Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001603303
Ethics application status
Approved
Date submitted
21/11/2017
Date registered
7/12/2017
Date last updated
7/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
The proposed study will answer the key question whether Botulinum toxin injection in the spastic (tight) lower limb muscles following stroke improves walking and the quality of life.
Scientific title
Efficacy of Botulinum Toxin A on Walking and Quality of Life in Post-Stroke Lower Limb Spasticity- a randomized double-blind placebo controlled Study
Secondary ID [1] 293403 0
None
Universal Trial Number (UTN)
Nil Known
Trial acronym
Nil
Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Post stroke lower limb spasticity 305533 0
Stroke 305546 0
Spasticity 305547 0
Lower limb spasticity 305548 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention group will receive BT injection (up to 400 units of Botulinum toxin, Allergan reconstituted with 2ml of normal saline) into the lower limb spastic muscles, single injection. The specific dose is determined by assessing the spasticity by Modified Ashworth Scale (MAS) and the number of spastic muscle. The study physician (myself for this trial) will administer the intervention and also the placebo. The trial will be conducted in the specialised multidisciplinary spasticity clinic consisting of the rehabilitation physician, nurse, physiotherapist, and the orthotist. Besides the intervention (active or placebo) all participants will receive a structured physiotherapy program. Strategies will be placed to monitor and ensure the reliability and validity of the interventions. The process fidelity i.e. the consistency in which intervention content will be delivered, will be monitored by the study physician and the nurse. The content fidelity i.e. delivery of the intervention components delivered as per prescription, will be ensured by the study physician and the physiotherapist. We will employ some strategies such as treatment manuals, written exercise program and telephone intervention to ensure intervention adherence. Structured physiotherapy will be delivered by a senior physiotherapist experienced in treating the stroke patients. The therapy will consist of stretching, balancing, strengthening exercises, and gait training. Each session will last for 45 minutes (duration) in the physiotherapy department of the Queen Elizabeth Hospital, two times per week (frequency) and will be of moderate intensity (Borg's scale 4-6). A similar home exercise program will also be developed. Participants will undergo baseline assessment and follow ups as described in the protocol at three weeks, three months and five months. Home exercise program will be monitored by the physician and the physiotherapist by making telephone calls



Intervention code [1] 299644 0
Treatment: Drugs
Intervention code [2] 299645 0
Rehabilitation
Comparator / control treatment
The participants in the placebo group will be receiving identical looking placebo (normal saline) injections. Both the intervention and the placebo group will receive similar structured physiotherapy.

Structured physiotherapy will be delivered by a senior physiotherapist experienced in treating the stroke patients. The therapy will consist of stretching, balancing, strengthening exercises, and gait training. Each session will last for 45 minutes (duration) in the physiotherapy department of the Queen Elizabeth Hospital, two times per week (frequency) and will be of moderate intensity (Borg's scale 4-6). A similar home exercise program will also be developed. Participants will undergo baseline assessment and follow ups as described in the protocol at three weeks, three months and five months. Home exercise program will be monitored by the physician and the physiotherapist by making telephone calls







Control group
Placebo

Outcomes
Primary outcome [1] 303998 0
Gait velocity

The gait velocity will be measured in the Gait Rite (Electronic walkway) along with recording of other temporospatial gait parameters.
Timepoint [1] 303998 0
3 weeks
Primary outcome [2] 304166 0
2 Minutes Walking Distance
Timepoint [2] 304166 0
3 weeks
Secondary outcome [1] 340691 0
Quality of Life (SF 12)
Timepoint [1] 340691 0
Baseline assessment
3 weeks
3 months
5 months
Secondary outcome [2] 340692 0
Timed Up and Go
Timepoint [2] 340692 0
Baseline assessment
3 weeks
3 months
5 months
Secondary outcome [3] 340693 0
Berg Balance Score
Timepoint [3] 340693 0
Baseline assessment
3 weeks
3 months
5 months
Secondary outcome [4] 340694 0
Goal Attainment Scale (GAS)
Timepoint [4] 340694 0
Baseline assessment
3 weeks
3 months
5 months

