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Trial registered on ANZCTR


Registration number
ACTRN12616000029493
Ethics application status
Approved
Date submitted
21/12/2015
Date registered
18/01/2016
Date last updated
14/02/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Implanted (brain) Stimulators to Augment stroke Rehabilitation Therapy (iSTART trial)
Scientific title
Safety and feasibility trial of motor cortex stimulation via Implanted Pulse Generators (IPG) to modulate interhemispheric inhibition in order to augment rehabilitation post stroke.
Secondary ID [1] 287446 0
nil
Universal Trial Number (UTN)
Trial acronym
ISTART
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Stroke 296161 0
Condition category
Condition code
Neurological 296445 296445 0 0
Other neurological disorders
Stroke 297402 297402 0 0
Ischaemic
Stroke 297428 297428 0 0
Haemorrhagic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The cohort of stroke patients will be identified and will have had a cortical/subcortical stroke proven on imaging (CT/MRI). Those eligible for surgery will undergo a further MRI Stealth and tractography scan to determine preservation of motor tracts and for surgical planning. They will also undergo transcranial magnetic stimulation (TMS) to determine presence of Motor Evoked Potentials (MEPs). The eligible participants and those who consent to the surgical procedure will then undergo implantation of the stimulators on the contralateral side of the lesion on the motor cortex extradurally.

This will involve the patient being anaesthetised under general anaesthesia (GA), being positioned and with the use of the MRI STEALTH neuronavigation system to identify the contralateral motor cortex to the stroke side. One burr hole will be performed at the site identified followed by a small trepanation of the skull. Two (2) Lamitrode 44 electrodes (St Jude Medical, Neurodivision, Plano, Tx, USA) will be placed on the dura overlying the motor cortex as demonstrated by the MRI. We will then do a subcutaneous tunnelling of the electrode lead behind the ear to mid thorax, connect an extension lead of 60cm (St Jude Medical) and tunnelling that further to exit at the right or left abdominal fossa which will be connected to an external pulse generator. This operation is estimated to take about 60 to 90 minutes. They will then stay in the High Dependency Unit overnight for observations and have intravenous antibiotics for 24 hours post surgery. A postoperative STEALTH CT scan will also be performed to exclude any extradural hematoma and to fuse lead placement with the preoperative tractography data. The patients will then have their stimulation intensity identified via a recording of a motor-evoked potential (MEP) elicited in the unaffected upper limb from the external pulse generator pulses. The intensity will be set as midway point between the field potential and active motor thresholds. After approximately 10 days and following the initial setting of stimulation intensity as stated before, the external pulse generator and the extension lead will be removed. The remaining electrode lead (in the mid thorax) will then be connected to the Proclaim Internal Pulse Generator (IPG) (St Jude Medical). This procedure will be done under local anaesthetic and will take about 15 minutes. The IPG will then be programmed to reflect the established stimulation intensity. This system/implant will remain in-situ indefinitely as there are no long-term risks from leaving the electrodes implanted.

Following this, both implanted and non-implanted groups will undergo intense physiotherapy sessions for the next 12 weeks. In the implanted group, one group will be randomised to have an immediate start (day 3) and the other group will have a delayed start i.e. starting at day 45. During and after this period of physiotherapy, they will assessed on their upper limb motor function. The physiotherapy sessions will consist of:
- daily (week days) x one hour intervention at the School of Physiotherapy
- home (GRASP) programme to be done daily (including weekends) {Graded Repetitive Arm Supplementary Programme (GRASP) is a programme designed to improve upper limb function in post-stroke patients. It comes with a manual that will be distributed and taught to the patients to allow them to do the exercises-range of motion, strengthening, weigh-bearing, functional tasks and fine motor skills, at home to supplement the intense physiotherapy sessions. They are encouraged to spend at least half an hour each day doing those exercises at home)
- participants will rotate around a circuit of exercises which will include:
stretching, strengthening individual major upper limb muscles (progressive resisted), functional upper limb activities (both unilateral and bilateral tasks)
Exercises will be individualised to the participant's current ability and side affected. The programme is designed by Professor Leigh Hale (Head of Physiotherapy) and will be delivered by final year undergraduate physiotherapy students under the supervision of a School of Physiotherapy neurorehabilitation clinical educator/supervisor. Depending on when the participants are available, the participants can either attend as a group or individually-this will not change their exercises as they will be individualised exercises. All patients will be given an exercise book as a log book to determine their attendance and exercises performed at home.
Intervention code [1] 292817 0
Treatment: Surgery
Intervention code [2] 293539 0
Treatment: Devices
Comparator / control treatment
There will be 2 groups-the implanted and non-implanted group. The implanted group will receive neuromodulation and physiotherapy sessions whereas the non-implanted group will only receive physiotherapy. In addition, in the implanted group, there is a fixed sequence design with double blind randomised activation of stimulation (delayed start).
Control group
Active

