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Trial registered on ANZCTR


Registration number
ACTRN12619000692134p
Ethics application status
Submitted, not yet approved
Date submitted
29/04/2019
Date registered
8/05/2019
Date last updated
8/05/2019
Date data sharing statement initially provided
8/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
External brain stimulation to augment rehabilitation therapy in individuals post stroke
Scientific title
Safety and feasibility trial of motor cortex stimulation via an external pulse generator in order to augment rehabilitation in individuals post stroke
Secondary ID [1] 298084 0
Nil known
Universal Trial Number (UTN)
U1111-1232-5002
Trial acronym
ESTART
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Stroke 312597 0
Condition category
Condition code
Stroke 311106 311106 0 0
Haemorrhagic
Stroke 311107 311107 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
External intermittent theta burst stimulation delivering bursts of electrical pulses to the motor cortex on the opposite hemisphere from the stroke; combined with a physiotherapy rehabilitation programme designed to maximize the improvement in functioning of the affected arm and hand. Sham stimulation + rehabilitation (concurrent) to all participants for the first 3 weeks to measure the response to rehabilitation, followed by randomization into two groups as below:
a) Burst stimulation + rehabilitation from week-4 to week-7 (4 weeks), and
Sham stimulation + rehabilitation from week-8 to week-11 (4 weeks) (Group 1); or
b) Sham stimulation + rehabilitation from week-4 to week-7, and
Burst stimulation + rehabilitation from week-8 to week-11 (Group 2).

Burst/sham stimulation will be delivered by a researcher using the STARSTIM R32 device (Neuroelectrics, Barcelona SLU, Spain). Stimulation electrodes will be placed to target the motor cortex. At initial optimization, stimulation intensity will be determined by the effect of single electrical pulses (500 µs to 1000 µs duration) on the size of motor evoked potentials (MEPs) elicited from the opposite affected cortex and measured in the paretic hand, using a single transcranial magnetic stimulation (TMS) pulse. Interstimulus intervals will be varied between 3 and 15 ms in random order and the optimal timing and intensity (up to a maximum of 1 mA) determined that reduces the amplitude of the averaged MEP by 15% or more. We have found it optimal in our animal studies to set the intensity at the minimum level that induces interhemispheric inhibition measured in this way, and that the same stimulation intensity applied during burst stimulation modulates this inhibition and improves recovery from stroke. If the intensity is unable to be determined here using this TMS procedure, a standard intensity (0.5 mA to 1 mA) will be used, based on the effect of a single pulse of the electrical stimulation recorded from scalp electrodes fitted over the opposite hemisphere. This intensity range resulted in improved motor function in our pilot implanted stimulation protocol, studied in two human participants.
The initial burst stimulation pattern will consist of 50 Hz pulse triplets repeating at 5 Hz for 2 seconds in every 10 seconds, at the intensity set as above. The stimulation design can be adjusted during the trial to further optimize augmentation of participants’ rehabilitation capability. This might include burst or spike frequency adjustment, or minor subthreshold adjustments of stimulation intensity, as well as pseudorandom presentation of the proposed stimuli.

Physiotherapy rehabilitation protocol:
All participants will receive an intensive one-on-one physiotherapy programme for a total of 11-weeks aimed at maximising function of the affected upper limb. This will comprise:
- Three (week days) x one hour intervention at the School of Physiotherapy
- Home (GRASP) programme to be done daily (including weekends)
- Participants will rotate around a circuit of exercises which will include:
o Stretching
o Strengthening individual major upper limb muscles (progressive resisted)
o Functional upper limb activities (both unilateral and bilateral tasks)
- Exercises will be individualised to the participant’s current ability and side affected.
- The programme will be delivered by a physiotherapist specialised in neurorehabilitation.

The stimulation (burst/sham) will be delivered concurrently with the physiotherapy rehabilitation programme (i.e. one-hour three-times a week)
Intervention code [1] 314315 0
Treatment: Devices
Intervention code [2] 314316 0
Rehabilitation
Comparator / control treatment
Active control: Comparison of rehabilitation to rehabilitation+intermittent theta burst stimulation

Sham stimulation + rehabilitation to all participants for the first 3 weeks to measure the response to rehabilitation, followed by randomization into two groups as below:

a) Burst stimulation + rehabilitation from week-4 to week-7 (4 weeks), and
Sham stimulation + rehabilitation from week-8 to week-11 (4 weeks) (Group 1); or

b) Sham stimulation + rehabilitation from week-4 to week-7, and
Burst stimulation + rehabilitation from week-8 to week-11 (Group 2).

