Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615001162505
Ethics application status
Approved
Date submitted
31/07/2015
Date registered
30/10/2015
Date last updated
2/06/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
The impact of Botox on muscle structure and function in children with cerebral palsy
Scientific title
A RCT of the efficacy of the first intramuscular botulinum toxin type-A treatment on muscle structure and function in children with cerebral palsy: A multi-centre trial
Secondary ID [1] 287186 0
Nil known
Universal Trial Number (UTN)
U1111-1172-7671
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cerebral palsy 295759 0
Condition category
Condition code
Neurological 296040 296040 0 0
Other neurological disorders
Musculoskeletal 296041 296041 0 0
Other muscular and skeletal disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study observes the effect of BoNT-A treatment, currently standard best practice clinical care, for lower limb spasticity in children with CP. All participants with CP in this study will have a clinical indication for lower limb BoNT-A treatment and will receive all assessments, treatment and care that is prescribed by their treating paediatric specialist or orthopaedic surgeon. Participants will receive one intramuscular injection of BoNT-A treatment to the muscles of the lower leg as required a priori and performed by the participants treating paediatric specialist or orthopaedic surgeon. The source of the BoNT-A will be Botox (Registered Trademark, Allergan Pharmaceuticals). Total maximum dose of 7U/kg BoNT-A per leg will be administered with dilution 100units in 2ml saline.
Medial and lateral gastrocnemius muscle: 4U/kg BoNT-A will be administered to four sites in the medial and lateral gastrocnemius (two sites medially and two sites laterally) as indicated by increased spasticity with active dorsiflexion, reduced passive ankle dorsiflexion range of motion while maintaining full knee extension and equinus gait during paediatric specialist and physiotherapy assessment.
Soleus muscle: 2U/kg BoNT-A will be administered to one site in the soleus as indicated by reduced passive ankle dorsiflexion range of motion while maintaining knee flexed during paediatric specialist and physiotherapy assessment.
Tibialis Posterior muscle: 1U/kg BoNT-A will be administered to one site in the tibialis posterior as indicated by a dynamic varus foot deformities during the stance phase of walking gait.
To ensure the anatomically correct administration of the intramuscular BoNT-A injection, the site/s of the injection will be localised using ultrasound and/or electrical stimulation. Injections will be performed within 1 week following baseline measurements in the treatment group.

The doses in the research project will be administered as above. However, participants who have been identified as clinically indicated for additional BoNT-A (e.g. upper limb BoNT-A) will receive this as part of standard clinical care and safe practice guidelines.
Intervention code [1] 293120 0
Treatment: Drugs
Comparator / control treatment
Control: Six months period of no BoNT-A treatment. Participants randomised to the waitlist group will perform study assessments 6 and 4 months before the child’s clinical BoNT-A treatment and then on the day of the scheduled BoNT-A treatment.
Control group
Active