Eligibility
Key inclusion criteria
• Male or female subjects aged 20 to 80 years of age are eligible for this study if they had a stroke resulting in focal spasticity in the knee causing stiff knee and/or equinovarus deformity, as demonstrated by a score of more than 3 for quadriceps (rectus femoris), gastrocnemius, soleus, tibialis posterior, flexor hallucis longus or flexor digitorum longus on the Modified Ashworth Scale.
• All patients should be walking normally prior to stroke. Any patients with lower limb spasticity (MAS 3+) resulting in a limp, or any difficulty in weight bearing on the leg or walking such as reduced speed of gait following stroke will be included.
Minimum age
20 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• This study will exclude patients with significant speech or cognitive impairment
• Significant lower limb problems such as fracture or arthritis, evidence of fixed
contracture
• Use of botulinum toxin type A in the previous six months, other non-stroke
neurological disorders causing lower limb spasticity
• Significant illness, such as malignancy, or contraindication to botulinum toxin type A,
will exclude people from the study.
• Pregnant and lactating mothers will also be excluded from the study.
• Individuals with osteoarthritic knee or hip having pain score of 3/10 or more on VISUAL
Analog Scale will be excluded.
• Individuals with significant depression (Geriatric Depression Scale (12 or more/15) and
Beck Depression Inventory (30 or more/63) will be excluded from the study.
• Individuals on antispasticity medications such as Baclofen, Tizanidine, Dantrolene,
Diazepam will be excluded from the study.

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)
The study physician administering the injection and the patient will be blinded to the syringe contents and the which group the subject is allocated to i.e. intervention or placebo. The pharmacist who is external to the study will provide the injections. Participants in both the both the intervention and the placebo group will receive the identical looking injection and the structured physiotherapy program designed to improve walking and other lower limb functions. Participants will undergo stratified randomization (ischaemic versus haemorrhagic stroke) by block permutation.
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
Efficacy
Statistical methods / analysis
Sample Size Calculation

We identified serious sample inadequacies in most of the RCTs included our systematic review. Chief among these was the problem of inadequate sample calculations for repeated measures design. In studying a number of outcome measures over time the authors failed to calculate sample size based on repeated measures criteria. The sample size for this study is, therefore, based on repeated measures design of baseline and three follow-ups at 3 weeks, 3 months and 5 months post intervention. In a repeated measures ANOVA, the within subjects factor of time allows for a common time effect in both the treatment and control groups, the treatment main effect adjusts for the differences between the treatment and control groups at baseline, and the interaction between treatment and time tests the treatment effect. In including estimates of the variance and correlations between measures the largest sample size calculation for the outcome measures proved to be gait speed and allowing for a power of 90% and significance level of 0.5 a sample size of n=30 was required for each group. Allowing for dropouts in the study we increased the sample size to n=40 in each group giving a final study sample of n=80.

Statistical Methods

The data will be summarised using means with standard deviations and medians with inter-quartile range. Group differences in change in gait speed will be assessed using the Student t-test or the Wilcoxon (Mann-Whitney) test as appropriate. Generalised linear models will be used to assess group effects with adjustment for known confounders such as gender and age. All tests will be two-tailed and assessed at the 5% alpha level. Other advanced statistical tests and modelling techniques will be selected as appropriate and informed by the univariate analyses.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/01/2018
Actual
Date of last participant enrolment
Anticipated
15/06/2021
Actual
Date of last data collection
Anticipated
22/11/2021
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 9421 0
The Queen Elizabeth Hospital - Woodville
Recruitment postcode(s) [1] 18125 0
5011 - Woodville

Funding & Sponsors
Funding source category [1] 297891 0
Commercial sector/Industry
Name [1] 297891 0
Investigator Initiated Trial Grant from Allergan
Country [1] 297891 0
Australia
Funding source category [2] 298026 0
Charities/Societies/Foundations
Name [2] 298026 0
The Hospital Research Foundation
Country [2] 298026 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
The Hospital Research Foundation
Address
The Hospital Research Foundation (THRF)
60 Woodville Road
Woodville, SA 5011
Country
Australia
Secondary sponsor category [1] 296944 0
Commercial sector/Industry
Name [1] 296944 0
Allergan Australia
Address [1] 296944 0
Allergan Australia Pvt Ltd
Level 4, 810 Pacific Highway, Gordon
New South Wales 2072
Australia
Country [1] 296944 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298940 0
Human Research Ethics Committee (TQEH/LMH/MH), Central Adelaide Local Health Network.
Ethics committee address [1] 298940 0
The Queen Elizabeth Hospital. Basil Hetzel Institute DX 465101. 28 Woodville Road. Woodville South SA 5011.
Ethics committee country [1] 298940 0
Australia
Date submitted for ethics approval [1] 298940 0
19/05/2017
Approval date [1] 298940 0
23/10/2017
Ethics approval number [1] 298940 0
HREC/17/TQEH/109

