ANZCTR - Registration

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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]

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

Condition category

Condition code

Neurological

Parkinson's disease

Neurological

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]

Treatment: Devices

Intervention code [2]

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]

Change in tremor measured by accelerometer

Timepoint [1]

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]

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]

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]

Change in participant stiffness using clinical assessment of arms

Timepoint [3]

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]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

30/08/2015

Date of last participant enrolment

Anticipated

21/12/2019

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]

St Vincent's Private Hospital - Fitzroy

Recruitment hospital [2]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [3]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [4]

Cabrini Hospital - Malvern - Malvern

Recruitment hospital [5]

St Andrew's War Memorial Hospital - Brisbane

Recruitment postcode(s) [1]

3065 - Fitzroy

Recruitment postcode(s) [2]

3084 - Heidelberg

Recruitment postcode(s) [3]

3144 - Malvern

Recruitment postcode(s) [4]

4001 - Brisbane

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Colonial Foundation

Address [1]

432 St Kilda Rd, Melbourne VIC 3004

Country [1]

Australia

Funding source category [2]

Government body

Name [2]

NHMRC

Address [2]

GPO Box 1421

Canberra ACT 2601

Country [2]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St Vincent's Hospital Melbourne HREC-D Committee

Ethics committee address [1]

Research Governance Unit

St Vincent's Hospital

PO Box 2900 

Fitzroy VIC 3065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/11/2014

Approval date [1]

05/01/2015

Ethics approval number [1]

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

Dr Wes Thevathasan

Address

Melbourne Brain Centre
Kenneth Myer Building
30 Royal Pde
Parkville VIC 3052

Country

Australia

Phone

+61402 308 686

Fax

w_thevathasan@hotmail.com

Contact person for public queries

Name

Hugh McDemott

Address

The Bionics Institute of Australia
384-388 Albert St
East Melbourne VIC 3002

Country

Australia

Phone

+613 9667 7526

Fax

hmcdermott@bionicsinstitute.org

Contact person for scientific queries

Name

Hugh McDermott

Address

The Bionics Institute of Australia
384-388 Albert St
East Melbourne VIC 3002

Country

Australia

Phone

+613 9667 7526

Fax

hmcdermott@bionicsinstitute.org

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Subthalamic nucleus deep brain stimulation evokes resonant neural activity.	2018	https://dx.doi.org/10.1002/ana.25234
Embase	Deep brain stimulation for Parkinson's disease modulates high-frequency evoked and spontaneous neural activity.	2019	https://dx.doi.org/10.1016/j.nbd.2019.104522
Embase	On the neural basis of deep brain stimulation evoked resonant activity.	2019	https://dx.doi.org/10.1088/2057-1976/ab366e

N.B. These documents automatically identified may not have been verified by the study sponsor.

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