Outcomes
Primary outcome [1] 295708 0
Muscle growth: Triceps surae muscle structure using freehand 3D ultrasound. Volume of the medial and lateral gastrocnemius, soleus and tibialis anterior muscles for both legs will be obtained using a freehand 3D ultrasound approach. Freehand 3D ultrasound is preferred over MRI, because it is less expensive, can be completed in a matter of seconds and does not require patient sedation in young populations. Muscle growth will be calculated as a ratio of the muscle volume and time form baseline to re-assessments (2 months and 6 months).
Timepoint [1] 295708 0
The primary time point for the study is 6 months. For the intervention group the time point will be 6 months from the intervention (intramuscular injection of BoNT-A). For the waitlist group the time point will be 6 months from initial baseline assessment (study waitlist period commencement). Outcome measures at 6 months correspond with the end of the pharmaceutically active period of BoNT-A.
Secondary outcome [1] 316282 0
Gait quality: 2D video gait analysis using the Edinburgh Visual Gait Score for Cerebral Palsy (EVGS). The EVGS is a valid and reliable tool for assessing gait quality. The EVGS is a tabulated scoring system that records lower limb joint angles and movements during a representative stride. Simultaneous sagittal and coronal plane (side-view and front/rear-view) 2D video will be recorded during walking gait over a 10m distance. Gait quality will be independently scored off-site by one physiotherapist experienced in EVGS scoring and masked to group allocation, order of assessment and previous data.
Timepoint [1] 316282 0
The secondary outcomes will also be assessed at 6 months. For the intervention group the time point will be 6 months from the intervention (intramuscular injection of BoNT-A). For the waitlist group the time point will be 6 months from initial baseline assessment (study waitlist period commencement).
Secondary outcome [2] 318442 0
Walking speed/Step length: 10m walk test (10MWT). The 10MWT provides clinical information regarding gait capacity. The 10MWT will assess the time (seconds) and number of footsteps needed to walk 10 metres and demonstrates high reliability in children with cerebral palsy. The 10MWT test will be performed on a 14m straight, flat, non-slippery walking surface and recorded using video for later analysis. The participants will be instructed to walk at a self-selected fast speed for the 14m distance and the time and footsteps will determined for the middle 10m of the distance. Four test trials will be completed and the mean walking speed (distance/time) and step length will be calculated of the last three trials during later analysis.
Timepoint [2] 318442 0
The secondary outcomes will also be assessed at 6 months. For the intervention group the time point will be 6 months from the intervention (intramuscular injection of BoNT-A). For the waitlist group the time point will be 6 months from initial baseline assessment (study waitlist period commencement).
Secondary outcome [3] 318443 0
Lower Limb Anaerobic Power: Ramp test. Lower limb anaerobic power has a moderate to strong relationship to gross motor capacity in children with spastic type CP. Lower limb power will be determined using a modified anaerobic power ramp ascent test. Participants will be instructed to walk at a self-selected fast speed up a 4m ramp (8 deg slope) five times. Video timing will record the time for each trial. Mean ascent time (seconds) for the middle 3m (period of constant velocity) will be determined and lower limb power calculated, P=(m×g×h)/t (where P=power (joules), m=body weight (kg), g=acceleration due to gravity (9.81m.s^-2), h=height (m) gained ascending the ramp, t=time to ascend the ramp (secs)).
Timepoint [3] 318443 0
The secondary outcomes will also be assessed at 6 months. For the intervention group the time point will be 6 months from the intervention (intramuscular injection of BoNT-A). For the waitlist group the time point will be 6 months from initial baseline assessment (study waitlist period commencement).
Secondary outcome [4] 318444 0
Habitual Physical Activity (HPA): Three day accelerometer. A tri-axial accelerometer worn during waking hours for three days will measure HPA performance. Accelerometers have been utilised in a large prospective, longitudinal study of children with spastic type CP aged 18mth-5yrs and criterion validity demonstrated in children with spastic type CP aged 18-36mths. A belt and accelerometer will be provided to the family for the child to wear at the end of the first assessment. The child will wear the belt around the waist with the accelerometer (wGT3X-BT Monitor, ActiGraph, Florida) attached. The belt and accelerometer are light in weight and do not impede movement. Accelerometer data is recorded at 10Hz and will begin recording automatically at a designated time and day set by the investigator. The family need to apply the belt and accelerometer to the child on the prescribed day. The belt and accelerometer are removed during sleep and bathing/swimming. Following the 3 days of data collection the belt and accelerometer will be returned to the investigator using a pre-paid envelope. Data from the accelerometer will be analysed using Actigraph software and dedicated Matlab scripts.
Timepoint [4] 318444 0
The secondary outcomes will also be assessed at 6 months. For the intervention group the time point will be 6 months from the intervention (intramuscular injection of BoNT-A). For the waitlist group the time point will be 6 months from initial baseline assessment (study waitlist period commencement).

Eligibility
Key inclusion criteria
1. Confirmed diagnosis of unilateral or bilateral spastic type CP with a predominant spastic motor type and more involvement of the lower limb.
2. Aged 2-5 years at study entry.
3. Gross Motor Functional Classification System (GMFCS) classification of I-II, independently ambulant.
4. Maximum passive ankle dorsiflexion greater than or equal to -5 degrees (5 degrees plantarflexed).
5. Prescribed intramuscular BoNT-A injection to the lower leg for spasticity treatment
Sufficient co-operation and cognitive understanding to participate in the assessments.
Minimum age
2 Years
Maximum age
5 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria:
1. Predominant lower limb dystonia motor type
2. Previous lower limb intramuscular BoNT-A injections
3. Previous lower limb surgical interventions
4. Contraindications for BoNT/A injection treatment

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)
Consenting participants who meet the inclusion/exclusion criteria will be recruited and stratified based on intramuscular BoNT-A injection treatment site/s into two sub-groups, 1) lower leg muscles only (muscles including medial and lateral gastrocnemius, soleus, tibialis posterior) or 2) hamstring and lower leg muscles, and randomised to a Wait-list group or Immediate BoNT-A treatment group using concealed allocation. In justification for stratifying the consenting participants that meet criteria, the group may include some children with lower limb spasticity of both the calf and hamstring. We do not expect that intramuscular BoNT-A injection to the hamstring will impact triceps surae muscle growth (our primary outcome measure) however it may influence other measures – lower limb power, walking speed, gait quality, habitual physical activity and functional performance. Stratification will ensure that equal numbers of participants receiving 1) lower leg intramuscular BoNT-A treatment only or 2) hamstring and lower leg intramuscular BoNT-A treatment will be allocated to the Wait-list and Immediate groups for comparison. Randomisation will be performed centrally at one site (QLD) a research administrator will coordinate the randomisation process.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



The people analysing the results/data
Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Data will be analysed using the intention to treat analysis according to consort guidelines. A General Linear Mixed Model will be used to assess the effect of a group (BoNT-A versus wait-list controls) on structural and functional performance outcome measures at 6 months relative to baseline. Baseline values will be used as a covariate in all analyses. All variables will be tested for normal distribution and transformed where appropriate (p<0.05).

