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Trial registered on ANZCTR


Registration number
ACTRN12615001368527
Ethics application status
Approved
Date submitted
4/12/2015
Date registered
16/12/2015
Date last updated
16/12/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Closed-loop Deep Brain Stimulation (DBS) for treatment of movement disorders
Scientific title
Closed-loop deep brain stimulation for treatment of movement disorders: An externalised lead study
Secondary ID [1] 288076 0
None
Universal Trial Number (UTN)
U1111-1177-2581
Trial acronym
None
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Movement Disorders 296940 0
Condition category
Condition code
Neurological 297185 297185 0 0
Parkinson's disease
Neurological 297186 297186 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be admitted to hospital as part of the standard clinical management for their prescribed DBS procedure. As appropriate, the participant’s involvement will proceed in three stages; electrode lead externalisation, study period and procedure completion.
In the electrode lead externalisation stage, participants will be routinely implanted with commercial DBS electrodes (e.g. Medtronic) as part of their prescribed DBS implantation procedure. A routine lead externalisation procedure will then be performed using a commercial externalisation kit (e.g. Medtronic Externalisation Lead Kit).

In some cases, only a brief intraoperative externalisation period will be used. This will allow a subset of experiments to be conducted in a reduced timeframe, minimising the burden to participants and providing key data that will optimise subsequent experiments performed over extended externalisation periods. The study period will last for approximately 20 minutes, during which time different forms of stimulation will be applied and assessed. Stimulation with different pulse width, shape and rate parameters will be tested. The amplitude of stimulation will be progressively stepped up over a period of 5-10 minutes whilst clinical effects are monitored. A washout period of up to 5 minutes will be observed between conditions, depending on the duration of applied stimulation and when symptoms return. In Intra-operative procedures, typically 2-4 conditions will be tested for 5-10min each depending on the time available, the condition of the patient and the research hypothesis being tested. In each condition the stimulation amplitude will be typically stepped from a starting level (e.g. 0.5mA) to a predefined maximum. The starting and maximum amplitude levels, as well as the stimulus parameters, will be selected at the discretion of the research team depending on the stimulation target, the patient’s condition and the research hypothesis being tested. Stimulation parameters tested will include symmetric and asymmetric biphasic pulses, stimulation rates up to 250pps (130Hz typical) and pulse widths up to 1ms (60microseconds typical). Intraoperative assessment is possible as it is standard clinical practice for the patient to be awake during electrode implantation surgery. The experimental session in intraoperative procedures will be administered by our Neurologist and research engineers.

When using extended externalisation, the study period will commence after an appropriate recovery period and will typically occur over 5-6 days. The recovery period will depend on the participant and appraised by our Neurologist. This recovery period can be anywhere between 1 to 2 days after stage 1 surgery. During this period experimental sessions will be scheduled for 2 hours twice per day, depending on each participant’s condition. Within each day, sessions will be conducted both off- and on- the participants' standard movement disorder medications, with appropriate wash-out/-in times allowed (varying between 5 and 30 minutes depending on prior stimulation and when symptoms return). The experimental sessions in the extended externalisation procedure will be primarily administered by our research engineers with the Neurologist attending the first session if possible.

Where possible, two forms of stimulation will be applied to the implanted electrodes using the externalised leads, conventional open-loop stimulation and biomarker-controlled closed-loop stimulation. Initially, conventional open-loop DBS will be used to evaluate stimulation parameter settings and to identify suitable biomarkers. Based on published data and comparable studies, a subset of approximately 12 stimulation parameter sets (determined by time available, eg a two hour session equals 120 minutes, thus 12 lots parameters can be tested over 10 minutes depending on the time available and the discretion of our neurologist and or Research Engineers). These parameters will be applied in a random order at intervals of about 10 minutes (including a wash-out period). Conditions may make testing of all 12 parameters not feasible in which case a subset will be chosen. The subset of stimulation conditions tested will be chosen by the research team depending on the time available, the implanted location of the DBS electrodes and the condition of the patient. Stimulation with different pulse width, shape and rate parameters will be tested. The stimulating electrode configuration will also be varied. During stimulation, objective measures of participant state (e.g. finger tapping ability, rigidity and/or speech quantification) will be recorded along with conventional clinical assessments (e.g. UPDRS) and subjective observations. Bioelectric signals, such as local field potentials, may also be recorded during stimulation and will be subsequently analysed to seek correlations between each participant’s clinical state and oscillatory activity in various frequency bands.