Outcomes
Primary outcome [1] 296073 0
Safety of the intervention
The safety will be determined by the number and type of adverse events that occur whilst having the implant.
The risk of having an adverse event in this procedure is that of any surgical or anaesthetic complication such as bleeding and infection. As the implants are implanted extradurally, there are no real risks for intracerebral or subdural hematomas; an extradural hematoma is theoretically possible but has not been encountered in over 60 cortical implants performed by the Principal Investigator (PI). Nonetheless, participants will undergo a post operative CT scan to determine position of the electrodes and also to rule out any underlying hematoma.
Participants will be given 24 hours antibiotic prophylaxis to minimise risk of infection (risk is rare being 2-4%). If they did pose to have a risk of infection, inflammatory and infection markers like Full Blood Count (FBC) / White Cell Count (WCC) and C-Reactive Protein will be monitored.
There is also a theoretical risk of seizures but these are isolated reports showing that the seizures were relate to intensity of stimulation. In this study, we use sub threshold stimulation and burst parameters that are known to be safe in TMS protocols and in previous implanted electrode studies performed by the PI. If there was a seizure, we would perform an EEG to confirm seizure activity, then stop the stimulation and treat with anti-epileptics.
Timepoint [1] 296073 0
We will be continually assessing the patients at week 6, 12 and 26 post implantation. At each stage, we will be assessing their general well-being and seeing that they do not suffer any medical complications.
Primary outcome [2] 296956 0
Feasibility of the procedure
The feasibility of the procedure will be gauged from the success of each participant complying to at least 80% of the rehabilitation sessions and ability to successfully complete each of the clinical tests and procedures.
Timepoint [2] 296956 0
The patients will continually be assessed at Week 6, 12 and 26 post implantation. Their attendance at each procedure and physiotherapy sessions will be taken and recorded.
Secondary outcome [1] 317444 0
The patients will be evaluated at pre-op, 6 weeks post implantation, 12 weeks post implantation and then at 6 months post implantation by the physiotherapists to evaluate their upper limb function. They will be assessed with the following:
- Muscle strength testing (hand held dynamometer)
- Fugl Meyer-upper limb assessment (UEFM)
- Motor dexterity (nine hole peg test)
- Wolf Motor Function
- Action Research Arm Test (ARAT)
- Stroke upper limb capacity scale
Timepoint [1] 317444 0
They will be evaluated at pre-op, week 6 after implantation, week 12 after implantation and then at 6 months after implantation.
Secondary outcome [2] 319658 0
Individual acceptability of the intervention, determined by qualitative interview.
Timepoint [2] 319658 0
The participants will also answer a series of questionnaires (as attached in the protocol) in the form of a qualitative interview 6 months post implantation.

Eligibility
Key inclusion criteria
1. Aged at least 18 years on the day of consent
2. capable of understanding and signing an informed consent form
3. have a cortical or subcortical stroke at least 4 months earlier, screened by prior CT/MRI and verified by study MRI
4. been assessed by physiotherapy and deemed suitable (UEFM 20 to 50-moderate to mild upper limb function; Motor Assessment Scale: 2/6 on the Upper Arm Function scale; likely to be able to participate in 80% or more of the 12 weeks of daily physiotherapy post-surgery sessions)
5. suitable and fit for surgery
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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
8. patients in whom any anticoagulation treatment cannot be transiently stopped in the preoperative period, analogous to what is done in the routine brain surgery (5 to 10 days stop before the surgery, and 2 days postoperatively, depending on the medication use)

