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Trial registered on ANZCTR


Registration number
ACTRN12619001519145
Ethics application status
Approved
Date submitted
12/10/2019
Date registered
4/11/2019
Date last updated
27/02/2020
Date data sharing statement initially provided
4/11/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating alternative treatment methods for Mal de Debarquement Syndrome
Scientific title
Using Theta Burst Stimulation Treatment with the Vestibular Ocular Reflex Protocol to alleviate symptoms in patients with Mal de Debarquement Syndrome
Secondary ID [1] 299531 0
None
Universal Trial Number (UTN)
U1111-1241-9101
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mal de Debarquement Syndrome 314783 0
Condition category
Condition code
Neurological 313114 313114 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be allocated to one of four treatment groups; Group 1: Real Combination (Real VOR + Real TBS [n = 10]), Group 2: Sham TBS Combination (Real VOR + Sham TBS [n = 10]), Group 3: Sham VOR Combination (Sham VOR + Real TBS [n = 10]) and Group 4: Sham Combination (Sham VOR and Sham TBS [n = 10]). The participants will be blinded to the treatment allocation until all study materials had been collected at the end of the study. All patients will be required to complete an intake questionnaire, a Hospital Anxiety and Depression Scale (HADS), the Beck’s Depression Inventory (BDI), a Dizziness Handicap Inventory (DHI), a Misery Scale and a Visual Analogue Scale (VAS) questionnaire. They will also be required to complete a symptom diary one week before and four weeks after treatment week, and will have a follow-up 4 months later. The results from the diary data will indicate how effective the real combination treatment and the sham combination treatments (VOR alone or TBS alone) are on reducing primary perceptual symptom levels and secondary symptoms in MdDS patients. Posturography will be measured each day of the treatment week, this is how we will monitor adherence to the intervention, and this data will indicate how effective the two treatments are on improving posture.

TBS Treatment
For TBS, one site on the head will be stimulated at each session. Each session will be repeated five times per day. The total treatment will comprise 20 stimulation sessions over 4 days.

Determining Motor Threshold: Before the start of the treatment, the active motor threshold will be determined. This procedure helps the investigator decide what strength of magnetic stimulation is appropriate for each patient. They will sit in a chair and be asked to keep their head still during the stimulation procedures. Surface electrodes (wires) will be attached with tape to the skin over the muscles of their hands. A coil will be placed over their head and single magnetic pulses will be used to stimulate their brain in the area that controls their hand muscles. The intensity of the stimulation will be raised or lowered gradually until the level at which a muscle barely twitches in their hand is found. This part of the procedure will take between 10 and 15 minutes.

Actual TBS procedure: The investigator will continue to monitor activity in the muscles of the patient’s hands. The coil will be positioned over a part of their head and intermittent TBS (iTBS) will be used to stimulate the brain region. At each location, the stimulation will last approximately 2 minutes. There will be a 10-minute break between each stimulation. The total duration of this procedure per day will be about 1 hour. We will use iTBS, in which 600 pulses will be applied in bursts of three pulses at 50 Hz, repeated five times per second, for a total of 40 s and repeated after a 20-second break. Patients will therefore receive a total of 1200 pulses per session. Five sessions will be repeated each day (20 sessions total across 4 days). This technique has been demonstrated to reduce neural activity for at least 1h (Huang et al., 2005). Patients will be stimulated at 80% of their active motor thresholds; those in the sham condition were stimulated at 10% of their active motor thresholds (Holbrook et al., 2016).

The main risk involved in TBS is a possibility of triggering seizures. Because of this risk, safety procedures have been established that specify the safe duration of iTBS at the intensities and frequencies to be used in this study. The investigator wishes to minimise the risk to subjects participating in this study. Therefore, we will be using TBS duration of 25% less than the amount used in traditional protocols to provide an additional margin of safety (Oberman et al., 2011).

VOR Treatment
All patients will undergo four consecutive days of optokinetic (OKN) stimulation while seated in a chair in a darkened OKN drum, specifically built for the experiment. A full-field OKN visual stimulus will be projected on the drum walls, filling the visual field of the patient, including peripheral vision. Patients will be seated at 60 cm from the wall of the drum. During the treatment, the OKN stripes will move with a speed of 10°/sec. The patients are required to stare passively at the stripes. The patient’s head will be rolled at a constant frequency of 0.165 Hz by the researcher with the help of a metronome. During the four days of treatment, patients will up to 3 sessions per day, each session lasting for 4 minutes. A 10 - 30-minute interval will be provided between each session of OKN stimulation. Patients will follow a standardised protocol. Patients will follow the same number of sessions within all groups. However, the patient will have the right to stop at any moment.