At all times within these procedures wash-out/-in times allowed will vary between 5 and 30 minutes depending on prior stimulation and when Participants' symptoms return.

Closed-loop stimulation controlled using the identified biomarkers will then be employed when feasible. Closed-loop stimulation testing would last at the discretion of the Research Team and dependant upon the Participant's comfort. The testing sessions may last between 30min to over several hours (or even days if considered safe to do so by our Neurologist and Research Team). Objective measures of participant state, conventional clinical assessments and subjective observations will be recorded during stimulation to determine the effectiveness of closed-loop DBS. Different stimulation parameter sets (e.g. time-varying patterned stimulation) that were found to be effective for open-loop stimulation may be evaluated using closed-loop stimulation. Following the study period, the participants prescribed DBS procedure will be completed and clinical management will proceed as usual.
Intervention code [1] 293387 0
Treatment: Devices
Intervention code [2] 293396 0
Treatment: Surgery
Comparator / control treatment
Control is the participant off of stimulation, ie when the device has been surgically inserted but is not stimulating
Control group
Active

Outcomes
Primary outcome [1] 296787 0
Change in tremor measured by accelerometer
Timepoint [1] 296787 0
Upon stimulation anywhere between during the surgical procedure used to insert the electrodes and up to 7 days after device insertion by surgery.
Primary outcome [2] 296788 0
Change in bradykinesia measured using a timed procedure such as pressing two buttons a small distance apart using the same finger. This treatment may vary according to the participants symptoms as the symptoms present in Parkinson's disease vary patient to patient. For example is a patient does not display Bradykinesia as part of their Parkinson's disease symptomology, this test will not be run.
Timepoint [2] 296788 0
Upon stimulation anywhere between during the surgical procedure used to insert the electrodes and up to 7 days after device insertion by surgery.
Primary outcome [3] 296789 0
Change in participant stiffness using clinical assessment of arms
Timepoint [3] 296789 0
Upon stimulation anywhere between during the surgical procedure used to insert the electrodes and up to 7 days after device insertion by surgery.
Secondary outcome [1] 319364 0
In some instances change in frequency of freeze of gait by counting how many times the participant freezes and for how long when performing a task such as walking from point A to point B, turning around and returning to point A.
Timepoint [1] 319364 0
Upon stimulation anywhere between 1 and up to 7 days after device insertion by surgery.

Eligibility
Key inclusion criteria
Adult participants with movement disorders who have been or are being implanted with deep brain stimulation systems. This is a highly select group who have been deemed eligible for awake neurosurgery after screening by a neurologist, neuropsychiatrist and neurosurgeon.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Diabetes (increases infection risk), 2) Any other significant disease or disorder which in the opinion of the investigator taking consent could put the participant at risk, compromise their ability to participate or influence the results of the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Inter-participant differences between stimulation conditions will be assessed using appropriate statistical tests, such as ANOVA (e.g. repeated measures) and posthoc t-tests (paired and independent samples). Sample sizes were set by power analyses using an effect size calculated from comparable studies and an alpha error probability of 0.05. Effect size was F=0.48. Power (1-beta err prob) was 0.95. Limitations in the quantity and quality of useable data that is inevitable in clinical studies of this type were also taken into account.The participant sample size for this study is greater than reported in comparable publications such as Little S, Pogosyan A, Neal S, et al. Adaptive Deep Brain Stimulation in Advanced Parkinson Disease. Ann Neurol. Sep 2013;74(3):449-457 and Little S, Joundi RA, Tan H, et al. A torque-based method demonstrates increased rigidity in Parkinson’s disease during low-frequency stimulation. Experimental brain research. 2012;219(4):499-506.

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)
QLD,VIC
Recruitment hospital [1] 4849 0
St Vincent's Private Hospital - Fitzroy
Recruitment hospital [2] 4850 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [3] 4851 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [4] 4852 0
Cabrini Hospital - Malvern - Malvern
Recruitment hospital [5] 4859 0
St Andrew's War Memorial Hospital - Brisbane
Recruitment postcode(s) [1] 12350 0
3065 - Fitzroy
Recruitment postcode(s) [2] 12351 0
3084 - Heidelberg
Recruitment postcode(s) [3] 12352 0
3144 - Malvern
Recruitment postcode(s) [4] 12364 0
4001 - Brisbane

