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Trial registered on ANZCTR


Registration number
ACTRN12621000321842
Ethics application status
Approved
Date submitted
3/08/2020
Date registered
23/03/2021
Date last updated
23/03/2021
Date data sharing statement initially provided
23/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and effectiveness of frameless linac-based stereotactic radiosurgery on tremor in patients with essential tremor or Parkinson’s disease (TREMOR study)
Scientific title
Safety and effectiveness of frameless linac-based stereotactic radiosurgery on tremor in patients with essential tremor or Parkinson’s disease (TREMOR study)
Secondary ID [1] 301841 0
None
Universal Trial Number (UTN)
U1111-1255-8116
Trial acronym
TREMOR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tremor in essential tremor 318325 0
Tremor in Parkinson's disease 318813 0
Condition category
Condition code
Neurological 316339 316339 0 0
Parkinson's disease
Neurological 316340 316340 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is a trial of frameless linac-based stereotactic radiosurgical thalamotomy using coordinate-based targeting of the ventral intermediate (VIM) nucleus. All participants will receive 130Gy to be delivered to Dmax utilising a 4mm tertiary conical collimator. This dose will be delivered in a single fraction (i.e. one treatment session) for most participants, but if participants are not able to complete the treatment in one session and have received less than 110Gy they will have the opportunity to receive the remaining radiation dose no later than the next day. The treatment will take approximately 1 hour.

Prior to treatment, participants will undergo a planning MRI and planning CT scan. Treatment will be planned and delivered at Icon Cancer Centre Richmond by a qualified investigator and radiation therapy team.

