The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12617000379314
Ethics application status
Approved
Date submitted
24/02/2017
Date registered
13/03/2017
Date last updated
13/03/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
A clinical trial to study the safety and efficacy of Botox for arm tremor in people with multiple sclerosis (MS)
Scientific title
A randomized controlled trial of the efficacy of Botulinum Toxin type A in the treatment of MS tremor: a clinical, imaging and electrophysiological approach
Secondary ID [1] 291278 0
Nil known
Universal Trial Number (UTN)
U1111-1193-4989
Trial acronym
TREMTOX
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Sclerosis 302226 0
Tremor 302227 0
Condition category
Condition code
Neurological 301825 301825 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a 24 week randomized controlled study of onabotulinumtoxina compared to placebo. Randomization is 1:1. An open-label extension starts at the 24 week visit with further follow-up to 48 weeks.

Details of the therapeutic intervention is as follows:
Botulinum toxin A (onabotulinumtoxina) affects neuromuscular transmission by blocking calcium-mediated exocytosis of acetylcholine. Transmission of acetylcholine is restored over 2 to 4 months in human motor endplates, although the clinical effects may persist for 6 months.
The medication is administered as an intramuscular injection. A maximum dose of 150 IU will be administered at baseline and/or at 6 months with the actual dosed determined by the treating neurologist.
Dosages are individualised to target muscles according to the type of tremor observed. Data from our previous study (Van der Walt et al. Neurology, 2010) showed that the average dose per person is 83 IU per treatment with an average of 5 muscles injected. There is no minimum dose.

Placebo
The placebo intervention will be normal saline.
Intervention code [1] 297292 0
Treatment: Drugs
Comparator / control treatment
Placebo in the form of normal saline will be used at the baseline visit.
Control group
Placebo

Outcomes
Primary outcome [1] 301241 0
Blinded movement disorder expert rating (randomized videos) the proportion of participants with a two point change in tremor severity as rated by the Bain score (form 0 to 10) for overall tremor severity.
Timepoint [1] 301241 0
At 6, 12 and 24 weeks post injection from the baseline dose.
Primary outcome [2] 301424 0
Blinded movement disorder expert rating (randomized videos) he proportion of participants with a two point change in tremor severity during writing as rated by the Bain writing score (form 0 to 10)
Timepoint [2] 301424 0
6, 12 and 24 weeks from the baseline dose
Primary outcome [3] 301425 0
Blinded movement disorder expert rating (randomized videos) the proportion of participants with a two point change in tremor severity during the drawing of an archimedes spiral as rated by the Bain spiral score (form 0 to 10).

Timepoint [3] 301425 0
6, 12 and 24 weeks from baseline injections
Secondary outcome [1] 332095 0
The proportion of participants with a 30% change in tremor amplitude using electromagnetic motion tracker technology
Timepoint [1] 332095 0
At week 6 and week 12 post baseline injections and
week 32 (week 8 post open-label) injections
Secondary outcome [2] 332096 0
The proportion of participants with a 30% change in the UTRA score (0-4) and CRST (combined rating scale for tremor) scores for functional tasks that include: pouring water, drinking water or drawing straight lines.
Timepoint [2] 332096 0
At week 6 and week 12 post baseline injections and
week 32 (week 8 post open-label) injections and
week 48 (week 16 post open-label) injections
Secondary outcome [3] 332602 0
The proportion of participants who experience objective weakness in the injected muscles after Botox or placebo. The weakness will be graded objectively using the standard Medical Research Council score (MRC).
Timepoint [3] 332602 0
At week 6 and week 12 post baseline injections and
week 32 (week 8 post open-label) injections
Secondary outcome [4] 332643 0
The proportion of subjects who experiences subjective muscle weakness (in injected muscles) after Botox or placebo will be graded as mild (minimal weakness, not interfering with function), moderate (detectable weakness but able to use the affected limb) and severe (severe weakness, unable to use the limb).
Timepoint [4] 332643 0
At week 6 and week 12 post baseline injections and
week 32 (week 8 post open-label) injections
Secondary outcome [5] 332644 0
Duration of treatment response assessed by calculating the proportion of participants with an unchanged Bain tremor score (for overall tremor severity) following open-label injection of Botulinum toxin type A given at the 24 week visit.
Timepoint [5] 332644 0
week 32 week and week 48 following open-label injection

Eligibility
Key inclusion criteria
1. a definite diagnosis of RRMS (38) or SPMS (39)
2. aged between 18 and 65 years
3. no other neurological disease to explain presence of tremor
4. no MS relapse or treatment with corticosteroids in the 3 months prior to
enrollment
5. normal or near-normal upper limb strength (Medical Research Council (MRC) score > 4+/5).
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Treatment of tremor with Botulinum toxin type A of any brand within the 6 months prior to enrollment
2. A known contraindication to Botox injection
3. Pregnancy, breastfeeding or unwillingness to use adequate contraception.
4. Inability to cease other tremor treatments (wash-out period of 4 weeks for any tremor reducing agents)
5. A MS relapse during the study that affects upper limb function will be a withdrawal criterion.
6. Any contra-indication to MRI will exclude the patient from MRI protocol.