Participants in the SHAM/SHAM group will undergo four consecutive days of OKN stimulation while seated in a chair in a darkened OKN drum, specifically built for the experiment. A full-field OKN visual stimulus will be projected on the drum walls, filling the visual field of the patient, including peripheral vision. Patients will be seated at 60 cm from the wall of the drum. During the “treatment”, the OKN stripes will not move. The patients are required to stare passively at the stripes. The patient’s head will be rolled at a constant frequency of 0.165 Hz by the researcher with the help of a metronome. During the four days of treatment, patients will receive various sessions per day depending on the severity of the patient’s condition. A 10 - 30-minute interval will be provided between each session of OKN stimulation.

Participants in the SHAM/SHAM group will undergo four consecutive days of OKN stimulation while seated in a chair in a darkened OKN drum, specifically built for the experiment. A full-field OKN visual stimulus will be projected on the drum walls, filling the visual field of the patient, including peripheral vision. Patients will be seated at 60 cm from the wall of the drum. During the “treatment”, the OKN stripes will not move. The patients are required to stare passively at the stripes. The patient’s head will be rolled at a constant frequency of 0.165 Hz by the researcher with the help of a metronome. During the four days of treatment, patients will receive various sessions per day depending on the severity of the patient’s condition. A 10 - 30-minute interval will be provided between each session of OKN stimulation.

Participants in the SHAM/SHAM group will also be given the sham TBS treatment. The sham TBS treatment will be administered by an experienced operator who will not be involved in participant recruitment and will not meet the participants beforehand. One treatment session per day of iTBS will be administered over one target site (Dorsolateral Prefrontal Cortex), they will be stimulated at 40% of their active motor threshold instead of 80% maximum stimulator output.

Control patients will still complete the pre and post treatment questionnaires, and have their posturography measured after each treatment session, (sham VOR and sham TBS) each day.
Intervention code [1] 315784 0
Treatment: Devices
Intervention code [2] 315785 0
Treatment: Other
Comparator / control treatment
Participants in the SHAM/SHAM group will undergo four consecutive days of OKN stimulation while seated in a chair in a darkened OKN drum, specifically built for the experiment. A full-field OKN visual stimulus will be projected on the drum walls, filling the visual field of the patient, including peripheral vision. Patients will be seated at 60 cm from the wall of the drum. During the “treatment”, the OKN stripes will not move. The patients are required to stare passively at the stripes. The patient’s head will be rolled at a constant frequency of 0.165 Hz by the researcher with the help of a metronome. During the four days of treatment, patients will receive various sessions per day depending on the severity of the patient’s condition. A 10 - 30-minute interval will be provided between each session of OKN stimulation.

Participants in the SHAM/SHAM group will also be given the sham TBS treatment. The sham TBS treatment will be administered by an experienced operator who will not be involved in participant recruitment and will not meet the participants beforehand. One treatment session per day of iTBS will be administered over one target site (Dorsolateral Prefrontal Cortex), they will be stimulated at 40% of their active motor threshold instead of 80% maximum stimulator output.

Control patients will still complete the pre and post treatment questionnaires, and have their posturography measured after each treatment session, (sham VOR and sham TBS) each day.

Control group
Placebo

Outcomes
Primary outcome [1] 321653 0
Evaluating subjective outcomes using the Visual Analogue Scale (VAS) questionnaire.
Timepoint [1] 321653 0
Baseline, last day of treatment (primary time point) and four months post treatment
Primary outcome [2] 321654 0
Objective evaluation of posture (balance/motion symptoms) using a Wii Fit board with posturography software.


Timepoint [2] 321654 0
1. Baseline
2. Each day of treatment (before and after first treatment, and after second treatment)
3. Last day of treatment (primary time point)
Primary outcome [3] 321719 0
Evaluating subjective outcomes using the Hospital Anxiety and Depression Scale (HADS) questionnaire.

Timepoint [3] 321719 0
Baseline, last day of treatment (primary time point) and four months post treatment
Secondary outcome [1] 375770 0
Evaluating subjective secondary outcome using the Misery Scale questionnaire to evaluate motion sickness.
Timepoint [1] 375770 0
Baseline, and at 4 weeks and 4 months after treatment (secondary timepoint)
Secondary outcome [2] 376003 0
Evaluating subjective secondary outcome using the Dizziness Handicap Inventory (DHI) questionnaire.
Timepoint [2] 376003 0
Baseline, and at 4 weeks and 4 months after treatment (secondary timepoint)
Secondary outcome [3] 380639 0
Evaluating subjective secondary outcome (ie.. depression) using the Beck's Depression Inventory (BDI)

Timepoint [3] 380639 0
Baseline, and at 4 weeks and 4 months after treatment (secondary timepoint)

Eligibility
Key inclusion criteria
1) A chronic perception of rocking dizziness that started after disembarking from sea, air, or land based travel; or developed spontaneously
2) Symptoms lasting at least three months
3) No other cause for symptoms after evaluation by a neurologist or otolaryngologist with appropriate testing for peripheral inner ear or other central nervous system cause for symptoms.
4) A diagnosis of Mal de Debarquement Syndrome
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Unstable medical or psychiatric condition (e.g. mania or psychosis),
2) Pregnant or planning to become pregnant during study enrolment,
3) Contraindications to receiving TBS