A number of quality assurance measures are in place to ensure all treatment plans are reviewed and approved by the appropriate parties (e.g. medical physicist) to ensure safety and accuracy. Post-treatment, imaging is taken and reviewed by radiation therapists to check the treatment delivery. All reviews will be documented in the medical record.
Intervention code [1] 318137 0
Treatment: Other
Comparator / control treatment
No control group (single-arm study)
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324584 0
The proportion of participants experiencing improvement in tremor as assessed by the Fahn-Tolosa-Marin Tremor Rating Scale (FTM)
Timepoint [1] 324584 0
Primary timepoint is 12 months post-treatment, but outcome also measured at baseline and 6 months post-treatment.
Secondary outcome [1] 385077 0
The number of participants experiencing treatment-related adverse events measured using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (e.g. nausea, vomiting, alopecia, scalp dryness or flaking, headache, seizures or epilepsy, intracranial haemorrhage, cerebral oedema, radiation necrosis)
Timepoint [1] 385077 0
3 months, 6 months and 12 months post-treatment
Secondary outcome [2] 385078 0
Tremor severity based on median score of the Fahn-Tolosa-Marin Tremor Rating Scale and Tremor Research Group (TRG) Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale
Timepoint [2] 385078 0
Baseline, 6 months and 12 months post-treatment
Secondary outcome [3] 385079 0
Activities of daily living measured by median score of Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Upper Extremity (v2.0)
Timepoint [3] 385079 0
Baseline, 6 months and 12 months post-treatment
Secondary outcome [4] 385080 0
Activities of daily living measured by median score of Tremor Research Group (TRG) Essential Tremor Rating Assessment Scale (TETRAS) Activities of Daily Living subscale
Timepoint [4] 385080 0
Baseline, 6 months and 12 months post-treatment
Secondary outcome [5] 386264 0
Patient reported quality of life measured by median score in Quality of Life in Essential Tremor Questionnaire (QUEST) (for patients with essential tremor) or Parkinson’s Disease Questionnaire-8 (PDQ-8) (for patients with Parkinson's Disease)
Timepoint [5] 386264 0
Baseline, 6 months post-treatment and 12 months post-treatment
Secondary outcome [6] 386265 0
The proportion of participants who select 9 or 10 when asked the following question: How likely would you be to recommend linac-based stereotactic radiosurgery treatment to family or friends if they were suffering from a medically refractory tremor? (Scale of 0-10 from extremely unlikely to extremely likely)
Timepoint [6] 386265 0
12 months post-treatment
Secondary outcome [7] 386266 0
The proportion of participants who select 9 or 10 when asked the following question: How likely would you be to recommend linac-based stereotactic radiosurgery treatment to family or friends if they were suffering from a medically refractory tremor? (Scale of 0-10 from extremely unlikely to extremely likely)
Timepoint [7] 386266 0
12 months post-treatment
Secondary outcome [8] 386268 0
The proportion of participants who select yes when asked: Having undergone the treatment, if you could go back in time to before receiving linac-based stereotactic radiosurgery treatment, would you choose again to undergo the treatment?
Timepoint [8] 386268 0
12 months post-treatment
Secondary outcome [9] 386270 0
A comparison of how well traditional indirect coordinate-based targeting of the VIM nucleus matches with an image-guided approach incorporating distortion corrected advanced MRI sequences and deterministic tractography. This will be performed as a technical retrospective review by the radiation therapists, physicists and radiation oncologists involved in the study. The treatment plan for each patient will be created using each of the two approaches and then compared.
Timepoint [9] 386270 0
Coordinate-based targeting will be performed during the treatment planning process and will be used to treat all patients.
Secondary outcome [10] 392987 0
Safety of treatment measured by comparison of group data for the Test of Premorbid Functioning performed during the neuropsychological assessment
Timepoint [10] 392987 0
Baseline and 6 months post-treatment
Secondary outcome [11] 392988 0
Safety of treatment measured by comparison of group data for the Hopkins Verbal Learning Test - Revised (HVLT-R) performed during the neuropsychological assessment
Timepoint [11] 392988 0
Baseline and 6 months post-treatment
Secondary outcome [12] 392989 0
Safety of treatment measured by comparison of group data for the Symbol Digit Modality Test (SDMT) performed during the neuropsychological assessment
Timepoint [12] 392989 0
Baseline and 6 months post-treatment
Secondary outcome [13] 392990 0
Safety of treatment measured by comparison of group data for the Digit Span performed during the neuropsychological assessment
Timepoint [13] 392990 0
Baseline and 6 months post-treatment
Secondary outcome [14] 392991 0
Safety of treatment measured by comparison of group data for the Verbal Fluency test (letter and category) performed during the neuropsychological assessment
Timepoint [14] 392991 0
Baseline and 6 months post-treatment
Secondary outcome [15] 392992 0
Safety of treatment measured by comparison of group data for the Trail Making Test performed during the neuropsychological assessment
Timepoint [15] 392992 0
Baseline and 6 months post-treatment
Secondary outcome [16] 392993 0
Safety of treatment measured by comparison of group data for the Victoria Stroop Test performed during the neuropsychological assessment
Timepoint [16] 392993 0
Baseline and 6 months post-treatment
Secondary outcome [17] 392994 0
Safety of treatment measured by comparison of group data for the Visual Objects and Space Perception (VOSP) performed during the neuropsychological assessment
Timepoint [17] 392994 0
Baseline and 6 months post-treatment
Secondary outcome [18] 392995 0
Safety of treatment measured by comparison of group data for the Boston Naming Test performed during the neuropsychological assessment
Timepoint [18] 392995 0
Baseline and 6 months post-treatment
Secondary outcome [19] 392996 0
Safety of treatment measured by comparison of group data for the Finger Tapping Test performed during the neuropsychological assessment
Timepoint [19] 392996 0
Baseline and 6 months post-treatment

Eligibility
Key inclusion criteria
1) Age great than or equal to 18 years.
2) Clinical diagnosis of essential tremor or tremor dominant Parkinson’s disease made by a
neurologist
3) Tremor of at least one upper limb resulting in significant disability despite medical treatment
4) Medication refractory tremor or intolerant to medications
5) Not a suitable surgical candidate or declined surgery
6) Assessed as able to tolerate MRI scan and treatment session(s) with light sedation
7) Has been reviewed and approved for enrolment by the multidisciplinary study team

