
Physiotherapy Department
QE II Medical Centre
Hospital Avenue
Nedlands, WA
6009
Country 37010 0
Australia
Phone 37010 0
+61 8 9346-3333 ; pager 4235
Fax 37010 0
+61 8 9346 3037
Email 37010 0
jimena.garcia-vega@health.wa.gov.au
Contact person for public queries
Name 37011 0
Ms Jimena Garcia-Vega
Address 37011 0
Sir Charles Gairdner Hospital
Physiotherapy Department
QE II Medical Centre
Hospital Avenue
Nedlands, WA
6009
Country 37011 0
Australia
Phone 37011 0
+61 8 9346- 3333 ; pager 4235
Fax 37011 0
+61 8 9346 3037
Email 37011 0
jimena.garcia-vega@health.wa.gov.au
Contact person for scientific queries
Name 37012 0
Prof Barbara Singer
Address 37012 0
Centre for Musculoskeletal Studies
School of Surgery
University of Western Australia (M424)
Park Avenue
Crawley, WA
6009
Country 37012 0
Australia
Phone 37012 0
+61 8 6488 7079
Fax 37012 0
Email 37012 0
barbara.singer@uwa.edu.au

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No Supporting Document Provided



Results publications and other study-related documents

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