Sample size calculation: There are no published RCTs examining the effect of BoNT-A on muscle volume in children with spastic type CP. The total change in medial gastrocnemius muscle physiological cross sectional area (highly related to volume) in the BoNT-A treatment group from a recent study of similar aged children with spastic type CP was 0.5+/-0.3cm^2 (n=13) compared to 1.5+/-0.5cm^2 (n=18) in the TD group. It is not possible to separate the effects of BoNT-A treatment from no BoN-T treatment using this data. If the average growth rate of the gastrocnemius prior to BoNT-A injection (0.55+/-0.2cm^2/month) is compared to that after the injection (0.34+/-0.1cm^2/month) it is shown that growth has slowed by >35% of the pre-injection rate. If we assume that the growth rate would remain constant without the injection, then the effect size for this difference over a 12 month period would be 1.4. We will conservatively estimate that the growth rates in the untreated group will only be as high as 85% of the growth rate prior to BoNT-A injection, 0.47+/-0.17cm^2/month, which would result in an effect size of 0.9. To detect this difference between the groups with >90% power (beta=0.1) would require 20 participants in each group (a=0.05, 2-tail, allocation ratio=1). The drop-out rate for our aforementioned prospective study of muscle volume changes was 2 in 15. Allowing for 10% attrition we will allocate 25 children to each group.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
9/11/2015
Actual
13/11/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,WA,VIC
Recruitment hospital [1] 4116 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [2] 4117 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 4118 0
Princess Margaret Hospital - Subiaco
Recruitment postcode(s) [1] 12138 0
4101 - South Brisbane
Recruitment postcode(s) [2] 12139 0
3052 - Parkville
Recruitment postcode(s) [3] 12140 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 291749 0
Charities/Societies/Foundations
Name [1] 291749 0
Cerebral Palsy Alliance Research Foundation
Country [1] 291749 0
Australia
Primary sponsor type
Individual
Name
Dr Lee Barber
Address
Queensland Cerebral Palsy and Rehabilitation Research Centre, School of Medicine
The University of Queensland
Level 6, Centre for Children’s Health Research, 62 Graham Street, South Brisbane, QLD 4101
Country
Australia
Secondary sponsor category [1] 290419 0
Individual
Name [1] 290419 0
Professor Roslyn Boyd
Address [1] 290419 0
QCPRRC, School of Medicine
The University of Queensland
Level 6, Centre for Children’s Health Research, 62 Graham Street, South Brisbane, QLD 4101
Country [1] 290419 0
Australia
Secondary sponsor category [2] 290420 0
Individual
Name [2] 290420 0
A/Prof Catherine Elliott
Address [2] 290420 0
Department of Paediatric Rehabilitation, Princess Margaret Hospital for Children, Roberts Road, Subiaco, WA 6008.
Country [2] 290420 0
Australia
Secondary sponsor category [3] 290421 0
Individual
Name [3] 290421 0
Professor Kerr Graham
Address [3] 290421 0
Hugh Williamson Gait Analysis Laboratory, Royal Children’s Hospital Melbourne, 50 Flemington Road, Parkville, VIC 3052.
Country [3] 290421 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293269 0
QLD Children's Health Services, The Royal Children’s Hospital, Herston (EC00175)
Ethics committee address [1] 293269 0
Ethics committee country [1] 293269 0
Australia
Date submitted for ethics approval [1] 293269 0
Approval date [1] 293269 0
22/07/2014
Ethics approval number [1] 293269 0
HREC/14/QRCH/39
Ethics committee name [2] 293270 0
Princess Margaret Hospital for Children, Subiaco (EC00268)
Ethics committee address [2] 293270 0
Ethics committee country [2] 293270 0
Australia
Date submitted for ethics approval [2] 293270 0
Approval date [2] 293270 0
25/09/2014
Ethics approval number [2] 293270 0
2014069EP
Ethics committee name [3] 293271 0
The Royal Children’s Hospital, Melbourne (EC00238)
Ethics committee address [3] 293271 0
Ethics committee country [3] 293271 0
Australia
Date submitted for ethics approval [3] 293271 0
Approval date [3] 293271 0
22/07/2014
Ethics approval number [3] 293271 0
HREC/14/QRCH/39

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 59186 0
Dr Lee Barber
Address 59186 0
QCPRRC, School of Medicine
The University of Queensland
Level 6, Centre for Children’s Health Research
62 Graham Street
South Brisbane, QLD 4101
Country 59186 0
Australia
Phone 59186 0
+61730697334
Fax 59186 0
Email 59186 0
[email protected]
Contact person for public queries
Name 59187 0
Lee Barber
Address 59187 0
QCPRRC, School of Medicine
The University of Queensland
Level 6, Centre for Children’s Health Research
62 Graham Street
South Brisbane, QLD 4101
Country 59187 0
Australia
Phone 59187 0
+61730697334
Fax 59187 0
Email 59187 0
[email protected]
Contact person for scientific queries
Name 59188 0
Lee Barber
Address 59188 0
QCPRRC, School of Medicine
The University of Queensland
Level 6, Centre for Children’s Health Research
62 Graham Street
South Brisbane, QLD 4101
Country 59188 0
Australia
Phone 59188 0
+61730697334
Fax 59188 0
Email 59188 0
[email protected]

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