In addition, the following criteria will apply (to be assessed by the study movement disorders
neurologist):
For patients with essential tremor:
a) tremor refractory to adequate trials of at least two medications, one of which should
be a first line therapy of either propranolol or primidone (an adequate medication
trial is defined as a therapeutic dose of each medication or the development of side
effects as the medication dose is titrated)
o postural and intention tremor severity score of greater than or equal to 2 in the
extremity marked for treatment as measured by the FTMRS while stable on
medication
b) significant disability due to essential tremor despite medical treatment (FTMRS score
of 2 or above in any one of the items 16-21)
c) may have bilateral appendicular tremor

For patients with tremor dominant Parkinson’s Disease:
a) will have a tremor dominant and postural instability/gait difficulty (TD/PIGD) ratio >
1.5 in the medicated [ON] state as calculated from the Unified Parkinson's Disease
Rating Scale (UPDRS) formula as described by Jankovic et al. (Jankovic et al. 1990)
b) tremor remains disabling when medical therapy is optimal or not tolerated for the treatment of other cardinal signs of Parkinson’s disease (bradykinesia, rigidity, etc.), as determined by a neurologist at the site
c) a resting tremor severity score of greater than or equal to 3 in the hand/arm as measured by the medicated (ON) UPDRS question #20 or a postural/action tremor greater than or equal to a 2 for question #21
d) subject exhibits a significant disability from their PD tremor despite medical treatment where a significant disability is defined as a Parkinson’s disease tremor with at least a score of 3 on #16 of the medicated (ON) UPDRS
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Presence of head tremor that would interfere with treatment delivery
2) Patients with central neurodegenerative disease other than Parkinson’s disease
3) Drug-induced parkinsonism
4) Unable to undergo MRI due to the presence of a metallic implanted device such as a pacemaker or defibrillator or cochlear implant
5) Prior cranial irradiation
6) Change in medication(s) in the four weeks prior to enrolment or plans to change medication(s) during the 12-month follow-up period
7) Presence of significant cognitive impairment as determined by meeting the DSM-5 criteria for Major Cognitive Disorder
8) Unstable psychiatric disease, defined as active uncontrolled depressive symptoms, psychosis, delusions, hallucinations, or suicidal ideation. Subjects with stable, chronic anxiety or depressive disorders may be included provided their medications have been stable for at least 60 days prior to study entry and if deemed appropriately managed by the site neuropsychiatrist
9) Unable to provide informed consent
10) Unable or unwilling to attend follow-ups or comply with protocol requirements
11) Pregnant or planning to become pregnant

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)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary statistic is the proportion of participants experiencing long-term improvement in tremor rates according to the Fahn-Tolosa-Marin Tremor Rating Scale (FTM). This statistic will be analysed using binomial-based methods and compared to FTM scores reported in the literature for other SRS trials. A secondary but related statistic is the median FTM rating before and after treatment. This statistic will be analysed using either standard non-parametric or resampling methods as dictated by the distribution of the sample data. Tremor rates will also be assessed using Tremor Research Group's The Essential Tremor Rating Assessment Scale (TETRAS). The level of agreement between TETRAS measures and those on the FTM will be displayed using a Bland-Altman approach and analysed using the weighted Kappa coefficient. Data concerning the relationship between linac targeting accuracy and tremor change will be tabulated and described graphically and analysed using measures of association involving an ordinal variable. Survey data providing before and after quality of life changes will be summarised, displayed and analysed as appropriate for the scale of variable(s) involved.