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)
Allocation completed by unblinded trial pharamcist
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Group Comparisons: Aim 1 and Aim 2
Continuous variables will be assessed for skew, with normally distributed variables summarized using mean and SE and skewed variables summarized using median and interquartile range (IQR). Differences in score change between BoNT-A or placebo from baseline to, respectively, 6, 12 and 24 weeks will be assessed through a Wilcoxon signed- rank test. Muscle weakness between groups will be tested using the McNemar test. The significance level will be adjusted for multiple comparisons for the primary outcomes (p=0.05/3). All analyses were performed using Stata (version 11.0; StataCorp, College Station, TX).
Correlations between response to treatment and baseline covariates:
Correlation analyses between primary and secondary outcomes at 6,12 and 24 weeks and baseline variables will be performed using Pearson parametric correlation procedures. Where data are not normally distributed, Spearman rank correlations will be performed. Multiple tests will be corrected using the Bonferroni probability value correction procedure.

Study Power
Using a basic test for difference in proportion of patients who demonstrated improvement in tremor in both groups from our previous study, and taking the midpoint of the improvement range (26-40%) or 33% improvement in Botox group and 10% in placebo group then: 80% power=49 per group. We therefore propose to recruit 50 patients per treatment group.

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)
VIC
Recruitment hospital [1] 7565 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 15455 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 295744 0
Government body
Name [1] 295744 0
NHMRC
Address [1] 295744 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 295744 0
Australia
Primary sponsor type
University
Name
University of Melbourne
Address
Grattan St.
Parkville
VIC
3052
Country
Australia
Secondary sponsor category [1] 294586 0
Hospital
Name [1] 294586 0
Royal Melbourne Hospital
Address [1] 294586 0
Grattan ST
Parkville
VIC
3050
Country [1] 294586 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297043 0
Melbourne Health HREC
Ethics committee address [1] 297043 0
Royal Melbourne Hospital
Grattan St
Parkville, VIC
3050
Ethics committee country [1] 297043 0
Australia
Date submitted for ethics approval [1] 297043 0
Approval date [1] 297043 0
07/04/2015
Ethics approval number [1] 297043 0
HREC 2015.069

Summary
Brief summary
The treatment and pathophysiology of tremor in Multiple Sclerosis (MS) remains a significant challenge and unmet need, requiring further clinical research. We recently performed a phase II, randomized, controlled, crossover study demonstrating the efficacy of Botulinum toxin type A (BoNT-A) for treatment of MS tremor. This peer-reviewed NHMRC funded project proposes a detailed study of phenomenological, electrophysiological characteristics of MS tremor patients before and after BoNT-A or placebo treatment. The results of this study will help generate class I evidence that is required to translate treatment of MS tremor with BoNT-A into clinical practice. We aim to define predictors of the response to treatment and to better understand the underlying pathophysiology of MS tremor.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72790 0
Dr Anneke van der Walt
Address 72790 0
Department of Neurology
Royal Melbourne Hospital
Grattan St
Parkville VIC
3050
Country 72790 0
Australia
Phone 72790 0
+61393429092
Fax 72790 0
+61393495997
Email 72790 0
anneke.vanderwalt@mh.org.au
Contact person for public queries
Name 72791 0
Ms Lisa Taylor
Address 72791 0
MS research Unit
Royal Melbourne Hospital
Grattan St
Parkville VIC
3050
Country 72791 0
Australia
Phone 72791 0
+61393427061
Fax 72791 0
+61393495997
Email 72791 0
lisa.taylor@mg.org.au
Contact person for scientific queries
Name 72792 0
Dr Anneke van der Walt
Address 72792 0
Department of Neurology
Royal Melbourne Hospital
Grattan St
Parkville VIC
3050
Country 72792 0
Australia
Phone 72792 0
+61393427061
Fax 72792 0
+61393495997
Email 72792 0
anneke.vanderwalt@mh.org.au

No data has been provided for results reporting
Summary results
Not applicable