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)
The cohort of patients identified for implantation will be randomised to either an immediate start (day 3) or delayed start (day 45). They will be randomised by a 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
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Other
Other design features
Controls have simultaneous rehabilitation only. Intervention group will be randomised to an immediate or delay start to receive neurostimulation.
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
5/02/2016
Actual
8/03/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment outside Australia
Country [1] 7158 0
New Zealand
State/province [1] 7158 0
Otago and Wellington

Funding & Sponsors
Funding source category [1] 292024 0
Government body
Name [1] 292024 0
Ageing Well National Science Challenge - Ministry of Business, Innovation and Employment (MBIE)
Country [1] 292024 0
New Zealand
Primary sponsor type
Government body
Name
Ministry of Business, Innovation and Employment
Address
Ministry of Business, Innovation and Employment
Ageing Well National Science Challenge
School of Physiotherapy
University of Otago
PO Box 56
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 290694 0
None
Name [1] 290694 0
None
Address [1] 290694 0
None
Country [1] 290694 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293511 0
Health and Disability Ethics Committee
Ethics committee address [1] 293511 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington 6011
Ethics committee country [1] 293511 0
New Zealand
Date submitted for ethics approval [1] 293511 0
25/09/2015
Approval date [1] 293511 0
04/02/2016
Ethics approval number [1] 293511 0

Summary
Brief summary
As we know, stroke affects about 9000 people each year in New Zealand, with a disproportionate ratio affecting the Maori and Pacific people. About 85% of these people often don't regain their upper limb function and one can imagine that this affects activities of daily living and hence quality of life. It has been suggested in physiological studies that there is enhanced interhemispheric inhibition between the neural circuits of the motor cortex. This makes recovery after stroke difficult and potentially explains why some patients never regain complete upper limb function. In rat models, it has shown that intermittent burst stimulation significantly improves forelimb function in rats after stroke; this has shown promise for us to do a translational study with human beings.

The i-START trial aims to recruit up to 10 participants that will be implanted with the electrodes and another 10 participants as the control group. For the patients who meet the inclusion criteria, they will have resting state EEG and the integrity of the descending motor pathways assessed from motor-evoked potentials (MEPs) elicited in the affected limb using single-pulse transcranial magnetic stimulation (TMS). Following that, they will have a structured assessment of their upper limb function by the physiotherapists. If all the assessments are acceptable, they will undergo a functional MRI and tractography imaging for surgical planning.

For the group receiving implanted stimulators, they will be either randomised to an immediate or delayed start, where the stimulator will either be switched on immediately or left off until 6 weeks after implantation has elapsed. Both the implanted and non-implanted group will undergo an intense physiotherapy session each day for the next 12 weeks.
Both groups will be assessed at week 6, 12 and 26 to determine the acceptability of retaining the stimulators as well their upper limb function.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 60202 0
Prof Dirk de Ridder
Address 60202 0
Professor & Neurological Foundation Chair of Neurosurgery
Department of Surgical Sciences
Dunedin School of Medicine
University of Otago
201 Great King Street
Dunedin 9016
New Zealand
Country 60202 0
New Zealand
Phone 60202 0
+6434749337
Fax 60202 0
Email 60202 0
[email protected]
Contact person for public queries
Name 60203 0
John NJ Reynolds
Address 60203 0
Dept of Anatomy
University of Otago Medical School
P.O. Box 913
Dunedin 9054
NEW ZEALAND

(Delivery address:
270 Great King Street
Dunedin 9016)
Country 60203 0
New Zealand
Phone 60203 0
+64 3 4795781
Fax 60203 0
Email 60203 0
[email protected]
Contact person for scientific queries
Name 60204 0
John NJ Reynolds
Address 60204 0
Dept of Anatomy
University of Otago Medical School
P.O. Box 913
Dunedin 9054
NEW ZEALAND

(Delivery address:
270 Great King Street
Dunedin 9016)
Country 60204 0
New Zealand
Phone 60204 0
+64 3 4795781
Fax 60204 0
Email 60204 0
[email protected]

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