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Trial registered on ANZCTR


Registration number
ACTRN12618001889246p
Ethics application status
Not yet submitted
Date submitted
12/11/2018
Date registered
20/11/2018
Date last updated
20/11/2018
Date data sharing statement initially provided
20/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
New parameters for brain stimulation in the treatment of depression
Scientific title
Translation of preclinical findings: the effect of low intensity repetitive Transcranial Magnetic Stimulation (rTMS) on depression score and biomarkers in patients with major depression.
Secondary ID [1] 296522 0
none
Universal Trial Number (UTN)
U1111-1223-2586
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Depression 310304 0
Condition category
Condition code
Mental Health 309034 309034 0 0
Depression

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
rTMS will be delivered in a head to head trial at an intensity of 50mT (estimated at 50mT at the level of the cortical surface) as an add on to the standard FDA-approved protocol of 100% of Motor Threshold equivalent to ~1000mT; (Gaynes et al., 2014; O’Reardon et al., 2007; Price et al., 2010) in a patient cohort, to compare outcomes to the standard protocol alone.

Treatment resistant patients (n=40; male and female) will be recruited through collaboration with Dr Greg Price and Dr Joseph Lee at the SCGH; Mental Health Unit; Neurophysiology Service. Dr Greg Price will deliver the treatment protocol and Dr Joseph Lee will do psychological assessments.

The study will consist of 4 weeks of treatment comprising 20 sessions (weekdays for 4 weeks) of rTMS to the left dorsolateral prefrontal cortex. Patients will be randomly assigned to the standard protocol (100%MT;1000mT) or add-on protocol (standard protocol+50mT) stimulation group.

Standard protocol: patients will receive 40 trains of rTMS at 10Hz at 100%MT equivilent to ~ 1000mT, with an inter-train interval of 30 seconds comprising of a total of 20 sessions (weekdays for 4 weeks)

Add on protocol: patients will receive alternating trains during the session of standard protocol rTMS (10 trains of rTMS at 10Hz at 100%MT) followed by 50 mT rTMS (10 trains of rTMS at 10Hz at ~1%MT) with an inter-train interval of 15 seconds repeated till a total of 80 trains of 10Hz stimulation is provided comprising of a total of 20 sessions (weekdays for 4 weeks)

Intervention code [1] 312833 0
Treatment: Devices
Comparator / control treatment
Active control / Standard protocol: patients will receive 40 trains of 100%MT;1000mT rTMS at 10Hz, with an inter-train interval of 30 seconds
Control group
Active

Outcomes
Primary outcome [1] 307997 0

Outcome Name: Depression
Metric/method of measurement: The primary endpoint will be the percentage change in HAM-D-21 response (score), defined by a significant change from the initial score on the Hamilton Depression Scale (HAM-D-21)
Timepoint [1] 307997 0
Timepoint: Directly following end of 4 week treatment period
Primary outcome [2] 308140 0
number of remissions defined by a HAM-D-21 score of <8 directly following 4 week treatment period and 6 months after;
Timepoint [2] 308140 0
Time points: Baseline, Immediately after end of 4 week rTMS treatment period and 6 months after treatment commencement.
Secondary outcome [1] 353611 0
the change and presence of predictive markers of the therapeutic response: serum biomarkers (a amino-nbutyric acid)
Timepoint [1] 353611 0
Time points: Baseline, Immediately after end of 4 week rTMS treatment period and 6 months after treatment commencement.
Secondary outcome [2] 354103 0
the change and presence of predictive markers of the therapeutic response: serum biomarkers (3-methylhistidine)
Timepoint [2] 354103 0
Time points: Baseline, Immediately after end of 4 week rTMS treatment period and 6 months after treatment commencement.

Eligibility
Key inclusion criteria
ICD-10-AM diagnosis of major depression. Subsequent depression scale scores will act as a validation check (any discrepancies to be reviewed by PI), but initial inclusion will be purely by clinical diagnosis. Aged above 18 years

Participants need not meet formal criteria for treatment resistance, but must have shown an unsatisfactory response to a previous treatment regime. The judgement to recommend a participant for this trial is, therefore, explicitly a clinical decision by the recruiting physician. However, we do require that the antidepressant medication regime be stable in type and dosage for 4 weeks prior to the rTMS trial.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Presence of cardiac pacemakers, medication pumps, cochlear implants or metal objects in the head or eyes that could be dangerous if heated or moved by the magnetic pulses.
Significant medical illness, substantial risk of suicide, current psychosis, current substance dependence, a history of seizures, epilepsy, stroke or major head trauma, or a history of alcohol dependence.