Summary
Brief summary
The proposed research project will answer the key question whether Botulinum toxin injection in post stroke lower limb spasticity improves walking and other functional activities, and quality of life. In addition to injections of the toxin/placebo people, the participants who have had a stroke will also participate in a structured physiotherapy program and a home exercise program (standard care). The research project is designed to show whether, following stroke, botulinum toxin injection in the lower limb spastic muscles combined with an exercise program helps people to walk faster and longer and improves their quality of life.
Trial website
Trial related presentations / publications
Public notes
Presentation
Does Botulinum Toxin improve walking and quality of life in post-stroke lower limb spasticity? A systematic review. Annual Scientific Meeting of Rehabilitation Medicine Society of Australia and New Zealand 17-20 September 2017, Canberra.

Publications
Wing Hong C, Datta Gupta A. The effectiveness of botulinum toxin type A on gait and quality of life of adult post-stroke patients with lower limb spasticity: a systematic review protocol. JBI Database System Rev Implement Rep. 2016; 14(6): 23-29.

Datta Gupta A, Wing Hong Chu, Howell S, Chakraborty S, Koblar S, Visvanathan R, Cameron I, Wilson D. A systematic review: Efficacy of Botulinum Toxin on Walking and Quality of Life in Post-Stroke Lower Limb Spasticity. Accepted and under consideration of publication in Systematic Reviews Journal, 20`17.

Datta Gupta A, Wilson D. Spasticity/Dystonia – Current Pharmaceutical Benefits Scheme Guidelines for Treatment with Botulinum Toxin – A Case for Change. Accepted and under consideration of publication in the Medical Journal of Australia 2017.
Attachments [1] 2201 2201 0 0
/AnzctrAttachments/373917(v21-11-2017-16-38-22)-RCT Protocol Post stroke Lower Limb Spasticity Version 5 231017 CLEAN FINAL (5).doc (Protocol)
Attachments [2] 2202 2202 0 0
/AnzctrAttachments/373917(v21-11-2017-16-39-14)-Ethics Approval Letter - Gupta Botox Q20170509.pdf (Ethics approval)
Attachments [3] 2203 2203 0 0
/AnzctrAttachments/373917(v21-11-2017-16-39-45)-HREC17TQEH109PICFVERSION3101017 (002) (1).doc (Participant information/consent)
Attachments [4] 2204 2204 0 0
/AnzctrAttachments/373917-RMSANZ Position Statement Botulinum Toxin Confidential (Final Draft 14April2017).pdf (Supplementary information)
Attachments [5] 2205 2205 0 0
/AnzctrAttachments/373917(v21-11-2017-16-41-10)-Effectiveness_of_botulinum_toxin_type_A_on_gait.4 (1) (1).pdf (Publication)

Contacts
Principal investigator
Name 78726 0
Dr Anupam Datta Gupta
Address 78726 0
Department of Rehabilitation Medicine
The Queen Elizabeth Hospital, 8B
28 Woodville Road, Woodville South
South Australia-5011
Country 78726 0
Australia
Phone 78726 0
+61 8 82227322
Fax 78726 0
+61 8 82228593
Email 78726 0
anupam.dattagupta@adelaide.edu.au
Contact person for public queries
Name 78727 0
Dr Anupam Datta Gupta
Address 78727 0
Department of Rehabilitation Medicine
The Queen Elizabeth Hospital, 8B
28 Woodville Road, Woodville South
South Australia-5011
Country 78727 0
Australia
Phone 78727 0
+ 61 8 82227322
Fax 78727 0
+ 61 8 82228593
Email 78727 0
anupam.dattagupta@adelaide.edu.au
Contact person for scientific queries
Name 78728 0
Dr Anupam Datta Gupta
Address 78728 0
Department of Rehabilitation Medicine
The Queen Elizabeth Hospital, 8B
28 Woodville Road, Woodville South
South Australia-5011
Country 78728 0
Australia
Phone 78728 0
+61 8 82227322
Fax 78728 0
+61 8 82228593
Email 78728 0
anupam.dattagupta@adelaide.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

Current supporting documents:


Updated to:
Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23573Study protocol3https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-019-1325-3 

Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseEfficacy of botulinum toxin in modifying spasticity to improve walking and quality of life in post-stroke lower limb spasticity - A randomized double-blind placebo controlled study.2019https://dx.doi.org/10.1186/s12883-019-1325-3
N.B. These documents automatically identified may not have been verified by the study sponsor.