Funding & Sponsors
Funding source category [1] 292505 0
Charities/Societies/Foundations
Name [1] 292505 0
Colonial Foundation
Address [1] 292505 0
432 St Kilda Rd, Melbourne VIC 3004
Country [1] 292505 0
Australia
Funding source category [2] 292506 0
Government body
Name [2] 292506 0
NHMRC
Address [2] 292506 0
GPO Box 1421

Canberra ACT 2601
Country [2] 292506 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Bionics Institute Of Australia
Address
384-388 Albert St
East Melbourne VIC 3002
Country
Australia
Secondary sponsor category [1] 291214 0
None
Name [1] 291214 0
Address [1] 291214 0
Country [1] 291214 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293980 0
St Vincent's Hospital Melbourne HREC-D Committee
Ethics committee address [1] 293980 0
Research Governance Unit

St Vincent's Hospital

PO Box 2900

Fitzroy VIC 3065

Ethics committee country [1] 293980 0
Australia
Date submitted for ethics approval [1] 293980 0
24/11/2014
Approval date [1] 293980 0
05/01/2015
Ethics approval number [1] 293980 0
HREC 14 SVHM 41

Summary
Brief summary
Deep brain stimulation (DBS) is an established treatment for people with Parkinson's disease and other movement disorders whose symptoms are resistant to drug therapy alone. DBS uses electrical pulses applied to target regions of the brain (e.g. the subthalamic nucleus) to reduce symptoms such as tremor, rigidity and reduced movement at will. Standard DBS treatment is performed in an ‘open-loop’ fashion, where stimulation is continuously applied regardless of presenting symptoms. This leads to periods of unnecessary or inappropriate stimulation that can cause side effects, for example slurring speech, and limit battery life of the generator of the stimulation (or
"pacemaker") thus decreasing efficiency of the device and treatment. These issues may be overcome by using 'closed-loop' stimulation, in which stimulation is only applied when symptoms indicate it is necessary. This study aims to identify in the brain suitable markers or measurable characteristics that we can then use to optimise stimulation. In particular we wish to evaluate closed-loop stimulation in participants with temporarily 'externalised' electrode leads. Externalising electrode leads is an established clinical practice involving a delay (typically 5-6 days) between implantation of the deep brain electrodes and implantation of the pacemaker. During this time an external connection to the electrodes is available, which can be used for stimulation and recording using equipment that is more flexible than standard implantable pacemakers. An externalisation period is also possible during routine follow-up surgical procedures, such as implanted pacemaker battery replacement. It is intended that approximately 30 participants will be studied in Melbourne and Brisbane. Experimental sessions will be scheduled twice per day over the externalisation period, depending on each participant’s condition. Within each day, sessions will be conducted both off and on medications. During sessions, objective measures of participant symptoms will be recorded along with conventional clinical assessments (e.g. the Unified Parkinson's Disease Rating Scale). Additionally, brain electrical activity will be recorded for use in deriving suitable markers or measurable characteristics. Comparisons will be made between different pacemaker stimulation patterns within a participant. Experimental protocols standard for this type of study will be observed including blinding of assessments, randomizing the order of conditions, allowing ‘wash-out’/‘ wash-in’ periods and taking account of the possibility of an implantation ‘stun effect’ and variability in electrode positioning. Following the externalisation period, the participants prescribed DBS procedure (e.g. system implantation, battery replacement) will be completed and clinical management will proceed as usual..
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61982 0
Dr Wes Thevathasan
Address 61982 0
Melbourne Brain Centre
Kenneth Myer Building
30 Royal Pde
Parkville VIC 3052
Country 61982 0
Australia
Phone 61982 0
+61402 308 686
Fax 61982 0
Email 61982 0
w_thevathasan@hotmail.com
Contact person for public queries
Name 61983 0
Prof Hugh McDemott
Address 61983 0
The Bionics Institute of Australia
384-388 Albert St
East Melbourne VIC 3002
Country 61983 0
Australia
Phone 61983 0
+613 9667 7526
Fax 61983 0
Email 61983 0
hmcdermott@bionicsinstitute.org
Contact person for scientific queries
Name 61984 0
Prof Hugh McDermott
Address 61984 0
The Bionics Institute of Australia
384-388 Albert St
East Melbourne VIC 3002
Country 61984 0
Australia
Phone 61984 0
+613 9667 7526
Fax 61984 0
Email 61984 0
hmcdermott@bionicsinstitute.org

No information has been provided regarding IPD availability
Summary results
No Results