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)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be done in a 1:1:1:1 ratio (VOR&TBS, VOR only, TBS only, sham) so that each group get 25% of the total number of patients. The order of the four conditions will be pseudo-randomized (www.random.org).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Factorial
Other design features
NA
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Due to the rarity of the condition, this study aims to use a sample of 40 MdDS patients (10 per group) within a multiple site study format. Although power may not be sufficient, the study aims to use two-way repeated measures ANOVA (or non-parametric equivalent). A recent study by Mucci et al., 2018 'Sham-Controlled Study of Optokinetic Stimuli as Treatment for Mal de Debarquement Syndrome', 12 - 13 MdDS patients were recruited for the two treatment groups.

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)
NSW
Recruitment outside Australia
Country [1] 21918 0
Belgium
State/province [1] 21918 0

Funding & Sponsors
Funding source category [1] 304022 0
University
Name [1] 304022 0
Western Sydney University
Address [1] 304022 0
Locked Bag 1797
Penrith NSW 2751
Country [1] 304022 0
Australia
Primary sponsor type
University
Name
Western Sydney University
Address
Locked Bag 1797
Penrith NSW 2751
Country
Australia
Secondary sponsor category [1] 304199 0
None
Name [1] 304199 0
Address [1] 304199 0
Country [1] 304199 0
Other collaborator category [1] 280987 0
Individual
Name [1] 280987 0
Rocco Cavaleri
Address [1] 280987 0
Western Sydney University, Campbelltown Campus, Narellan Rd & Gilchrist Dr, Campbelltown NSW 2560
Country [1] 280987 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304514 0
The Western Sydney University Human Research Ethics Committee
Ethics committee address [1] 304514 0
Locked Bag 1797
Penrith NSW 2751
Ethics committee country [1] 304514 0
Australia
Date submitted for ethics approval [1] 304514 0
31/10/2019
Approval date [1] 304514 0
13/01/2020
Ethics approval number [1] 304514 0
H13563

Summary
Brief summary
Mal de Debarquement Syndrome (MdDS) is a rare neurological condition that affects the vestibular system and currently has no cure. Symptoms of MdDS include a continuous swaying, rocking, or motion-like feeling that typically arises following a motion experience such as traveling on sea, which leaves patients with a feeling of chronic “sea legs” or “sea sickness” though they are on stable ground. The underlying cause is currently unknown, and thus treatments for this condition are often ineffective. This project seeks to investigate the efficacy of a combination of Theta Burst Stimulation (a form of Transcranial Magnetic Stimulation) and the Vestibular Ocular Reflex Protocol (a manual therapy) in reducing objective and subjective measures of the condition. It is hypothesized that MdDS patients will report an improvement of symptoms after the combined therapy, which will significantly affect their quality of life, compared to the sham treatment.
Trial website
Trial related presentations / publications
Public notes
Participants will be required to undergo four days of treatment in Campbelltown, NSW, Australia

Contacts
Principal investigator
Name 97218 0
Dr Cherylea Browne
Address 97218 0
Western Sydney University, Campbelltown Campus, Narellan Rd & Gilchrist Dr, Campbelltown NSW 2560
Country 97218 0
Australia
Phone 97218 0
+61 2 46203941
Fax 97218 0
Email 97218 0
c.browne@westernsydney.edu.au
Contact person for public queries
Name 97219 0
Dr Cherylea Browne
Address 97219 0
Western Sydney University, Campbelltown Campus, Narellan Rd & Gilchrist Dr, Campbelltown NSW 2560
Country 97219 0
Australia
Phone 97219 0
+61 2 46203941
Fax 97219 0
Email 97219 0
c.browne@westernsydney.edu.au
Contact person for scientific queries
Name 97220 0
Dr Cherylea Browne
Address 97220 0
Western Sydney University, Campbelltown Campus, Narellan Rd & Gilchrist Dr, Campbelltown NSW 2560
Country 97220 0
Australia
Phone 97220 0
+61 2 46203941
Fax 97220 0
Email 97220 0
c.browne@westernsydney.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?
All of the individual participant data collected during the trial, after de-identification
When will data be available (start and end dates)?
Immediately following publication until 5 years after publication.
Available to whom?
Case-by-case basis at the discretion of the Principal Investigator
Available for what types of analyses?
Any purpose deemed appropriate by the Principal Investigator
How or where can data be obtained?
Access subject to approvals by Principal Investigator, requirement to sign data access agreement. Contact Dr Cherylea Browne c.browne@westernsydney.edu.au
What supporting documents are/will be available?
No other documents available
Summary results
No Results