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)
VIC
Recruitment hospital [1] 17170 0
Icon Cancer Centre Richmond - Richmond
Recruitment postcode(s) [1] 30869 0
3121 - Richmond

Funding & Sponsors
Funding source category [1] 306264 0
Charities/Societies/Foundations
Name [1] 306264 0
Icon Cancer Foundation
Address [1] 306264 0
Level 1, 22 Cordelia St, South Brisbane QLD 4101
Country [1] 306264 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Icon Institute of Innovation and Research
Address
Level 1, 22 Cordelia St, South Brisbane QLD 4101
Country
Australia
Secondary sponsor category [1] 306828 0
None
Name [1] 306828 0
Address [1] 306828 0
Country [1] 306828 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306472 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 306472 0
246 Clayton Road,
Clayton VIC 3168
Ethics committee country [1] 306472 0
Australia
Date submitted for ethics approval [1] 306472 0
22/07/2020
Approval date [1] 306472 0
10/03/2021
Ethics approval number [1] 306472 0
RES-20-0000-542A

Summary
Brief summary
In this study, we are trying to find out if using stereotactic radiosurgery to treat tremor is safe and effective in patients who have tremor dominant Parkinson’s or essential tremor and are unable to undergo conventional therapy. Some patients with tremor do not respond to, tolerate or are unsuitable for conventional medical drug therapy. In this group of patients, uncontrolled tremors can have a negative impact on everyday activities, which may result in a decline in their quality of life. Today, the standard treatment for these patients is deep brain stimulation which involves a surgical procedure to place electrodes or needles into the central part of the brain and a stimulator into the chest wall. However, some patients are not able to have deep brain stimulation because of advancing age and/or poor health, and some patients are not willing to undergo surgery. Stereotactic radiosurgery can be used as a non-invasive alternative to deep brain stimulation to treat tremor in these patients. Stereotactic radiosurgery is a form of radiation therapy that delivers high doses of radiation to a specified target while sparing surrounding tissue and organs. Until now, stereotactic radiosurgery for tremor has mostly been delivered using a system called Gamma Knife. Our study is exploring the use of a different delivery system called a linear accelerator or ‘linac’. A linac, unlike the Gamma Knife, generates x-rays from electricity and is very similar to the radiation delivery systems used widely in conventional radiation therapy for cancer treatment. Participants will be asked to provide some basic information about themselves, such as medical history, and undergo a set to study assessments prior to treatment. These assessments include neurological examination, which would include testing for things such as strength and sensation, balance assessment looking at their ability to sit, stand, walk (if possible) and perform fast movements with their hands, assessment of abnormal positioning of their limbs during movement (called dystonia) and rating of the severity of their tremor from mild to severe using a specific scale. In addition, participants will be asked to complete two questionnaires that ask about the impact of their tremor and their ability to perform specific tasks and their overall mood. These assessments will be repeated at six months and twelve months post-treatment. Study doctors will also ask participants about any side effects they are experiencing after the treatment. We will then use this information to evaluate the impact of the study treatment on tremor in this group of patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104010 0
Dr Kevin So
Address 104010 0
Icon Cancer Centre
Level 4, 32 Erin Street
Richmond VIC 3121
Country 104010 0
Australia
Phone 104010 0
+61433209225
Fax 104010 0
Email 104010 0
Kevin.So@icon.team
Contact person for public queries
Name 104011 0
Ms Skye Nolan
Address 104011 0
Icon Cancer Centre
Level 4, 32 Erin Street
Richmond VIC 3121
Country 104011 0
Australia
Phone 104011 0
+61 399368277
Fax 104011 0
Email 104011 0
Vic.Research@icon.team
Contact person for scientific queries
Name 104012 0
Dr Kevin So
Address 104012 0
Icon Cancer Centre
Level 4, 32 Erin Street
Richmond VIC 3121
Country 104012 0
Australia
Phone 104012 0
+61 399368277
Fax 104012 0
Email 104012 0
Kevin.So@icon.team

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will not be shared
What supporting documents are/will be available?
No other documents available
Summary results
No Results