For sham stimulation, to create an identical skin sensation, the current will be applied for 60 s ramp up and 60 s ramp down at the beginning and at the end of each stimulation session respectively, with no current applied in between,
Control group
Active

Outcomes
Primary outcome [1] 319918 0
Action Research Arm Test (ARAT)
Timepoint [1] 319918 0
Baseline, 3 weeks, 7 weeks, 12 weeks of intervention phase; and 6 months post-intervention
Primary outcome [2] 319921 0
Wolf Motor Function
Timepoint [2] 319921 0
Baseline,
3 weeks, 7 weeks, and 12 weeks of intervention phase, and
6months post-intervention
Primary outcome [3] 319922 0
Upper Extremity Fugl-Meyer
Timepoint [3] 319922 0
Baseline,
3 weeks, 7 weeks, and 12 weeks of intervention phase, and
6months post-intervention
Secondary outcome [1] 369778 0
Functional MRI (exploratory)
Timepoint [1] 369778 0
Baseline, Immediately post-intervention and 6 months post-intervention
Secondary outcome [2] 369876 0
Resting EEG (exploratory)
Timepoint [2] 369876 0
Baseline,
3 weeks, 7 weeks, 12 weeks of intervention phase;
6 months post-intervention
Secondary outcome [3] 369877 0
Adverse events (participant self-reported; e.g. headache).
Timepoint [3] 369877 0
Baseline, throughout the intervention phase, and 6 months post-intervention

Eligibility
Key inclusion criteria
To be included in the study, participants must meet all of the following inclusion criteria:
1. Capable of understanding and signing an informed consent form
2. Have a cortical or subcortical stroke at least 4 months earlier, screened by prior CT/MRI and verified by study MRI
3. Aged at least 18 years on the day of consent
4. Confirmation of intact cortical tracts by the presence of a TMS-elicited MEP recorded from the paretic upper limb.
5. Been assessed by Physiotherapy and deemed suitable (likely to be able to participate in 80% or more of the 11 weeks of three-days-a-week of physiotherapy sessions).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
To be included in the study, participants must meet none of the following exclusion criteria:
1. History of epileptic seizures
2. Participants with pacemakers/defibrillators
3. Participants who have contraindications for MRI and TMS
4. Female participants who are or intend to become pregnant
5. Participants who, in the opinion of the investigators, do not understand the information and procedures of the study, or would not be compliant with them (in particular the study restrictions and risks involved).
6. Participants who have pain, significant musculotendinous or bony restrictions of the affected upper limb, chronic disease (other than stroke) that will independently cause significant disability or weakness of the affected upper limb.
7. Any participant for whom the investigators believe, for any reason, that participation would not be an acceptable risk.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Not yet 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 outside Australia
Country [1] 21440 0
New Zealand
State/province [1] 21440 0
Otago

Funding & Sponsors
Funding source category [1] 302616 0
Other Collaborative groups
Name [1] 302616 0
NSC Ageing Well
Address [1] 302616 0
Ageing Well National Science Challenge
School of Physiotherapy
University of Otago
PO Box 56
Dunedin 9054
New Zealand
Country [1] 302616 0
New Zealand
Primary sponsor type
Individual
Name
Professor John Reynolds
Address
Department of Anatomy,
School of Biomedical Sciences,
University of Otago
PO BOX 56,
Dunedin- 9054
Country
New Zealand
Secondary sponsor category [1] 302527 0
Individual
Name [1] 302527 0
Professor Dirk De Ridder
Address [1] 302527 0
Department of Surgical Sciences,
Dunedin School of Medicine,
University of Otago
PO BOX 56,
Dunedin- 9054
Country [1] 302527 0
New Zealand

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 303249 0
Health and Disability Ethics Committe
Ethics committee address [1] 303249 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140

Street address:
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 303249 0
New Zealand
Date submitted for ethics approval [1] 303249 0
02/05/2019
Approval date [1] 303249 0
Ethics approval number [1] 303249 0

Summary
Brief summary
After stroke, 85% of patients never regain full function in the arm and hand. Recovery from stroke requires that nerve cells in adjacent brain areas take over some of the lost function. However, this is thought to be difficult to achieve in brain areas around a stroke because of an increase in the activity of circuits that tend to ‘turn off’ or ‘inhibit’ these areas. We plan in this study to alter the activity of this circuit using external electrical stimulation delivering bursts of electrical pulses to the brain area opposite from the stroke side. This will be combined with a physiotherapy programme designed to maximise the improvement in functioning of the affected arm and hand.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93006 0
Prof John Reynolds
Address 93006 0
Department of Anatomy,
School of Biomedical Sciences
University of Otago
PO BOX 56
Dunedin 9054
Country 93006 0
New Zealand
Phone 93006 0
+64 34795781
Fax 93006 0
Email 93006 0
john.reynolds@otago.ac.nz
Contact person for public queries
Name 93007 0
Prof John Reynolds
Address 93007 0
Department of Anatomy,
School of Biomedical Sciences
University of Otago
PO BOX 56
Dunedin 9054
Country 93007 0
New Zealand
Phone 93007 0
+64 34795781
Fax 93007 0
Email 93007 0
john.reynolds@otago.ac.nz
Contact person for scientific queries
Name 93008 0
Prof John Reynolds
Address 93008 0
Department of Anatomy,
School of Biomedical Sciences
University of Otago
PO BOX 56
Dunedin 9054
Country 93008 0
New Zealand
Phone 93008 0
+64 34795781
Fax 93008 0
Email 93008 0
john.reynolds@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, will be de-identified and the results will be published in scientific journals. All outcome variables data will be available for further research use (e.g. meta-analyses).
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following main results publication
Available to whom?
Researchers on a case-by-case basis at the discretion of Primary Sponsor
Available for what types of analyses?
Meta-analyses or reviews
How or where can data be obtained?
Access subject to approvals by Principal Investigator
What supporting documents are/will be available?
No other documents available
Summary results
No Results