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)
Random sequence prior to recruitment.
central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
SPSS will be used to randomly generate a 1:1
list of treatment numbers (10Hz=0;
Variable=1). As participants sign the consent
form, they are allocated a sequence number
that corresponds to a treatment number.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
The person doing assessment (Dr Lee) will be blind to treatment. The assessor is not in the treatment area so does not hear the treatment
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Power analysis based on our published LI-rTMS data in preclinical models indicates that 16 individuals/group for behaviour (equivalent of behavioural changes in humans), or 8 individuals per group for biochemical/neurological changes (equivalent for blood samples in humans), will provide 0.8 power to detect changes of 20%.

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 in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 12364 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 24624 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 301107 0
Charities/Societies/Foundations
Name [1] 301107 0
Perron Institute for Translational Neuroscience
Address [1] 301107 0
Ground Floor, RR Block, QE II Medical Centre
8 Verdun St, Nedlands, WA 6009
Country [1] 301107 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Perron Institute for Neurological and Translational Neurosciences
Address

RR Block
QEII Medical Centre,
8 Verdun Street
Nedlands
Western Australia 6009
Country
Australia
Secondary sponsor category [1] 300718 0
Government body
Name [1] 300718 0
North metropolitan health service, mental health
Address [1] 300718 0

UU Block, SCGH Mental Health Unit
Verdun Street
NEDLANDS WA 6009
Country [1] 300718 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 301857 0
North Metropolitan Area Mental Health Services Human Research Ethics Committee [EC00273]
Ethics committee address [1] 301857 0
NMHS Mental Health REGO
Executive Officer
Gascoyne House, Graylands Campus
Locked Bag No. 1
PO CLAREMONT WA 6910
Ethics committee country [1] 301857 0
Australia
Date submitted for ethics approval [1] 301857 0
20/11/2018
Approval date [1] 301857 0
Ethics approval number [1] 301857 0

Summary
Brief summary
Depression is one of the most prevalent and costly medical conditions worldwide (WHO, 2012). Although antidepressant medication is effective for many patients, up to 40% remain drug-resistant. Non invasive brain stimulation in the form of repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression with response rates of up to 60%. However, outcomes are variable both within and between individuals, suggesting that treatment protocols remain suboptimal. This variability is not surprising because non-invasive brain stimulation techniques were first developed in humans with no systematic “bench-to-bedside” evaluation of protocols, resulting in poorly defined clinical guidelines.
Our lab has compared a range of brain stimulation protocols in a preclinical model of treatment resistant depression, and has shown that rTMS delivered at a 50mT intensity (at cortex) matches the behavioural effects obtained with rTMS delivered at 100% motor threshold equivalent to 1000mT intensity (currently used in human patients). However our 50mT protocol has additional benefits: it causes structural changes in the brain, leading to long lasting improvements in mood and cognition.
This project will test efficacy of our low intensity protocol (50mT)as an add-on to the gold standard protocol (100%;1000mT) in a patient cohort (40 participants), using psychiatric assessment to evaluate changes in mood and cognition, and detection of two novel blood biomarkers for predictive ability.
Significance: first pre clinically validated rTMS protocol for human treatment; establish a pipeline for translation of other rTMS protocols arising from basic research at the Perron Institute.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88338 0
A/Prof Jennifer Rodger
Address 88338 0
School of Biological Sciences M317
The University of Western Australia, 35 Stirling Highway, Crawley WA 6009
Country 88338 0
Australia
Phone 88338 0
+61 8 6488 2245
Fax 88338 0
Email 88338 0
jennifer.rodger@uwa.edu.au
Contact person for public queries
Name 88339 0
A/Prof Jennifer Rodger
Address 88339 0
School of Biological Sciences M317
The University of Western Australia, 35 Stirling Highway, Crawley WA 6009
Country 88339 0
Australia
Phone 88339 0
+61 8 6488 2245
Fax 88339 0
Email 88339 0
jennifer.rodger@uwa.edu.au
Contact person for scientific queries
Name 88340 0
A/Prof Jennifer Rodger
Address 88340 0
School of Biological Sciences M317
The University of Western Australia, 35 Stirling Highway, Crawley WA 6009
Country 88340 0
Australia
Phone 88340 0
+61 8 6488 2245
Fax 88340 0
Email 88340 0
jennifer.rodger@uwa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
baseline and final depression rating
When will data be available (start and end dates)?
from the end date of project up to 5 years following
Available to whom?
Researchers in the Field
Available for what types of analyses?
Meta analyses, Subscale analyses.
How or where can data be obtained?
Electronic by request
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
Summary results
No Results